Tuesday, August 31, 2010

Oyster glue's secret ingredient

The natural cement produced by oysters to build extensive reef systems contains significantly more inorganic material than the glues of other marine species, and could spur development of new synthetic adhesives for biomedical devices or antifouling coatings for ships, say researchers in the US.

Jonathan Wilker and his team at Purdue University and colleagues at the University of South Carolina have been investigating how oysters bind to reefs and each other, in a bid to develop synthetic composite materials with properties that imitate the oyster glue.

The team analysed the chemical composition of oysters' adhesive using infrared spectroscopy, electron paramagnetic resonance spectroscopy and thermogravimetric analysis. They found higher protein content in the adhesive material than in oyster shell (10 per cent as opposed to 2 per cent), and evidence of protein cross-linking, iron species and radical species.

Monday, August 30, 2010

Cryospray Against Airway Tumors Leads to Unexpected Complications

Spray cryotherapy with liquid nitrogen has been used effectively for ablating esophageal tumors. Some facilities even perform the technique in an outpatient setting under sedation. However, spray cryotherapy for treating advanced airway lesions—when other treatment options are limited—is more recent, and few reports of its effectiveness have been published (J Thorac Cardiovasc Surg 2010;139:781-782).

To assess their efforts to date, thoracic anesthesiologists at Memorial Sloan-Kettering Cancer Center in New York City reviewed 24 spray cryotherapy procedures in 22 patients; all treatments involved airway-obstructing tumors. Ten of the patients (45%) experienced unexpected and serious respiratory or cardiovascular events; of these, three required reintubation and mechanical ventilation overnight. One patient suffered cardiac arrest and died in the operating room (Table).

Table. Complications From Cryospray
ComplicationN=30
(% of procedures)
Pneumothorax2 (2.8)
Hypoxemia5 (20.8)
Reintubation3 (12.5)
ST-segment changes3 (12.5)
Bradycardia6 (25)
Tachycardia3 (12.5)
Hypotension7 (29)
Death1 (0.04)

“We did not expect to see such an incidence of cardiac complications during this procedure,” said Alessia Pedoto, MD, lead author of the study presented at the 2010 annual meeting of the Society of Cardiovascular Anesthesiologists (abstract SCA41), in New Orleans.

The spray cryotherapy technique delivered liquid nitrogen by catheter through an endoscope at 2 to 4 psi at –196 C, causing rapid freezing and thawing of tissue—resulting in cell death and hemostasis (Figures 1 and 2). A minimum of three cycles of five seconds each was administered to each patient, with a complete visual thaw between each cycle. All patients underwent general anesthesia for combined rigid and flexible bronchoscopy.

Among the 24 procedures, hypoxemia developed in five (20.8%); ST-segment changes developed in three (12.5%); bradycardia in six (25%); and hypotension in seven (29%). More than one complication occurred per procedure.

“Bleeding and pneumothorax have been reported in very small series and we had two cases of pneumothorax we thought were related to the use of jet ventilation with cryospray,” Dr. Pedoto told Anesthesiology News. “We speculate that the use of cold liquid nitrogen is associated with an increase in airway pressure when the spray is used, affecting the heart and the conduction system,” she said.

According to the researchers, spray cryotherapy is a novel technique that can be used to re-establish airway patency in patients with symptomatic airway tumors. The advantages it might offer over airway laser therapy include no fire hazard and improved hemostasis. They said that further study is needed for better selection and improved safety of patients.

QuikClot goes Japanese

WALLINGFORD, Conn.--(BUSINESS WIRE)--Z-Medica Corporation, a medical device company developing innovative hemostatic agents, today announced that it has signed an exclusive distribution agreement with Nihon-Kohden, Japan's leading manufacturer, developer and distributor of medical electronic equipment . The agreement allows Nihon-Kohden the exclusive right to distribute Z-Medica’s QuikClot line of hemostatic agents to hospital, military and law enforcement markets throughout Japan. The companies have been working together since early 2009 to obtain regulatory approval. Such approval for the sale of Z-Medica’s full line of QuikClot hemostatic gauze products was approved by the Japanese Ministry of Health, Labor and Welfare in March 2010.
“We are very pleased that we have signed this distribution agreement with Nihon-Kohden because of their longstanding positive reputation and vast reach throughout the Japanese market,” said Brian Herrman, Chief Executive Officer, Z-Medica. “We believe that clinical practitioners outside of the US will find QuikClot to be a useful tool in achieving hemostasis in a fast, safe and convenient manner, and we intend to continue expanding our international distribution through best-of-breed partners such as Nihon-Kohden.”
QuikClot is a surgical gauze impregnated with kaolin, an inert material with no known contraindications, and can achieve hemostasis in severe bleeding situations in as little as three minutes. QuikClot is widely used throughout several clinical specialties, including cardiology, interventional radiology, critical care, dermatology, emergency medicine, orthopedics and OB/Gyn, and after months of testing against 12 other hemostatic products in the marketplace, the military version of the kaolin gauze (“Combat Gauze”) was chosen as the exclusive product for use by all US Military Forces in 2008. It continues to be the exclusive product used by all USA military forces for first line treatment of bleeding hemorrhage.
“We are very pleased to have this opportunity to market in Japan QuikClot which helps many patients who suffer from bleeding,” said Hiroshi Aida, General Manager of Import Business Operation, Nihon Kohden. “QuikClot also helps medical professionals with much shorter time for achieving hemostasis. It is a nice addition for our product portfolio.”
Z-Medica and Nihon-Kohden have been working together since early 2009 in order to gain the recently granted regulatory approval. The QuikClot line of products to be distributed by Nihon-Kohden in Japan include:
QuikClot Combat Gauze is a soft, white, sterile, nonwoven 3” by 12 feet rolled or z-folded gauze impregnated with kaolin. Each roll of QuikClot Combat Gauze is individually wrapped in an easy rip, military grade foil pouch. Indicated for temporary external control of traumatic bleeding, QuikClot Combat Gauze is flexible and pliable and contours to all wounds. Recommended as the number one hemostatic agent by the COTCCC (Committee on Tactical Combat Casualty Care Committee), QuikClot Combat Gauze is the only product carried by all branches of the US Military to control life-threatening hemorrhage.
QuikClot Emergency Dressing is an easy-to-use dressing which can achieve hemostasis in as little as three minutes, helping to prevent loss of life and limb. Because QuikClot requires very little training to administer, it can be effectively used by medical personnel, civilian first-responders and medical professionals in the field and in clinical environments. This dressing comes in various sizes, including a 4-ply 4” by 4” (10cm x 10cm) and a 6-ply 2”x2” (5cm x 5cm) format.
QuikClot Interventional Hemostatic Bandage consists of a soft, white, double sterile, hydrophilic pad impregnated with kaolin. It is double-wrapped in a blister package and foil pouch for aseptic technique. QuikClot Interventional Hemostatic Bandage is applied topically as an adjunct to manual compression and is indicated for the local management and control of external bleeding from vascular access sites and percutantous catheters or tubes utilizing sheaths up to 12 Fr.
QuikClot Trauma Pad consists of a soft, white, double sterile, three-ply 12”x12” (30cm x 30cm) pad impregnated with kaolin. It is double-wrapped in a peelable foil package for aseptic technique. QuikClot Trauma Pad is indicated for temporary external use to control traumatic bleeding and is also x-ray detectable to ensure proper removal.

