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State of the art in oncologic imaging of Lymphoma.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Ecosystems & Industrial Concentration in the Medical Device Sector, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Liver & Digestive Diseases Research, Medical Devices R&D and Inventions, Personalized and Precision Medicine & Genomic Research, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, tagged , , , , , , , on February 3, 2013| Leave a Comment »

State of the art in oncologic imaging of Lymphoma.

Author and Curator: Dror Nir, PhD

Article 11.3.6 State of the art in oncologic imaging of Lymphoma

This is the last post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging†‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on imaging used in management of Lymphoma.

The traditional tasks of imaging in the management of lymphoma include: staging, assessing response to therapy and confirming it reaching an end-point and detecting recurrence. The leading imaging modality is PET/CT. In their literature review the authors include several references claiming that the clinical outcome of lymphoma patients has improved significantly due to better prognosis – largely related to better disease characterization and identification of prognostic markers in recent years. Adoption of functional imaging that improved pre-treatment staging and assessment of the response to treatment contributed as well to this outcome 178 .179 “Most of the recent progress in management of lymphoma occurred after the widespread introduction of [18F]FDG PET and PET/CT. Accordingly, [18F]FDG PET is now part of the revised lymphoma response criteria.180 “

 

A 46-year-old male with diffuse large B cell lymphoma, stage IV was studied. Baseline maximum intensity projection (MIP) positron emission tomography (PET) image with [18F]fluorodeoxyglucose ([18F]FDG) (A) shows widespread disease, which is essentially resolved on interim scan after 4 cycles of chemotherapy (B). The interim scan also shows increased [18F]FDG uptake in bone marrow related to administration of granulocyte colony-stimulating factor (GCSF). (C,D) Transaxial CT and PET/CT fusion images at baseline show abnormal [18F]FDG uptake in extensive mediastinal and hilar lymphadenopathy as well as in bone lesions in a right rib and the right scapula. On interim scan (E,F) abnormal [18F]FDG uptake at all of these sites has resolved although residual enlarged lymph nodes remain. The sites are better seen on a contrast-enhanced CT (G) and measure up to 5.3 cm × 3.6 cm. Chemotherapy was continued for a total of 8 cycles. At the time of writing, the patient remained disease-free after 9 years of follow-up.

A 46-year-old male with diffuse large B cell lymphoma, stage IV was studied. Baseline maximum intensity projection (MIP) positron emission tomography (PET) image with [18F]fluorodeoxyglucose ([18F]FDG) (A) shows widespread disease, which is essentially resolved on interim scan after 4 cycles of chemotherapy (B). The interim scan also shows increased [18F]FDG uptake in bone marrow related to administration of granulocyte colony-stimulating factor (GCSF). (C,D) Transaxial CT and PET/CT fusion images at baseline show abnormal [18F]FDG uptake in extensive mediastinal and hilar lymphadenopathy as well as in bone lesions in a right rib and the right scapula. On interim scan (E,F) abnormal [18F]FDG uptake at all of these sites has resolved although residual enlarged lymph nodes remain. The sites are better seen on a contrast-enhanced CT (G) and measure up to 5.3 cm × 3.6 cm. Chemotherapy was continued for a total of 8 cycles. At the time of writing, the patient remained disease-free after 9 years of follow-up.

 

Subsequent to their acknowledgment of PET/CT as the most promising imaging modality for management of Lymphoma, the authors focused their review to on its role in this disease pathway. It being well understood that the clinical utility of [18F]FDG PET in lymphoma “depends on the intensity of radiotracer uptake in disease sites, which will affect the test accuracy for staging and characterizing residual masses after completion of therapy, as well as the role of the test in response assessment. The intensity of [18F]FDG uptake in lymphoma is determined by tumor histology, grade (eg, indolent versus aggressive NHL)”,181, 182  At the end of their extensive review the authors do mention that PET/MRI might become an important player in the management of this disease, especially in pediatric cases.

