Science Weekly: A postcard of our universe

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The cosmic microwave background; string theory; Britain’s earliest ancestors; and a shape-shifting exhibit

Software Releases This Summer

Target Health will be releasing 3 software products this Summer:

  • Target Document® Version 1.6 allows any company to run a paperless operation. This 21 CFR Part 11 compliant software allows for eSignatures, multiple document upload and download, paperless Trial Master File (TMF), bulletin board, etc. Both Pharma companies and CROs have licensed the software.

 

  • Target Encoder® Version 2 allows for the rapid encoding of MedDRA and WHO DRUG terms, maintenance of user defined dictionaries and full integration with any SQL database. This 21 CFR Part 11 compliant software is fully integrated with Target E*CRF®.

 

  • Target eCTR® Viewer Version 1, a 21CFR Part 11 compliant software, allows for viewing eSource documents from any EDC system. Target e*CTR has already been integrated with an Electronic Medical Record for full EMR/EDC integration. There will be a press release on this partnership shortly.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health             website at:

www.targethealth.com

Heart Beat May Provide Clues to Kidney Health

Individuals with a high resting heart rate and a low beat-to-beat 1) ___ rate variability have an increased risk of developing kidney disease, according to a study appearing in an upcoming issue of the Journal of the American Society Nephrology. The findings suggest that the behavior of the autonomic 2) ___ system may be a sentinel marker for late development of certain cases of kidney disease. The autonomic nervous system regulates 3) ___ body functions, including heart rate, blood pressure, temperature regulation, and responses to stress. Dysfunction of the autonomic nervous system (dysautonomia) has been linked to chronic 4) ___ disease (CKD) and its progression, but the details of this association are unclear. To study the relationship between dysautonomia and the subsequent development of kidney disease, Daniel Brotman, MD (Johns Hopkins University School of Medicine) and his colleagues examined data from 13,241 individuals enrolled in the Atherosclerosis Risk in Communities (ARIC) study, a prospective observational cohort of 15,792 individuals aged 45 to 64 years, drawn from four US communities. To assess 5) ___, the investigators measured heart rate variability, a practical way to measure autonomic balance. In most healthy young adults, resting heart rate will predictably accelerate and decelerate as a person breathes. In general, lower resting heart rates and greater beat-to-beat variability in heart rate indicate a healthy autonomic nervous system and good 6) ___ health. On the other hand, higher resting heart rates and lower beat-to-beat variability in heart rate are signs of dysautonomia. Dr. Brotman and his team found that patients with 7) ___ resting heart rates had a 2-fold increased risk of developing kidney failure many years later. Individuals with a lower beat-to-beat variability in heart rate had a 1.5-fold increased risk. Therefore, heart rate measurements could serve as a way to identify patients at higher risk of developing kidney damage. While the findings do not prove a cause-and-effect relationship, the authors postulate that dysautonomia may negatively impact the health of blood vessels in and around the kidneys.  The authors hope that their their findings will encourage further research to better define the putative role of the autonomic nervous system in precipitating and exacerbating renal 8) ___ in humans, and that this, in turn, may ultimately lead to novel therapeutic approaches once the mechanisms are better characterized.

ANSWERS: 1) heart; 2) nervous; 3) unconscious; 4) kidney; 5) dysautonomia; 6) cardiovascular; 7) higher; 8) disease

Interesting Glimpse of Mt. Sinai Hospital (NYC) in 1917

Update, July 11, 2010 by Mark L. Horn MD, MPH, and Chief Medical Officer at Target Health Inc.

Dr Horn continues to make his rounds at Mount Sinai Hospital in Manhattan.

 

Dr. Plotz’ home, The Mount Sinai Hospital in New York City, originally founded in the middle of the 19th century as the Jews’ Hospital, has a long and distinguished history in American Medicine. It has historically been a source of “clinician investigators”, physicians actively contributing to medical science while remaining active bedside clinicians. This history facilitated the transition of the hospital into a medical school – an uncommon if not unprecedented event – over a century after its founding, formally combining the basic science disciplines required to confer the MD degree with established expertise in clinical care and research. This integration of scientific discovery and clinical care, begun in the 19th century, evidenced by Dr. Plotz’ work on spirochetes in the early 20th, remains robust in the 21st.