About Z-Medica

Z-Medica Corporation is a medical device company developing innovative hemostatic agents. The company manufactures and markets its QuikClot® family of products for hemostasis for use by healthcare professionals, first responders, law enforcement officers and the military. QuikClot products rapidly enhance the body’s natural coagulation process, helping to achieve hemostasis faster. Z-Medica’s QuikClot® Combat Gauze™ product was chosen by the Committee on Tactical Combat Casualty Care (TCCC) as the United States Military’s sole source supplier for first-line hemostatic treatment, based on tests conducted by the Naval Medical Research Center and the U.S. Army Institute for Surgical Research. It continues to be the exclusive product used by all USA military forces for first line treatment of bleeding hemorrhage. QuikClot® products are also widely used by first responders, in hospital emergency rooms, interventional cardiology and radiology laboratories and other healthcare environments where bleeding requires fast and effective control. Z-Medica, named one of the Top 100 Technology “Companies to Watch” in 2008 by the Connecticut Technology Council, is a privately-held company based in Wallingford, CT. More information about Z-Medica Corporation is available at www.z-medica.com.

About Nihon Kohden

Nihon Kohden is Japan’s leading manufacturer, developer and distributor of patient monitors, defibrillators, ECGs, EEGs, EP/EMGs, hematology analyzers and other medical electronic equipment, with subsidiaries in the United States, Europe, and Asia, and distributors in nearly every country in the world. Nihon Kohden is a publicly held company listed in the First Section of the Tokyo Stock Exchange. In addition to designing medical equipment for hospital and clinic use, Nihon Kohden actively contributes to the advance of medical technology.

Sunday, August 29, 2010

FDA rules CollPlant wound dressing a device

The US Food and Drug Administration (FDA) has ruled that the CollPlant Holdings Ltd's (TASE: CLPT) wound dressing product, Vergenix, will undergo the certification process by the Center for Devices and Radiological Health (CDRH), which oversees medical devices.
Vergenix Wound Dressing is wound care sheet composed of pure recombinant human collagen scaffold that provides a moist wound healing environment. The product, a type I collagen, is produced by transgenic tobacco plants. It is designed to treat acute and chronic wounds, such as pressure ulcers, venous ulcers, diabetic ulcers, surgical wounds, abrasions, and second-degree burns.
US licensing procedures for medical devices are shorter than the procedure for pharmaceuticals. CollPlant believes that while Vergenix is based on human recombinant collagen produced through advanced biotechnological techniques, the FDA decision that the CDRH will review the product is very important for the company, as the regulatory procedures are significantly simpler, shorter, and cheaper than for biological and pharmaceutical products. This is a breakthrough since Vergenix will be a pioneering product for CollPlant's subsequent products.
CollPlant's share price rose 9.9% by mid-afternoon to NIS 1.20, giving a market cap of NIS 126 million.
Published by Globes [online], Israel business news - www.globes-online.com - on August 29, 2010

Saturday, August 28, 2010

US Military faces challenges from Chinese Knock-offs

As anyone who has served in combat knows, if a buddy is wounded, the first two things you need to do are make sure he can breathe and his bleeding is stopped.
For the past several years, troops serving in Afghanistan and Iraq have used an advanced Combat-Application-Tourniquet (C-A-T) developed by Composite Resources in Rock Hill, S.C. The tourniquet features a nylon strap and a plastic rod to tighten the strap to stop bleeding.
The regulation C-A-T costs about $28. But about two years ago the Army detected cheap knock offs made by a Hong Kong company that had entered the military's supply chain in Afghanistan and Iraq. The imitation sold for about $8.50.
They're accurate looking fakes, right down to the label and national stock number.
But as Col. John Kragh, a doctor at the U.S. Army Institute of Surgical Research at Fort Sam Houston, pointed out in June, the rod on the fake tourniquet "is bendable to a point where it cannot work right. It's like bending Gumby's arm."
He said the fake tourniquet could be fatal because it cannot stop bleeding. Kragh added a decentralized ordering system probably accounts for the presence of the fake tourniquets in the field, with low-level supply personnel ordering the knock offs over the Internet based on price.
The Defense Department issued a warning about the knock-offs in April, Kragh said, and the Food and Drug Administration this month put out a safety alert about the tourniquets, which are also used by civilian first responders.
The lesson here is a good deal isn't always that; it can even be deadly.

Poll Result - Which Geographical Manufacturing Area for Hemostatic Devices Causes Concern?

Controversies

2007 Chinese Export Recall


The 2007 Chinese export recalls were a series of scandals involving tainted food and products exported from China, starting with tainted pet food imported from China to the United States that poisoned pets. The recalls sparked international concern that many products made in China do not meet minimum quality standards. Soon after, the US halted imports of seafood from China after tests detected the presence of drugs unapproved in the US.China has gone on record to admit that nearly a fifth of products made in China do not reach minimum standards. Also, some children's toys made in China were found to contain excessive levels of lead, prompting widespread concern. In 2006, shipments of cough syrup and other medicines, imported from China to Panama and laden with the toxin diethylene glycol, caused mass poisonings and killed 83 people.
On December 19, 2007, The US House of Representatives passed legislation (H.R. 4040) that would significantly amend the current U.S. safety establishment for consumer products imported from China.