 Other research papers related to the management of Lymphoma were published on this Scientific Web site:

Imatinib (Gleevec) May Help Treat Aggressive Lymphoma: Chronic Lymphocytic Leukemia (CLL)

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Predicting Tumor Response, Progression, and Time to Recurrence

Cancer Innovations from across the Web

 

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State of the art in oncologic imaging of Colorectal cancers.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Liver & Digestive Diseases Research, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, tagged , , , , , , , , , on February 2, 2013| 2 Comments »

State of the art in oncologic imaging of Colorectal cancers.

Author-Writer: Dror Nir, PhD

Screen Shot 2021-07-19 at 7.31.39 PM

Word Cloud By Danielle Smolyar

This is the fourth post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging†‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on colorectal cancer imaging. It reviews current and developing radiologic practices in CRC with respect to screening, preoperative evaluation, surveillance, and post-treatment re-staging.

Colorectal cancer (CRC) is an example to successful imaging-based screening evident by noticeable reduction in mortality rates. The 5-year survival rate of CRC patients diagnosed at an early stage is 90%.1 121 According to this review; “(CRC) is the third most common cancer worldwide and the second most frequent cause of cancer death in the United States. The American Cancer Society estimates that 143,460 new cases of CRC will be diagnosed and 51,690 deaths from CRC will occur in the United States in 2012.120 Because of screening and removal of premalignant polyps, incidence rates have declined over the last 3 decades.”

The authors found out that the increased use of CT in CRC screening has the potential of reducing its costs and associated tisks 122 In addition, use of DW-MRI enabled better outcomes of CRC liver metastasis treatment as it enables tailored localized treatment of such lesions.123 124 Finally, the authors found that: “MRI for staging of rectal cancer has become standard practice and, in some instances, is performed in lieu of surgeon-performed endorectal US (ERUS), providing the radiologist with an even greater role in the management of patients with CRC.125 “

 Screening

“CRC is a largely preventable disease, as the progression of the adenoma-carcinoma sequence of mutations is slow and leaves ample time to intervene. Nonetheless, approximately 41% of the population (in the USA) eligible for screening remains unscreened. 126 Most screening is performed using non-imaging tests”

Any of these screening strategies will reduce mortality from CRC.126, 127 

Among imaging tests used for screening, barium enema has seen a continual decline in usage, at least in part due to the landmark study showing that this test detected only 39% of polyps identified at colonoscopy, including only 48% of those > 1 cm in size.131 The recent (and largest, with > 2500 patients) multicenter CT colonography (CTC, also known as virtual colonoscopy) screening study, performed by the American College of Radiology Imaging Network, found that CTC had sensitivity of 90% and similar specificity for polyps > 9 mm, and the number of centers using CTC has increased.122 Widespread deployment of CTC remains hindered, in part, by the 2009 decision of the Center for Medicare and Medicaid Service (CMS) to deny reimbursement based on 1) potential radiation risk, 2) impact of detection of extracolonic findings, and 3) efficacy in the 65 years and older age group of concern to CMS. Data from studies reported after this decision put CTC in a good position to be reconsidered for reimbursement. The median estimated effective dose is currently 5 to 6 mSv, a dose far less than that received from a standard CT exam and even comparable to or lower than that received from a barium enema examination. In fact, the radiation dose from CTC is equivalent to that received from cosmic radiation in a 1-year period.132 Extra-colonic findings occur in 7% to 11% of cases and lead to extra examinations in about 6% with a relevant new diagnosis made in 2.5%, according to the experience of the largest screening center in the United States.133 Furthermore, when detection of extracolonic cancers and aortoiliac aneurysms is included along with CRC screening, CT colonography (CTC) has been shown to be more clinically effective and more cost-effective than optical colonoscopy.134 In an observational study, CTC accuracy was maintained in patients aged 65 to 79 years, who were compared to the overall general population sample. In the older patients, CTC remained a safe and effective modality and program outcome measures, such as colonoscopy referral and extracolonic work-up rates, remained similar to those in other screened groups.135“

 Detection and Characterization

“Diagnosis and clinical staging of primary colonic adenocarcinoma is most often accomplished by combining colonoscopy with biopsy and performing cross-sectional imaging to detect metastatic disease.