Cultivation of Spirochaeta obermeieri By Harry Plotz (From the Pathological Laboratory of Mount Sinai Hospital, New York.) (Exp Med. 1917 July 1;26(1):37–39)

Up to the present, Spirochaeta obermeieri has not been grown from the blood of persons suffering from relapsing fever, nor has a spirochete of any species, as far as I have been able to discover, been cultivated directly from the blood of human beings. In this communication I wish to report the successful cultivation of Spirochaeta obermeieri directly from the blood of patients suffering from European relapsing fever. The studies were carried on in Serbia in the winter of 1915. The successful cultures, five in all, were made from cases clinically typical of European relapsing fever occurring in civilians and soldiers then residing in Macedonia. Following Noguchi’s successful experiments on the cultivation of other spirochetes, he succeeded in growing Spirochaeta obermeieri from mice infected with relapsing fever. This spirochete had previously been kept alive by continued passage from animal to animal for a considerable length of time. The question arose whether spirochetes thus propagated for a long time become more amenable to artificial cultivation. The method employed is the same as that used by Noguchi. All cultures were taken during the febrile period of the disease. After careful disinfection of the skin with alcohol and iodine, a vein in the antecubital space is punctured and 10 to 15 cc. of blood are withdrawn. A 15 cc. syringe with a thick bored needle is employed. It is important to withdraw the blood slowly, because rapid withdrawal may so injure the organisms that they will not grow. The needle is then removed from the syringe and the blood is slowly introduced into an Erlenmeyer flask containing 10 cc. of a 1.5 per cent sodium citrate solution in 0.85 per cent sodium chloride. The flask is gently agitated and the contents are then ready for culture. Culture tubes measuring 1.5 by 20 cm. are used. Into each tube is placed a piece of fresh sterile rabbit kidney tissue. The kidneys are removed aseptically and divided into about four pieces. About 5 cc. of the blood and sodium citrate mixture are added to each of a series of tubes. To this are added 15 cc. of sterile ascitic fluid. The ascitic fluid should be clear, free of bile and blood pigment, and should have a specific gravity of about 1.020. Noguchi has shown that an ascitic fluid which forms a fibrin filament when it comes in contact with the blood is best; no preservative should be added to the ascitic fluid and it should not be passed through a Berkefeld filter. Before use the fluid is tested out aerobically and anaerobically. Half the tubes are layered with sterile liquid paraffin. The tubes are incubated at 37°C. The cultures were observed over a period of 2 weeks, but no definite appearance of growth was noted in the medium. Occasionally a slight clouding at the lower part of the ascitic fluid appeared. The tubes not layered with liquid paraffin showed the best growth. Although only one or two spirochetes could be found in films made before culture, a distinct increase could be noted after 48 hours’ cultivation. In this series the maximum growth appeared on the 5th day and then gradually decreased. Preparations made from the junction of ascitic fluid and blood revealed masses and clumps of spirochetes. Preparations made from the upper part of the medium showed clumps and masses of spirochetes, but not so many as from the lower part. In young cultures the spirochetes appear shorter and thinner, but in older cultures they gradually become thicker and longer. The most striking appearance in young cultures is the spirochetal nodes which appears in practically every organism. These nodes are small thickenings which occur in the body of the spirochetes. From one to four may occur in the same organism. As the cultures become older these nodes become less numerous. I believe that these nodes probably represent the points where longitudinal division occurs. Transplants are made about the 5th day by withdrawing 0.5 cc. of ascitic fluid from the lower part of the medium, without blood. This is inoculated into a similar tube as described above, except that 2 cc. of defibrinated human blood are added to each tube. The presence of hemoglobin aids the subsequent growth. In this manner Spirochaeta obermeieri have been transplanted for five generations in two cultures.

Antibodies Found That Prevent Most HIV Strains From Infecting Human Cells

Finding individual antibodies that can neutralize HIV strains anywhere in the world has been difficult because the virus continuously changes its surface proteins to evade recognition by the immune system. As a consequence of these changes, an enormous number of HIV variants exist worldwide. Even so, scientists have identified a few areas on HIV’s surface that remain nearly constant across all variants. One such area, located on the surface spikes used by HIV to attach to immune system cells and infect them, is called the CD4 binding site. Two potent human antibodies have been discovered that can stop more than 90% of known global HIV strains from infecting human cells in the laboratory. According to the authors, these antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection. Moreover, the method used to find these antibodies could be applied to isolate therapeutic antibodies for other infectious diseases as well. The study found two naturally occurring, powerful antibodies called VRC01 and VRC02 in an HIV-infected individual’s blood. These antibodies used a novel molecular device they developed that homes in on the specific cells that make antibodies against HIV. The device is an HIV protein that the investigators modified so it would react only with antibodies specific to the site where the virus binds to cells it infects. The study also found that VRC01 and VRC02 neutralize more HIV strains with greater overall strength than previously known antibodies to the virus. The atomic-level structure of VRC01 was determined when it is attaching to HIV. This enabled the definition on how the antibody works and to precisely locate where it attaches to the virus. With this knowledge, the study team has begun to design components of a candidate vaccine that could teach the human immune system to make antibodies similar to VRC01 that might prevent infection by the vast majority of HIV strains worldwide. These study were published online in Science (DOI: 10.1126 / science.1187659; DOI: 10.1126 / science.1192819. With the antibodies in hand, the atomic-level molecular structure of VRC01 was determined when attached to the CD4 binding site. This structure was then examined in light of natural antibody development to ascertain the steps that would be needed to elicit a VRC01-like antibody through vaccination. Antibody development begins with the mixing of genes into new combinations within the immune cells that make antibodies. Examination of the structure of VRC01 attached to HIV suggested that, from a genetic standpoint, the immune system likely could produce VRC01 precursors readily. The study also confirmed that VRC01 does not bind to human cells-a characteristic that might otherwise lead to its elimination during immune development, a natural mechanism the body employs to prevent autoimmune disease.