2008 Chinese heparin and milk scandals

In March 2008, major recalls of heparin were announced by the U.S. Food and Drug Administration (FDA) due to contamination of the raw heparin stock imported from China.
The raw material for the recalled heparin batches was processed in China from pig's intestines by the American pharmaceutical firm Scientific Protein Laboratories. The U.S. Food and Drug Administration was quoted as stating that at least 81 deaths were believed linked to a raw heparin ingredient imported from the People's Republic of China, and that they had also received 785 reports of serious injuries associated with the drug’s use. According to the New York Times, "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock."
Upon investigation of these adverse events by the FDA, academic institutions, and the involved pharmaceutical companies, the contaminant was identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used as a treatment forarthritis. Since over-sulphated chondroitin is not a naturally occurring molecule, costs a fraction of true heparin starting material, and mimics the in-vitro properties of heparin, the counterfeit was almost certainly intentional as opposed to an accidental lapse in manufacturing. The raw heparin batches were found to have been cut from 2-60% with the counterfeit substance, and motivation for the adulteration was attributed to a combination of cost effectiveness and a shortage of suitable pigs in China.
When the FDA conducted an inspection of Baxter's Chinese Heparin supplier, it found serious deficiencies at the facility which the FDA detailed in a warning letter.
The FDA has stated that it does not have the funds nor bear the responsibility to inspect on a regular basis overseas manufacturers of active pharmaceutical ingredients such as heparin.
In November 2008, the FDA seized eleven lots of heparin from Celsus Laboratories Inc., a manufacturer in Cincinnati, Ohio.


One year later, the 2008 Chinese milk scandal refers to a food safety incident in mainland People's Republic of China involving milk and infant formula which had been adulterated with melamine, an organic base combined with formaldehyde to form plastic. The result was catastrophic - By 22 September, nearly 53,000 illnesses, over 12,800 hospitalizations, and four infant deaths had been reported, caused by kidney stones and other renal failure.The chemical appeared to have been added to milk in order to cause it to appear to have a higher protein content. The same chemical was also involved in a series of pet food recalls in 2007. In November 2009, two individuals were executed for endangering public safety and producing and selling toxic food.

2009 Made in India scandal

In June 2009, the Nigerian Government Drug Regulatory Authority (NAFDAC) reported about the detention of a large consignment of fake anti-malarial generic pharmaceuticals labeled Made in India but produced in China. The Laboratory analysis conducted by NAFDAC revealed the drugs to be fake and had it not been intercepted, about 64,200 adults would have been affected. The consignment containing Maloxine and Amalar tablets, used for the treatment of Malaria, were valued at 32.1 million Naira and were produced, packed and shipped from China. After Indian Authorities took up the matter, The State Food and Drug Administration (SFDA) of China was asked to investigate the matter[10]. In December 2009, 6 chinese traders were sentenced to death for their involvement.
In July 2009, customs officials in the South Indian port city of Chennai seized spurious cosmetics and mobile phone batteries worth Rs. 30 million, imported into India from Scheko in China. The 40 foot container was held up at the port for more than 75 days and opened on 13th July when the importer did not file a bill of entry. It was reported to contain over 187,000 batteries with Nokia holograms and stickers, and 126,000 cosmetic items including face packs, lipsticks and hair gels
.

Prepare your Hemostat's - Here Come the Anti-Coagulants

Aug 24 (Reuters) - Rival drugmakers are racing to develop
new oral anticoagulants to replace difficult-to-use warfarin for
the prevention of stroke in patients with atrial fibrillation, a
common irregular heart rhythm.
Industry analysts estimate the market will be worth well
over $10 billion in annual sales, making so-called Factor Xa and
direct thrombin inhibitors among the most valuable and closely
watch new drugs in development.
Medical experts and investors will focus on clinical trial
results for two of them -- Bayer (BAYGn.DE) and Johnson &
Johnson's (JNJ.N) Xarelto, and Bristol-Myers Squibb (BMY.N) and
Pfizer's (PFE.N) apixaban -- during the European Society of
Cardiology congress in Stockholm next week.
The table below shows a selection new oral anticoagulants in
development. Pradaxa and Xarelto have already been approved for
use in Europe and some other markets to prevent thrombosis after
surgery, but not yet for stroke prevention:

DRUG COMPANY MECHANISM STATUS

Pradaxa Boehringer Direct thrombin launched EU
Xarelto Bayer/J&J Factor Xa launched EU
apixaban Bristol/Pfizer Factor Xa Phase III
edoxaban Daiichi Factor Xa Phase III
YM150 Astellas Factor Xa Phase III
otamixaban Sanofi Factor Xa Phase III
betrixaban Merck Factor Xa Phase II
letaxaban Takeda Factor Xa Phase II
Source: Thomson Reuters

Wednesday, August 25, 2010

FibroGen - Recombinant Human Type III Collagen

SAN FRANCISCO--(BUSINESS WIRE)--FibroGen, Inc., today announced results of a 2-year clinical study demonstrating that surgical implantation of biosynthetic corneas formulated with the company’s proprietary recombinant human type III collagen (rhCIII) restored vision and promoted nerve regeneration (restoring sensitivity) in patients who had corneal damage and significant vision loss. The results of this phase 1, investigator-sponsored study were published today in Science Translational Medicine.1
“These clinical results suggest that our collagen could potentially provide an important option for patients by reducing risk of disease transmission and increasing supply of corneal implant material in the face of the worldwide shortage of human donor corneas”
Corneal damage and disease are major causes of blindness worldwide. In countries where tissue banking is available, such as the US, treatment is by implantation of human donor corneas. However, there is a severe shortage of human donor tissue worldwide. Patients who do receive donor human corneas, however, can still suffer complications, such as tissue rejection. Corneal prostheses, made from synthetic plastics are used in limited cases, but only where human donor grafts are contraindicated or have been repeatedly unsuccessful. These synthetic alternatives are not designed to replace donor tissues or promote tissue regeneration.
FibroGen pioneered the development of recombinant collagen production technology and is the only producer of rhCIII. Since 2005, FibroGen has collaborated with Dr. May Griffith of Linköping University, senior author of today’s publication, to develop biosynthetic corneas molded from chemically cross-linked rhCIII. The biosynthetic implants are designed to mimic the human cornea, which is composed mainly of the protein collagen.
“Recombinant human collagen is a viable replacement for naturally occurring human collagen that does not have the limitations of human donor tissue or animal-sourced collagens, such as risk of disease transmission and availability of donor supply,” said Dr. Griffith. “Our study provides proof-of-concept that corneal implants composed of recombinant human collagen can promote tissue regrowth and restore vision.”
“These clinical results suggest that our collagen could potentially provide an important option for patients by reducing risk of disease transmission and increasing supply of corneal implant material in the face of the worldwide shortage of human donor corneas,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “This product concept continues to be improved and additional studies are planned.”
About the Phase 1 Study