Although CT and MRI are widely used for preoperative whole-body staging, they are not recommended first-line methods for detection of primary lesions. In contradistinction, CTC has matured into an excellent diagnostic method for detection of CRC. Data drawn largely from screening studies tell us that its sensitivity for polyps > 10 mm is 90% or greater, and that it will detect nearly every cancer. In fact, a recent meta-analysis of more than 11,000 patients indicated that CTC had sensitivity of 96.1% (398 of 414) for CRC, and when cathartic cleansing and fecal tagging were used, no cancers were missed (Fig. 16).137 Detection of flat cancers remains a challenge with CTC as compared with endoscopic methods in which mucosal surface details are better appreciated. CTC not only detects CRC, but with its cross-sectional depiction also allows characterization of tumors using the TNM staging system138 with reasonable T- and N-stage accuracies of 83% and 80%, respectively.139 CTC is an operator-dependent technique that has shown great variability between radiologists with different degrees of training. Computer-aided detection (CAD) was developed for this reason and because 10,000 to 15,000 images must be scrutinized for each large adenoma detected. In a screening cohort of 3077 consecutive asymptomatic adults, stand-alone CAD had sensitivities of 97% and 100% for advanced neoplasia and cancer, respectively.140

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

With magnetic resonance colonography (MRC), detection of masses is limited because techniques employing air cause susceptibility artifacts, and those employing dark-lumen techniques with water-filling and intravenous gadolinium are under scrutiny because of concerns about the potential risk of nephrogenic systemic fibrosis. In addition, in the largest screening study, the sensitivity of MRC was only 70% in patients with colorectal lesions more than 10 mm in size.141

Imaging plays a critical role in detecting liver metastases in order to properly stage and treat the patient with colorectal cancer. NCCN guidelines recommend contrast-enhanced CT or MRI.142 “

MRI is the most promising imaging modality for management of rectal cancer.

Staging of this cancer is primarily accomplished with US, typically performed by surgeons. MRI using phased-array coils provides complete visualization of the pelvic anatomy and, especially, the circumferential resection margin, an important landmark for the standard total mesorectal excision.

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

 

 The MERCURY study125established the near equivalence of MRI to histopathology for identification of this margin, an important advantage of MRI over ERUS, with which the margin is not routinely visualized.147 T- and N- stage accuracies of MRI (87% and 74%, respectively) were similar to those of ERUS (82% and 74%, respectively).148 Accurate lymph node identification remains a problem for MRI. Toward this end, a new albumin-bound gadolinium agent has shown some promise, and further results are awaited.149”

 Role of Imaging in Assessing Treatment Response

“Imaging plays a critical role in 1) determining response to systemic and loco-regional treatment of liver metastases, 2) assessing response to local treatment and restaging rectal cancer primary lesions, and 3) detecting and assessing the treatment response of extra-hepatic metastatic disease. Systemic treatment (and in some centers, hepatic artery infusion) of non-resectable liver metastases with chemotherapy aims at reduction of the metastatic burden, which, occasionally may allow attempts at curative liver resection.

Due to the limitations of CT with regard to soft tissue contrast and fatty liver. MRI has greater sensitivity for remaining (or new) lesions < 1.0 cm due to its superior soft tissue contrast. In a recent meta-analysis of 25 eligible studies, MRI showed higher sensitivity than CT on a per-patient basis (P = .05) and on a per-lesion basis as well (P = .0001). With its 81.1% sensitivity and 97.2% specificity, MRI is thus the preferred modality.151 Nonetheless, under the current NCCN guidelines, CT remains the preferred modality.142 

Loco-regional (“liver-directed”) therapies include radiofrequency, microwave ablation, transarterial chemo- or particle embolization and irreversible electroporation. With these treatments, responding lesions can actually increase in size, and simple size criteria are no longer sufficient to determine response. The European Association for the Study of the Liver has issued new criteria to assess viability of remaining tumor based on enhancing residual volume by multiphase CT or MRI.152 However, the field is rapidly changing and there is no consensus on the optimal imaging strategy following loco-regional therapy.