Adverse Events Associated with Testosterone Administration

Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. As a result, a study published in the New England Journal of Medicine (2010;363:109-122) was performed in community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter). Study subjects were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities (MedDRA) classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. According to the authors, in this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The authors added that the small size of the trial and the unique population prevented broader inferences from being made about the safety of testosterone therapy.

Transdermal and Oral Hormone Replacement Therapy and the Risk of Stroke

According to an article published in the British Medical Journal (2010;340:c2519) a study was performed to determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy. The investigation was a population based nested case-control study in about 400 general practices in the United Kingdom contributing to the General Practice Research Database. Study participants were a cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorized into estrogens only, estrogens plus progestogen, progestogen only, and tibolone. estrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). The main outcome measures were rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date. During the course of the study there were 15,710 cases of stroke matched to 59,958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 relative to no use. The risk of stroke was not increased with use of low estrogen dose patches (rate ratio 0.81) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28) with both low dose and high dose.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

Berwick/CMS Update

Several months back we commented favorably on the appointment of Dr. Donald Berwick of the Institute for Healthcare Improvement to lead the Center for Medicare and Medicaid Services (CMS). Last week it emerged that the Administration has elected to “seat” Dr. Berwick through an interim appointment circumventing the Senate confirmation process ordinarily required for this post. Since the CMS is critical for the implementation of the Affordable Care Act. and has been without permanent leadership since 2006, the need to fill the vacancy with dispatch is clear. However, it is far from clear that it was either necessary or prudent to circumvent the approval process, thereby eliminating the opportunity to publicly vet sensitive and important issues related to the Act and address continuing public concerns about the new law. It is noteworthy that Senator Max Baucus, Democratic Chair of the Senate Finance Committee had the following comment…

Senate confirmation of presidential appointees is an essential process prescribed by the Constitution that serves as a check on executive power and protects Montanans and all Americans by ensuring that crucial questions are asked of the nominee — and answered

Since this controversial decision was announced, the Web has been saturated with videos showing Dr. Berwick praising Britain’s National Health Service and opining that humane health care is by definition redistributive of wealth. He will now have no public opportunity to offer additional perspective on these views. However one might feel about Dr. Berwick, the country would have benefited from an open and vigorous discussion of his views, his approach to implementing health care reform, and the issues he feels need to be most urgently addressed. Senate hearings may have been challenging, but they could have provided an effective forum to educate and mobilize the American people, helping us understand and confront some of the tough choices ahead in health care. It is true that this discussion would have caused discomfort, but all of us, including Dr. Berwick, would have been the better for having it. (by Mark Horn, MD, Chief Medical Officer, Target Health Inc.)

 

Another point of view by Joyce Hays, CEO, Target Health Inc:

Because the new law will expand Medicaid to cover 16 million more people with low incomes, this will be a challenge for the Center for Medicare and Medicaid Services, and a testing ground for new innovation.  One could argue that there are those in Congress who have repeatedly stalled many of the administrations nominees for many months,  whose clear intentions would have been to stall the appointment of Dr. Donald Berwick, and then to use this blocking tactic as  (political) a way to revive arguments against the new healthcare law, which will be a political football in this fall’s elections.  The agency that Dr. Berwick will be heading has been without a permanent administrator since October 2006.  This other point of view is that although a long difficult struggle in the Senate confirmation process would have informed the public, definitely a positive, there are too many desperate citizens without healthcare, and too many doctors who could get staggering cuts in Medicare payments by those in the Congress holding up the confirmation process.  The administration wanted to avert this damage.

The New York Times wrote: “One of Dr. Berwick’s first tasks will be to work with Congress to avert a 21 percent cut in Medicare payments to doctors, scheduled to occur late this year.

The American Medical Association has praised Dr. Berwick, saying he is “widely known and respected” for his efforts to improve the quality and safety of care. But cuts in Medicare payments could damage the quality of care and prompt doctors to turn away new Medicare patients, doctors say.  Hospital executives who have worked with Dr. Berwick describe him as a visionary, inspiring leader

For two decades Dr. Berwick has championed the interests of patients and consumers. At the same time, he has spoken of the need to ration health care and cap spending, has supported efforts to “reduce the total supply of high-technology medical and surgical care” and has expressed great admiration for the British health care system. “

For more information about our expertise in Medical Affairs, contact Dr. Mark Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.

Target Health has developed a full suite of eClinical Trial software including

1) Target e*CRF® (EDC plus randomization and batch edit checks)

2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials)

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