In the clinical study, 10 patients with corneal disease underwent resection, followed by surgical implantation with rhCIII-based biosynthetic corneas. Two-year post-surgery results demonstrated that 100% of the transplanted corneas remain viable at two years, cells from the patients’ own corneas had grown into the implant, and nerves that had been severed during surgery regrew. In addition, the blink reflex and tear film were restored. In terms of visual acuity, at 24 months, best spectacle-corrected visual acuity improved in six patients, remained unchanged in two patients and decreased in two. None of the patients experienced any rejection reaction or required long-term immunosuppressive therapy, serious issues associated with the use of human donor tissue.
Unmet medical need for a biosynthetic corneal implant

Loss of vision due to corneal disease or trauma affects over 10 million individuals worldwide, but lack of access to good quality donor tissue severely limits the number of transplant procedures that can be done, particularly in the developing world. In the US, an estimated 42,000 corneal grafts are performed annually using optical tissue from cadavers; however, graft rejection can occur, and failure rates are significant. In addition, the mandatory use of steroids with cadaver-sourced corneal material limits their successful use to certain patient populations. Fully synthetic prostheses (without biological activity) have been developed, but their use has been limited to cases where human donor tissue fails repeatedly or cannot be used. Moreover, apart from the US, in most countries, tissue donation and banking systems do not exist.
About FibroGen’s recombinant human collagens

FibroGen is the only producer of highly purified, fully characterized recombinant human type III collagen (rhCIII) intended to replace similar animal- or human-derived materials currently used in a variety of medical, pharmaceutical, and consumer applications. FibroGen uses proprietary recombinant methodology in a yeast expression system with human DNA sequences to develop synthetic versions of human collagens essentially identical to the native protein. Mixtures of various collagen types found in animal-sourced collagen are nearly impossible to segregate. FibroGen has been able to produce specific types of recombinant human collagen (e.g., types I or III) consistently and reproducibly. FibroGen has developed simple, scalable purification processes that provide highly purified and reproducible lots of protein in any desired quantity, and employs a series of rigorous analytical tests to ensure lot-to-lot consistency and high quality.

Tuesday, August 24, 2010

Facts about blood needs in the U.S.

  • Every two seconds someone in the U.S. needs blood.
  • More than 38,000 blood donations are needed every day.
  • A total of 30 million blood components are transfused each year in the U.S. (2006).
  • The average red blood cell transfusion is approximately 3 pints.h
  • The blood type most often requested by hospitals is Type O.
  • The blood used in an emergency is already on the shelves before the event occurs.
  • Sickle cell disease affects more than 80,000 people in the U.S., 98 percent of whom are African American. Sickle cell patients can require frequent blood transfusions throughout their lives.
  • More than 1 million new people are diagnosed with cancer each year. Many of them will need blood, sometimes daily, during their chemotherapy treatment.
  • A single car accident victim can require as many as 100 pints of blood.
  • One donation can save the lives of up to three people.

Go to www.redcrossblood.org to find out more about blood donation and to see if you are eligible.

Kensey Nash Q2 - Edited

Joseph Kaufmann
Our total revenue for the quarter of $21.9 million exceeded prior year by 7% and increased 10% sequentially. Total net sales of $15.1 million exceeded prior year by 12% and increased 14% sequentially. This growth was due to sports medicine, which increased 58% year-over-year and 9% sequentially; and our cardiology products, which are primarily Angio-Seal components, also increased 14% year-over-year and 3% sequentially.
As far as the Angio-Seal collagen sales, again, our third and fourth quarter collagen sales to St. Jude were very good. And we look at the comp compared to last year and our first quarter, it's primarily again due to timing. We expect our second quarter sales to St. Jude will reflect this and will show the improvement.........
It's products, it's quality, it's all that things that you think of every day, and that we think with hopefully some of the new products that we're brining to the marketplace, the biologic products, we believe are going to be a major factor in all of healthcare going forward. And Kensey Nash is going to be a major player in this space, not only in sports medicine, but also in general surgery and in other areas that we're very well positioned with the technology we have built here over the last five to 10 years or so within our organization....

Josh Jennings - Jefferies & Company

And then just last one just on the St. Jude supply agreement. Anymore color you could provide in terms of what happens? I know that's a tiered supply agreement for the component parts, but after 2011, it seems that that minimum 25% does that end in 2011 and you could renegotiate for 2012? And then lastly, is there any risk of the Angio-Seal royalty rate going away at some point?

Joseph Kaufmann

On the supply agreement, it's a two-year deal that starts at January 2011, so it goes out for '11 and '12. And then after that it will be determined whether it will be expanded, increased, decreased, or renewed, I don't know at this time.

As far as royalties are concerned, we are a royalty on Angio-Seal sales. As long as there is at least one claim on any patent, we're entitled to the full 6% royalty, there aren't any step-downs. So as long as there is patents in place that are being utilized, then that's when we continue to receive the royalty.


Sunday, August 22, 2010

‘War is the only proper school for surgeons’

BALAD, Iraq — Army Dr. Colin Meghoo stared at the dry-erase board at Baghdad’s Ibn Sina Hospital. In black marker were the names of the injured, and the procedures chosen to try to save their lives — many of which he had never seen performed.
It was September 2005, and Meghoo, now a lieutenant colonel, had just completed his surgical residency. Trained in repairing the car crash injuries and the occasional gunshot wound that trickled into his Texas emergency room, he now was confronted with the devastating and hugely varied wounds of modern warfare: legs and arms mangled by explosions, arteries severed by bullets, vital organs peppered with shrapnel.
“It was a bit overwhelming,” he recalled, “but then you think to yourself, ‘Wow, this doesn’t even exist in busy civilian hospitals. You need to be in a war zone to see this.’ ”
The ancient Greek physician Hippocrates said that “war is the only proper school for surgeons,” and the war in Iraq has been just that, but with an important development: Lessons were learned and shared immediately.
In the past, doctors had to wait until the gunfire stopped before examining what lessons had emerged.
There are dozens of volumes just about World War II, published long after the war, said Air Force Dr. (Lt. Col.) Raymond Fang, trauma director Landstuhl Regional Medical Center in Germany.
But in Iraq, improvising surgeons and up-to-the minute observational research have resulted in techniques that helped troops survive at a greater rate than in any previous war. Some are high-tech and novel; others were rediscovered; and a few are reinterpretations of old protocols. Moreover, these lessons were documented and shared as the war raged.
Military surgeons have been able to rewrite the book on trauma before U.S. troops have even left the country. “War Surgery in Afghanistan and Iraq: A Series of Cases, 2003-2007” was published by the U.S. Army in 2008, detailing 83 cases from 53 battlefield
doctors.
Now the lessons and techniques tested in Iraq are being honed in Afghanistan, and new ones are being explored.
“It’s not about the next war anymore,” Meghoo said, who recently completed his second tour at Forward Operating Base Sharana near the Afghanistan-Pakistan border.
The advances are needed now.