Recent meta-analyses of randomized controlled trials comparing low-intensity and high-intensity surveillance programs have shown advantages for more intense follow-up in Stages I-III disease;170-173 however, controversies remain regarding the optimal surveillance strategy. “

Lymphoma Imaging

To be followed…

Other research papers related to the management of Colorectal cancer were published on this Scientific Web site:

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

Read Full Post »

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Atherogenic Processes & Pathology, CABG, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Mitral Valve: Repair and Replacement, PCI, Personalized and Precision Medicine & Genomic Research, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Renal Denervation, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , on January 28, 2013| 16 Comments »

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 11/22/2018

  • Device Approvals, Denials and Clearances

https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/default.htm

  • FDA clears AI technology that evaluates echocardiograms – Ultrasound Images

https://www.healthdatamanagement.com/news/fda-clears-ai-technology-that-evaluates-echocardiograms

  • Heart Murmur Detection done by AI Algorithm (Eko Core and Eko Duo) Devices Outperform most Auscultatory Skills of Cardiologists

https://pharmaceuticalintelligence.com/2018/11/21/heart-murmur-detection-done-by-ai-algorithm-eko-core-and-eko-duo-devices-outperform-most-auscultatory-skills-of-cardiologists/

  • FDA Clears Remote Multichannel ECG Compared to Holter

https://www.cardiovascularbusiness.com/topics/electrophysiology-arrhythmia/fda-clears-remote-multichannel-ecg-compared-holter

  • Arterys Cardio AI – MR Images

Arterys CEO Fabien Beckers, along with Michael Poon, MD, Northwell Health cardiologist, will present “The Potential of a Web Platform to Transform Medical Imaging with AI and Cloud Computation” in the 2018 RSNA Machine Learning Showcase, Tuesday November 27 at 11:30am CST. Arterys will provide demonstrations of its AI-powered, web-based solutions, including:

Arterys Cardio AIMR combines the power of deep learning and cloud computing to automate analysis of cardiac MR images. By eliminating many tedious, manual tasks, Arterys Cardio AI enables clinicians to quickly and easily identify, determine treatment for and track heart problems. It is the first and only commercial solution to offer deep learning-based semi-quantitative perfusion and quantitative delayed enhancement analysis*.

https://www.marketwatch.com/press-release/arterys-to-demonstrate-suite-of-ai-powered-cloud-based-medical-image-analysis-solutions-at-rsna-2018-2018-11-21/print

  • AI software for detecting brain bleeds receives FDA approval – CT Images

November 08, 2018 | Melissa Rohman | Artificial Intelligence

The FDA recently administered 510(k) clearance to software developed by MaxQ AI that uses AI to detect brain bleeds on CT images, according to a report published Nov. 8 by AI in Healthcare.  

“The Accipio Ix Intracranial Hemorrhage platform uses AI technology to automatically analyze non-contrast head CT images, and can do so without impacting a physician’s workflow, altering the original series or storing protected health information,” according to the article.

The clinical diagnostics intelligence platform company hopes that the software can help physicians prioritizes patients who show symptoms of brain bleeds.