Stopping the blood
Wars have always birthed medical advancements.
During the Civil War, physicians found new ways to amputate limbs and began using rags soaked in chloroform to anesthetize patients. The typhoid vaccine was developed during World War I, when an Army officer also established the first blood depot. World War II brought the mass use of penicillin, and the Korean War, helicopter evacuation.
One of the legacies of Iraq is a new emphasis on stopping blood loss. Better body armor and helmets protected troops’ vital organs, but high-velocity bullets, rocket-propelled grenades and roadside bombs inflicted the exposed limbs with massive, bleeding wounds.
To stanch the bleeding, doctors turned to one of the oldest and simplest tools in battlefield medicine: the tourniquet. Tourniquets had been maligned and shunned since World War II because of fears that they caused gangrene and limb loss. They do, when used for long periods — but faster evacuation and hospitalization combined with tourniquets saved hundreds of lives in Iraq. A 2008 review of records at the 31st Combat Support Hospital in Baghdad showed that four in seven deaths could have been prevented had a tourniquet been used before the patient arrived.
“This is a simple mechanical thing done since the time of the Egyptians,” Fang said, “and now it’s returning.”
Soldiers in the field are issued one combat application tourniquet, or CAT; some carry more than half a dozen. Slipped around a limb, the tourniquet’s nylon strap is cinched, and the plastic bar on top is twisted, crimping the artery below. The lever is cranked with one hand, so servicemembers can secure their own tourniquets even when badly injured.
Sgt. Chris Bickford, a combat medic who has deployed to Iraq twice, said he trains all his soldiers to clamp on a tourniquet in less than 12 seconds.
“Before we could only use pressure dressings, and there was the chance you may lose the life,” he said. “Now the way the tourniquets are built, allowing them to be placed high on the limb — that saves lives.”
At the start of the Iraq war, innovative clotting agents such as QuikClot were also poured into open wounds. QuikClot, a loose substance made of synthetic absorbents that looks like dry clay, draws water from blood, helping it coagulate. But surgeons often had to pick out the sticky granules, and in some cases QuikClot burned tissue, or even the eyes of the patient on a windy day.
QuikClot’s manufacturer, Z-Medica Corp., soon replaced the loose product with a bag filled with the clotting agent, then, finally, combat gauze treated with it. Medics in the field now push the gauze into wound cavities. The gauze is “easier to carry and much more comfortable for the patient,” Bickford said.
Now the military is looking for alternatives to these synthetic materials, Fang said. One possibility is dried plasma, the liquid part of blood that has proteins and clotting factors. The dried plasma would be revived in a saline solution and then given to wounded troops intravenously or injected into the bone marrow. The latter technique keeps medics from having to search for a vein, a difficult task when soldiers are covered in thick packs and bleeding, said Col. Dallas Hack, director of the Combat Casualty Care Research Program.
“The bone marrow is a fairly large area,”” Hack said, “and you can do it by feel.”
Clinical trials of two forms of dried plasma, one freeze-dried and the other spray-dried, are under way, and it could be in the hands of medics within three to five years, Hack said.
Fang said long-held conventions about blood transfusions also changed. Doctors once pumped saline into hemorrhaging patients to restore hydration, and then added red blood cells and extra platelets. Now surgeons try to “emulate whole blood,” Fang said, forgoing saline and pumping in equal amounts of platelets, cells and plasma.
Before the war, surgeons had regarded the freshness of donor blood as unimportant — as long as it was used within a two-month window. But downrange doctors discovered that fresher red blood cells carry more oxygen, which keeps vital organs working better and provides more oxygen to the brain, helping prevent comas.
“There is a push downrange to use blood that is 14 days old or younger,” Fang said.
At forward operating bases in Iraq, loudspeakers often called for blood donors during periods of heavy fighting. Troops lined up at combat hospitals to donate as the wounded were carried in.
It’s a procedure that has continued in Afghanistan, Meghoo said, even at small outposts.
“You’d put the call out,” he said, “and people would just descend.”
Surgeons like Meghoo also practiced closer to the battlefield than in previous wars, often in the dusty tents of forward operating bases. There, teams lacked many resources of typical trauma hospitals, including imaging equipment such as CAT scanners and fluoroscopes. But they performed minimal yet crucial operations to stabilize a patient, often within the critical “golden hour” after injury, said Dr. (Col.) David P. Blake, director of trauma at the Balad hospital. After the initial lifesaving surgery, patients were taken to Balad, where they were warmed up and given fluids, allowing them to recover enough for the next surgery.
“You control what is immediately going to kill them,” Blake said, “and then you come back another day to address the details.”
Roadside bombs mangled limbs, leaving many soldiers amputees. To prevent this, surgeons improvised with shunts, tiny plastic tubes placed into damaged blood vessels. The combat surgeons found the shunts, which had been used occasionally by vascular surgeons, indispensable to keep blood flowing to troops’ injured limbs, hands or feet until the damaged vessels could be repaired.
Meghoo, for example, had a patient in Afghanistan who was shot in the leg by a high-velocity bullet. The patient’s femoral artery had been severed, and worse, the bullet had burned the edges of the artery, causing it to contract.
“That’s a huge hole,” he said, showing a picture of the gaping wound. “And I can’t sew the [artery] back together because the ends don’t reach anymore.”
To control the flow of blood, Meghoo placed two shunts into the patient’s leg, one in the artery and the other in the vein, and sent him on to another hospital for further care.
In previous wars, Meghoo said, he likely would have bled to death or lost a limb.

Battlefield advances

Devices developed at civilian hospitals were also brought to the battlefield, where doctors found new uses for them.
Before 2004, doctors opened and cleared wounds of blood-soaked gauze and other debris twice daily, a treatment that was painful for patients, but needed to keep their wounds clean. The frequent changing of dressings was common practice for centuries, Fang said, until surgeons at Balad experimented with a vacuum that sucks away the excess fluid, allowing a wound to be sealed for nearly three days.
With negative pressure wound therapy, the wound cavity is covered with a clear plastic bandage with a suction tube attached, then vacuum-sealed. Designed for chronic wounds, the suction helps troops’ tissues heal faster “because all that wound soup is not staying around,” said Lt. Col. Joe Sniezek, director of the Seventh Joint Combat Casualty Research Team.
Better still, patients on long evacuation flights no longer need to have their bloody dressings removed and cleaned in transit.
“It remains to be seen whether the outcome is better,” said Fang, “but it definitely makes it more comfortable for the patients.”
Several high-tech devices were tested for the first time on troops, including an infrared camera that helps doctors detect compartment syndrome, a crimping of the blood vessels in the leg or arm. Deep wounds cause muscle inside the limb to swell, potentially leading to gangrene. The only way to relieve the pressure, or even diagnose compartment syndrome, is to flay the leg or arm muscles open.
The surgery works, said Sniezek, but it’s a “morbid procedure, making an incision all the way down the limb.”
The infrared device, however, allows doctors to detect any difference between the temperatures of the body’s core and the limbs, an indicator that blood is not flowing correctly. If the temperatures are within normal range, surgeons can potentially avoid an unnecessary opening of the limb.
“This is a nice example of how new technologies are being integrated here on the battlefield,” said Sniezek, “and the study is now moving to Afghanistan.”
A cardiothoracic surgeon at Landstuhl was the first to save a patient with the Novalung — a simple-looking slender box with a complex membrane inside that acts as a temporary lung. It connects to blood vessels in the groin, allowing blood to flow from one leg into the box, where it passes through a filter that leaches off the carbon dioxide and infuses the cells with oxygen, mimicking the trade-off that takes place naturally in the lungs. The refreshed blood then returns to body through the other leg.
Unlike a heart-lung machine, the Novalung doesn’t require a mechanical pump because it “works off the body’s own blood pressure,” Fang said.
Approved by European regulators but not yet by the U.S. Food and Drug Administration, the Novalung has been used successfully on about a dozen troops transported to Landstuhl, Fang said. But each time they use it, doctors must submit to the FDA that it is being used to save a life.
“Every time there is a war we learn a lot, because we have to,” said Fang. “And what you learn over years of time is condensed.”
Meghoo recalled using the many lessons that he learned in Iraq during his recent deployment to FOB Sharana, where he was one of two surgeons working in a shed.
“It could be a very lonely feeling,” he said of being away from the safety net of a large hospital with many specialists. “You can’t pass things off to anyone else, and these people have big problems, and you are the only one who can fix them.”
On one occasion an Afghan woman had her right shoulder severed in a mortar attack. Blood gushed from the wound, making it impossible for Meghoo to reach the artery.
“It’s the equivalent of a fire hydrant,” he said. “You can’t go through the water to find the hole. You have to know where the shut-off valve is.”
Meghoo removed part of the woman’s collarbone, and then stemmed the flow of blood by temporarily cinching the artery.
“I remember that case,” he said, “because it was a skill I didn’t have until after I deployed to Iraq.”
The techniques discovered by military surgeons are trickling down to civilian hospitals as well, said Dr. James Dennis, a visiting vascular surgeon at Landstuhl who choked up while talking about the troops with catastrophic injuries whom he had treated in the intensive care unit.
“You can’t help but be moved by what these young people are going through,” said Dennis, whose 25-year-old son Trevor is in the Marines.
Dennis practices at a hospital in Jacksonville, Fla., that recently adopted the military’s protocol when giving blood transfusions to patients with massive injuries.
“They used to learn from us,” Dennis said of military surgeons. “Now we learn from them.”

Saturday, August 21, 2010

FDA Clears All-in-One Reconstitution/Administration Syringe for Xyntha

August 10, 2010 — The US Food and Drug Administration (FDA) has granted 510(k) clearance for a device (Prefilled Dual-Chamber Syringe; Pfizer, Inc) used to reconstitute and administer antihemophilic factor (recombinant) plasma/albumin-free intravenous infusion (Xyntha; Pfizer) in patients with hemophilia A.
The all-in-one syringe is the first to supply freeze-dried albumin-free recombinant factor VIII and also the diluent (0.9% sodium chloride), thereby eliminating the reconstitution transfer step and improving patient convenience.
"For the hemophilia A patient who is always on-the-go, any treatment option that can enhance convenience is critical to the management of his health and lifestyle," said Sue Geraghty, RN, MBA, nurse coordinator, University of Colorado School of Medicine Hemophilia and Thrombosis Center, Denver, in a company news release. "As an all-inclusive, travel-ready kit, the Prefilled Dual-Chamber Syringe offers patients with hemophilia A convenience in reconstituting Xyntha, potentially saving them both time and effort."
The first ready-to-use syringe will be marketed in November 2010 and is designed to provide 3000 IU antihemophilic factor in a 4-mL volume. Lower doses are expected to be available in 2011.
Albumin-free recombinant factor VIII uses a next-generation purification process designed to address the potential risk for murine and other viral contamination. Previously available in single-use vials containing 250, 500, 1000, or 2000 IU freeze-dried powder, the product is indicated for the control and prevention of bleeding episodes and for surgical prophylaxis in patients with hemophilia A.