With FDA approval, the AI software can be sold for commercial use within the U.S. and will be on display during this year’s Radiological Society of North America (RSNA) Annual Meeting in Chicago.

https://www.healthimaging.com/topics/artificial-intelligence/ai-detection-software-brain-bleeds-fda-approved

 

  • More in Artificial Intelligence

Chest x-ray AI similar, but quicker than radiologists at detecting diseases
AI may help radiologists interpret screening mammography without added reading time
Predictive model may reduce overtreatment of ground glass nodules
Philips launches IntelliSpace Discovery* Research platform at RSNA to support the development and deployment of Artificial Intelligence assets in radiology
Machine learning method helps radiologists diagnose uterine cancer
Radiomics, AI fall short of radiologists in breast lesion classification on MRI
New trial may allow CMAs to perform echocardiograms with AI-guided ultrasound
CDS tool improves reader diagnosis of bladder cancer response to treatment
AI estimates full-dose PET images from low-dose scans
Australian university hopes digital pathology method can address pathologist shortage

SOURCE

https://www.healthimaging.com/topics/artificial-intelligence/ai-detection-software-brain-bleeds-fda-approv

Cardiovascular Medical Devices in the News

March 13, 2018 — Determining the best occluder device size necessary to properly seal the left atrial appendage (LAA) before implanting the device may be feasible with the assistance of 3D printing, according to two separate presentations at ECR 2018 in Vienna.

SOURCE

https://www.auntminnieeurope.com/index.aspx?sec=sup&sub=car&pno=2

  • Machine learning can help assess atherosclerosis
    February 7, 2018 — Machine-learning techniques analyze imaging measurements to automatically stratify patients by the level of atherosclerotic burden, offering the potential of personalized prediction of disease progression and more effective treatment for individual patients, according to researchers from Italy.  Discuss

SOURCE

https://www.auntminnieeurope.com/index.aspx?sec=sup&sub=car&pno=3

  • CCTA biomarker may predict mortality from heart disease
    August 28, 2018 — The use of coronary CT angiography (CCTA) to measure fatty tissue around arteries could help predict the risk of mortality from heart disease, according to research published online on 28 August in the Lancet and being presented at the European Society of Cardiology congress in Munich.  Discuss

SOURCE

https://www.auntminnieeurope.com/index.aspx?sec=sup&sub=car&pno=1

  • SCOT-HEART: CCTA cuts risk of heart attack, death by 41%
    August 25, 2018 — Patients with chest pain who underwent coronary CT angiography (CCTA) with standard care had a markedly lower rate of myocardial infarction or death from coronary artery disease than those who only received standard care in a new study, published on August 25 in theNew England Journal of Medicine.  Discuss

SOURCE

https://www.auntminnieeurope.com/index.aspx?sec=sup&sub=car&pno=1

 

 

SOURCE

https://www.healthdatamanagement.com/tag/cardiovascular-disease

FDA’s Medical Devices Frontier in 2013

Michelle McMurry-Heath

Office of the Center Director, Center for Devices and

Radiological Health, U.S. Food and Drug Administration (FDA)

and

Margaret A. Hamburg

Office of the Commissioner, FDA

In their article Creating a Space for Innovative Device Development stated that the FDA announces a partnership with a new nonprofit organization—the Medical Device Innovation Consortium (MDIC) —to advance regulatory science in the medical technology arena.

The promise of MDIC is to eliminate the currently existing shortfalls in applied research in areas such as health-related engineering and regulatory science, which comprises the development of new tools, standards, and approaches to assess a product’s safety, efficacy, quality, and performance.

MDIC will foster regulatory science breakthroughs in the medical technology space with the ultimate goal of improving human health.

FDA and LifeScience Alley (LSA; https://www.lifesciencealley.org)—a biomedical science trade association—have worked together to develop the first medical device public-private partnership (PPP) whose sole objective is to advance the entire spectrum of regulatory science in this sector. MDIC will facilitate this groundbreaking collaboration among federal agencies, nonprofit organizations, industry, academic institutions, and other trade associations such as MassMedic (www.massmedic.com) and the California Healthcare Institute (www.chi.org). Key goals:

(1) encourage members to leverage their resources by focusing jointly on precompetitive

(2) early-stage technology development ef orts that otherwise would not take place because of the organizational structure of the device sector.