Wednesday, August 18, 2010

International Symposium on Critical Bleeding 2010

International Symposium on Critical Bleeding 2010
September 6-7, 2010 Copenhagen Denmark

Main sessions:

Critical bleeding – overview of concepts
Coagulopathy of Critical Bleeding
Coagulopathy of Trauma - a new entity or an old tale?
Monitoring of haemostasis
Blood products and critical bleeding – what is the evidence?
Case discussions
Alternatives to Blood transfusion
Resuscitation strategies for massive haemorrhage – how I do it
Surgeons and critical bleeding – State of the Art
Antithrombotics and critical bleeding

Website HERE

Combat casualty care conference shows promising research returns

Top scientists gathered this week at an annual conference to discuss therapies for traumatic brain injuries and lifesaving medical tools to deploy to the battlefield. The annual Advanced Technology Applications for Combat Casualty Care Conference, which is being held this week in St. Pete Beach, Fla., includes presentations on topics ranging from regenerative medicine to pain control to more sensitive vital system monitors. But the two biggest issues talked about were traumatic brain injury and hemorrhage research, said Col. Dallas Hack, director of the Combat Casualty Care Research Program in the U.S. Army Medical and Materiel Command at Fort Detrick.
"We want to save the most lives we can, and that's hemorrhage," Hack said during a phone conference Tuesday morning.
Col. Lorne Blackbourne, commander of the U.S. Army Institute of Surgical Research in San Antonio, Texas, said his command presented a paper on Monday showing that half of the service members who died of injuries suffered "potentially survivable" wounds. Eighty percent of those were hemorrhages, Blackbourne said. Of those hemorrhages, 30 percent were in the legs and arms, where a tourniquet can be used to stop bleeding; 20 percent were in the neck, groin, armpit and areas where a tourniquet cannot be used but pressure can be applied to stop bleeding; and 50 percent were in the chest or abdomen, where pressure cannot stop the bleeding.
Blackbourne said combat medics are better trained than ever before and the tourniquet technique, in use for about 300 years, is "the most valuable piece of equipment" in the battlefield. He said the more certain way of saving lives is to find ways of bringing blood products to the field though.
In the civilian world, bleeding patients may be pumped with salt water or other clear liquids to keep their blood pressure up until they reach the hospital in a matter of minutes. In a combat zone, on the other hand, bad weather or enemy fire may keep a bleeding service member from being airlifted to a hospital for hours. Without plasma to promote clotting, or a blood transfusion, the patient can bleed to death before reaching the hospital.
Hack said two products showcased at the conference, which is sponsored by the Department of Defense, may be approved for use within a few years. Freeze-dried plasma is already in human trials, and spray-dried plasma is about six months behind, he said.

Tuesday, August 17, 2010

Call for Abstracts: 4th International Symposium on Women’s Health Issues in Thrombosis and Haemostasis

Call for Abstracts: 4th International Symposium on Women’s Health Issues in Thrombosis and Haemostasis

February 4-6, 2011 Berlin, Germany

Participants are requested to submit an abstract to the secretariat no later than October 5, 2010 together with the registration form and fees. Authors will be notified regarding abstract acceptance. Accepted abstracts will be presented during a poster session. Abstracts selected by the Scientific Committee will be presented as short Oral Communications during the symposia. All accepted abstracts will be printed in the Book of Abstracts that will be distributed at the Symposium.

Secretariat and Symposium Organizers
Palex Tours Ltd. Israel
59 Ha'atzmaut Road, PO Box 33018, Haifa 33033, Israel

Tel: +972 - 4666 - 0510/11; Fax: +972 - 4852 - 2491
E-mail: whith2011@palex.co.il
Website: www.palexconventions.co.il/whith2011

Cutting back on blood use could halt infections, illness — and even death

SEATTLE — As a doctor and a patient, Dale Reisner knows the value of donated blood. But when the Seattle obstetrician had to have heart surgery four years ago, she did everything possible not to get a single drop.
“I don’t have any religious problems with it. If I was near death, I definitely would have taken blood, no question,” said Reisner, who is fine now at age 62. “But if I could avoid a transfusion by better pre-op preparation, then I was interested.”
Dr. Dale Reisner actively avoided a blood transfusion during surgery to repair a mitral valve in her heart.
Long dominated by Jehovah’s Witnesses — whose faith forbids blood transfusions — bloodless surgeries and blood conservation programs are now attracting mainstream patients worried about what some experts say are clear risks, including more infections, longer recuperation, increased illness and even death.
"The best blood is in your own veins,” said Dr. Lori Heller, medical director of the blood management program at Swedish Medical Center in Seattle, where Reisner had her surgery — without any transfusion. “We want to think before we transfuse.”
Decades of experience with Jehovah’s Witness patients, including 1.5 million members in the United States, has helped propel the new emphasis on blood management, said Sherri Ozawa, clinical director of the Institute for Patient Blood Management at Englewood Hospital and Medical Center in New Jersey.
“In the early days, it was, ‘We have Witness patients, what in the world do we do with them?’” she recalled. “Now we believe it should be the standard of care.”
More doctors, from cardiac surgeons to orthopedists, are offering patients ways to conserve their own blood and avoid transfusions. From drugs that boost blood levels before surgery to cell salvage and blood diversion techniques during operations and lower thresholds for giving blood at all, the techniques are a sea change in the attitude that more blood is always better.

Saturday, August 14, 2010

Interesting Thrombin Paper


Clinical use of Topical Thrombin as a Surgical Hemostat. Click to Enlarge - includes commentary on Oxidised Cellulose, Collagen and Gelfoam.

Wednesday, August 11, 2010

Egypt - Nearly 7 out of every 1,000 Egyptians acquire HCV infections every year, suggesting intense ongoing transmission