About 75% of the more than 5,000 device manufacturers in the United States are small companies with fewer than 20 employees (3).

Start-up device companies have limited capital, and a startup’s future of en depends on the success of one complex device. Advances in regulatory science would speed the translation of these next-generation technologies.

Medical Devices sector lacks the resources to support regulatory science research, as well as mechanisms for working together to pool their resources to solve scientific issues.

MDIC members will make it a priority to develop regulatory methods and tools that can be adopted by the medical device community and will provide a forum for medical device stakeholders to securely share proprietary precompetitive data. Each advance achieved by medical device stakeholders through the sharing and leveraging of resources will assist industry in developing new REGULATORY SCIENCE Creating a Space for Innovative Device Development.

GOALS OF PARTNERING WITH MDIC

MDIC was designed with f exibility in mind, so that it can adapt to address the most pressing needs of patients and of the device industry as they evolve over time.

In keeping with the goal of stakeholder engagement, MDIC is currently recruiting founding members who will work jointly with FDA to determine research priorities for the endeavor.

Much like other successful PPPs in the pharmaceutical space, such as the Foundation for NIH or Critical Path Institute, the founding members will be asked to represent their stakeholder communities in

(i) suggesting the most promising areas for research collaboration,

(ii) raising funds to support these areas of investigation, and then

(iii) issuing requests for grant proposals.

Researchers and engineers from all sectors—industry, government, academia, or nonprofit organizations—will be encouraged to apply, and preference will be given to research consortia that cross sectors and take interdisciplinary approaches to problems.

MDIC strives to support science conducted by research teams that have innovative ideas for the development of tools and methods for medical device design, testing, and regulatory approval.

MDIC’s potential to improve patient care is computational modeling and simulation of human pathophysiology, which can be used to augment in vitro and animal disease models in the preclinical stages of device development.

FDA’s Center for Devices and Radiological Health (CDRH) expects computational modeling to accelerate and streamline the regulatory review process but first needs to develop a strategy for assessing the technology’s credibility—its usefulness, quality, and reproducibility. CDRH has begun to develop a technological framework called the Virtual Physiological Patient (4), which, once completed, will provide a model for the human body as a single complex system. 

However, cross-sector research teams are required to develop the normal and diseased reference models that will serve as benchmarks for device performance and safety. Using computational modeling and simulation, device designs can potentially be ref ned even before they enter clinical trials, improving safety for patients and reducing the cost of device development for companies, computational modeling and simulation, device designs can potentially be ref ned even before they enter clinical trials, improving safety for patients and reducing the cost of device development for companies.

Another emerging research area is medical device interoperability—the development of devices that seamlessly operate with other medical devices and information systems (5). MDIC could establish a framework to identify gaps in the interoperability field, prioritize the gaps, and then fund research accordingly.

MDIC also could help prioritize the development of standards for innovative interoperable medical devices and build test beds for these technologies. is research will help to ensure that interoperability issues do not pose a hazard to patients.

With the emergence of new materials in medical devices, FDA must develop updated biocompatibility standards based on the most recent scientific advances.

MDIC could support the development of new preclinical biocompatibility assays that predict potential adverse health responses in people exposed to biomaterials or nanoparticles (6).

INNOVATION INFRASTRUCTURE With today’s fiscal realities, FDA cannot rely on government-funded “Manhattan projects” to bridge the funding gap for regulatory science. Partnerships bring together private-sector expertise, academic science ingenuity, and federal regulatory knowledge, and new structures are needed to promote these multifaceted collaborations.

It would be convenient if such partnerships formed organically, but all too of en, bureaucratic red tape gets in the way of sensible scientif c collaboration. MDIC will serve as a collaborative freeway to biomedical discovery and development by forming a foundation that makes it easy for industry, academia, and government to come together to set research priorities; to pool their distinct intellectual capital; and then to work together to advance knowledge that modernizes regulatory science and improves patient access to high-quality medical technology.

Sci. Transl. Med. 4, 163fs43 (2012). 

[ScienceTranslationalMedicine.org 5 December 2012 Vol 4 Issue 163 163fs43]

Statistics on Device use — Number of procedures in the United States (2009)

Number of domestic inpatient procedures (N = 48 million per year)

  • Insertion of coronary artery stent: 528,000
  • Diagnostic ultrasound: 902,000
  • CT scan: 497,000
  • Arteriography and angiocardiography: 1.9 million
  • Cardiac catheterization: 1.1 million
  • Total hip replacement: 327,000
  • Total knee replacement: 676,000

Source:

U.S. Centers of Disease Control www.cdc.gov/nchs/fastats/insurg.htm

This sector is best known for

  • surgical instruments,
  • cardiology devices, and
  • orthopedic implants, it also includes all of the
  • diagnostic tests and
  • imaging equipment currently used to pinpoint disease 
  • companion diagnostics, which are needed to fulfill the promise of personalized medicine (1).

FDA 510 (k) Pending for the Latest Cardiovascular Imaging Technology

Editor’s choice of the most innovative technology at RSNA 2012
By:

Dave Fornell

December 11, 2012
Toshiba is developing a radiation dose alert to show interventionalists how much dose they have delivered to their patient from X-ray angiography.
 The latest advances in cardiovascular imaging are usually shown first at the Radiological Society of North America (RSNA) annual meeting, the largest radiology show in the world, held the last week of November in Chicago. After spending five days walking three expo halls filled with more than 600 product vendors, the following is my editor’s choice for the most innovative new cardiovascular imaging technology.

New Angiography Systems

Siemens unveiled two new 510(k)-pending angiography systems, the Artis Q and Artis Q.zen, which incorporate new X-ray tube, detector and imaging software technology that can help reduce dose significantly, while offering improved image quality.

The new X-ray tube is intended to help physicians identify small vessels up to 70 percent better than conventional X-ray tube technology. The Artis Q.zen combines this innovative X-ray source with a new detector technology designed to support interventional imaging in ultra low-dose ranges to patients, doctors and medical staff, particularly during more complex, longer interventions.

The second generation of Siemens’ flat emitter technology replaced the coiled filaments used in conventional X-ray tubes to emit electrons. Flat emitters are designed to enable smaller quadratic focal spots that lead to improved visibility of small vessels.

The Artis Q.zen combines the X-ray tube with a detector technology that allows detection at ultra-low radiation levels. It can image with doses as low as half the standard levels applied in angiography. Instead of detectors based on amorphous silicon, a new crystalline silicon structure of the Artis Q.zen detector is designed to be more homogenous, allowing for more effective amplification of the signal, greatly reducing the electronic noise.

Siemens also introduced new software applications for interventional imaging. Clear Stent Live freezes an enhanced image of a stent during deployment with the balloon radio-opaque markers and uses it as an overlay on live fluoroscopy. Siemens says the main application will be for better visualization when implanting overlapping stents or stenting bifurcation lesions. It also helps suppress and stabilize heart motion on the image.

Other new 3-D applications are designed to image the smallest structures inside the head. Their high spatial resolution is crucial for imaging intracranial stents or other miniscule structures such as the cochlea in the inner ear. Moving organs such as the lungs can be imaged in 3-D in less than three seconds, reducing motion artifacts and the required amount of contrast agent.

GE Healthcare showcased its IGS (Image Guided System) 750 hybrid OR angiography system. It was displayed at RSNA 2011, but did not receive FDA clearance until earlier this year. It offers the mobility of a mobile C-arm, but the image quality and software features of a ceiling or floor mounted fixed system. It uses laser guidance for very accurate positioning. It can rove around the room on a powered caster system to enable different positioning around the table, or be parked out of the way during open surgical procedures.