The Arab Republic of Egypt has the highest rates of new hepatitis C virus (HCV) infection in the world, according to a new study published today in the prestigious Proceedings of the National Academy of Sciences. The study also estimates more than 500,000 new HCV infections occur in Egypt every year, likely signaling an epidemic in a country of more than 77 million people. This high rate of HCV transmission may be due to the lack of sufficient standard safety precautions in medical and dental facilities, the authors suggest. “Nearly 7 out of every 1,000 Egyptians acquire HCV infections every year, suggesting intense ongoing transmission. This is the highest level of HCV transmission ever recorded at a national level for a blood borne infectious disease transmitted parenterally, that is, by use of non-sterile medical instruments,” said Dr. F. DeWolfe Miller, lead author of this study and professor of epidemiology at the Department of Tropical Medicine and Medical Microbiology and Pharmacology at the University of Hawaii.Although the high prevalence of hepatitis C in Egypt has been well established for many years, and linked in part to limited safety measures during anti-bilharzia campaigns, published estimates of prevalence from different Egyptian communities failed to provide a nationwide picture of the magnitude of ongoing HCV infection transmission.
To estimate the rate of new HCV cases of infection in Egypt, the authors of the study performed epidemiologic modeling of data from a range of studies, including a 2008 national HCV survey with a representative sample and well-documented study design.“The study opened our eyes to a disease burden similar in scale and challenge to the HIV problem in sub-Saharan Africa: Millions of cases of an infection for which there is no vaccine, no effective treatment, and where case management is so expensive that it is beyond the reach of most patients,” said Dr. Laith J. Abu-Raddad, co-author of the study and assistant professor of public health at the Infectious Disease Epidemiology Group at the Weill Cornell Medical College–Qatar.
The study necessitates not only further analysis of HCV transmission in Egypt but also justifies the immediate increase of resources to strengthen public health measures aimed at reducing the transmission of HCV in clinical and non-clinical settings, according to the authors. Failure to address this problem will result in a massive disease burden in the nation in terms of HCV infection complications, including active liver disease, liver failure, or liver cancer.
“There is only one way to deal with the HCV challenge in this country: HCV prevention,” warned Dr. Miller. “Effective and stronger HCV prevention programs are urgently needed in Egypt. Failure to act could swamp the public health system over the coming decades with millions of cases of HCV disease complications with an economic and social cost that this nation does not have the means to confront.”
Key scientific findings of the study
• Nearly 7 out of each 1,000 Egyptians acquire HCV infection every year for a total of 537,000 new HCV infections every year. This is by far the largest ever recorded rate of occurrence of HCV at a national level of all countries in the world.
• One in every 10 Egyptians is a carrier of the HCV infection, which means that there are at least 4,459,000 persons infected with HCV who are infectious to others. This is the largest reservoir of HCV infection in the world.
• Contrary to the widely-held perception that this rate of occurrence reflects merely the limited safety measures during anti-bilharzia campaigns, HCV incidence likely continues at alarming levels due to limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities.

FDA APPROVES 8 MG VIAL OF NOVOSEVEN®

Novo Nordisk announced today that the U.S. Food and Drug Administration (FDA) has approved NovoSeven® RT (Coagulation Factor VIIa [Recombinant] Room Temperature Stable) in an 8 mg vial size, making the hemophilia A or B with inhibitors treatment available in 1, 2, 5 and 8 mg vials. The 8 mg vial allows a rapid initiation and administration of this medication for those patients who need a larger dose. In addition, FDA has also approved the extension of shelf life for all vial sizes from 24 months to 36 months at room temperature (at or below 77 degrees Fahrenheit).

NovoSeven® RT is specially formulated to treat people with hemophilia A or B with inhibitors. Hemophilia, which is typically diagnosed in childhood, is a chronic, inherited bleeding disorder that occurs when certain blood clotting factors are missing or do not work properly, resulting in easy bruising and prolonged bleeding from trauma. Spontaneous internal bleeding can occur as well, particularly in the joints and muscles. Inhibitors, a serious complication that can occur after treatment, develop in as many as 30 percent of those with hemophilia. In these cases, antibodies form that neutralize or attack the blood coagulation agents contained in the treatment, resulting in joint disease and making it more difficult to manage bleeds.

"When I get a bleed, I want to infuse my treatment right away. The faster I treat a bleed, the sooner I can continue with my daily routine," said Bob Hoyt, a member of the Novo Nordisk Changing Possibilities Coalition. "Using fewer vials will be a positive change for patients." Hoyt has been living with hemophilia with inhibitors most of his life.

For many people living with hemophilia with inhibitors, the 8 mg vial will allow for faster reconstitution - the time it takes to prepare the injection - than their current NovoSeven® RT regimen. Those who previously had to use three vials to deliver an 8 mg dose will now have to reconstitute only one vial. Though the amount of powder in the 8 mg vial is larger than the 5 mg vial, the vial will be the same size and will have a yellow cap to distinguish it from the smaller dose.

"We have heard from patients and physicians alike that when they are treating a bleed, every second counts. We at Novo Nordisk are committed to improving the lives of people living with hemophilia with inhibitors," said Eddie Williams, Vice President, Biopharmaceuticals, at Novo Nordisk. "The NovoSeven® RT 8 mg vial will allow patients to get the medicine they need much faster when experiencing a bleed, without having to manage multiple vials. We're also pleased that it will have a positive environmental impact as well - fewer vials may mean less waste."

The new vial size is expected to be available by November.

Monday, August 9, 2010

King Pharmaceuticals - Edited

Net sales of THROMBIN-JMI were $37 million, unchanged from the sales level of the first quarter of this year and were below last year’s second quarter sales of $49 million.
...THROMBIN revenues were flat versus the first quarter, we continue to diligently work with the hospital sales force to manage the lifecycle of this highly competitive and commoditized market.

William Tanner – Lazard Capital Markets

Brian, I know you had a couple 483 letters, at least, certainly this year. I wonder if you could give us a rundown on any outstanding issues that there may be at any of your plants or others relevant to King? Just a second question on the Purdue settlement, was there an attempt to encompass the oxycodone NT with that or is that something likely you have to revis in the future?

Brian Markison

Bill, thank you for the question on the Purdue settlement, but we really can’t and will not add much too it than what we’ve already said, but I appreciate the question. With the 483s, I’ll let Joe speak to that.

Joe Squicciarino

As you point out, we had two of our plants underwent inspection earlier this year, one in Rochester, Michigan, where we manufacture Bicillin, and the other is in Middleton, Wisconsin, where Thrombin-JMI is manufactured. So the outcome of the Rochester, Michigan 483s, we had relatively low number of observations. All of the corrective actions pertaining to those observations have been completed. We submitted the final report to the Detroit office of the FDA about a month ago. So nothing earth shattering there and we feel good about that audit and the outcome.

In Middleton Wisconsin, we had slightly higher number of observations; many of them or some of them I should say pertaining to process validation and a couple of other issues. We have addressed about half of the observations in Middleton. So they’re complete and the remaining observations that are yet to be addressed pertain to future production run, so we won’t be able to address those until those future production runs take place, but in both cases we’re in a good shape.

William Tanner – Lazard Capital Markets

Then just nothing else subsequent to those?

Joe Squicciarino

When you say, no, nothing…

William Tanner – Lazard Capital Markets

In terms of the other 43 letters?

Joe Squicciarino

No, no, we have not received any.

Brian Markison

Keep in mind, the Rochester facility is a single purpose plant for Bicillin only, and as Joe mentioned the Middleton facility is a single purpose plant for THROMBIN-JMI. Again, we believe that the Company’s management or the process is going to accept those steps well.