Hands-Free Physician Control of Images

GestSure displayed a new, FDA-cleared system that allows interventionalists in the cath lab, or surgeons in the operating room, to pick reference images to display on the overhead screens in the room and manipulate the images all hands-free. It allows physicians to pick and enlarge the images they need for better procedural navigation, while maintaining the sterile field.

A video sensor detects all the people in the work area and displays their outlines on a separate screen, with each person assigned a specific color. When one of those people raises their arms in the “hands up” pose, the system detects this and allows the person control of the system. Using the right arm/hand, they can scroll through images and use the left arm/hand as a mouse click by a pushing motion forward. The system detects the motions and translates them in real time to mouse actions on the overhead screen.

The software works as a vendor-neutral layer on top of existing PACS or advanced visualization software.

Outpatient, Office-Based Catheter Interventions

Outpatient, office-based peripheral vascular procedures are an increasing trend, according to GE healthcare, which showcased a new “mobile hybrid OR” solution. The trend includes setting up an outpatient cath lab in an office setting to reduce the costs of using hospital ORs or cath labs. The room system GE highlighted centers around its OEC 9900 Elite mobile C-arm and Venue 40, which is combined with a ultrasound system in an all-in-one unit. The GE Venue 40 tablet ultrasound system is mounted within the OEC 9900 Elite C-arm’s workstation to reduce the floor space required.

Wireless Ultrasound Transducer

Siemens introduced the world’s first wireless transducer ultrasound system, the Acuson Freestyle. It eliminates the impediment of cables in ultrasound imaging by using a battery-powered transducer, about the size of a large TV controller. The transducer can be submerged for cleaning. It is capable of 90 minutes of continuous scanning before the battery needs to be recharged.

The Freestyle is a point-of-care system that will expand ultrasound’s use in interventional and therapeutic applications. The transducer can be used to image up to 10 feet from the console. Siemens said it hopes to refine and expand the wireless transducer technology to its other systems in the coming years.

Engineers had to overcome several issues to create a wireless transducer. For example, a cardiac echo requires about 40 frames per second and each frame is equal to about 1 megabyte of data. To accommodate the amount of data and speed the computer processing involved, some of the electronics are placed in the transducer rather than processing the data in the machine console. The wireless system transmits the data over an 8 GHz ultrawideband radio frequency to the console. The amount of data and the bandwidth transmitted by the transducer is equal to about 10 4G smart phones working continuously.

Noiseless MRI

GE Healthcare introduced its 510(k)-pending noiseless MRI Silent Scan technology that it hopes to introduce in 2013 for its MR450W 1.5T system. The technology addresses one of the most significant impediments to patient comfort — excessive noise generated during the exam that can be in excess of 110 decibels. A combination of software and a pulse sequence lowers the noise level to that of a chirping bird outside a window.

Historically, acoustic noise mitigation techniques have focused on insulating components and muffling sound as opposed to treating the noise at the source. With Silent Scan, acoustic noise is essentially eliminated by employing a new advanced 3-D acquisition and reconstruction technique called Silenz, in combination with GE Healthcare’s proprietary design of the high-fidelity MR gradient and RF system electronics. Silent Scan is designed to eliminate the noise at its source.

640-Slice CT Scanner

Toshiba unveiled its 640-slice Aquilion One Vision edition CT scanner. The vendor already offers the highest-slice system on the market, the 320-slice Aquilion One. The new system is equipped with a gantry rotation of 0.275 seconds, a 100 kw generator and 320 detector rows (640 unique slices) covering 16 cm in a single rotation, with the industry’s thinnest slices at 500 microns (0.5 mm). The system can accommodate larger patients with its 78 cm bore and fast rotation, including bariatric and patients with high heart rates.

FFR-Like CT Culprit Vessel Analysis

TeraRecon released new research software in response to fractional flow reserve (FFR)-CT analysis being developed by HeartFlow. The HeartFlow software uses a supercomputing algorithm to look at the fluid dynamics of the iodine contrast flow in coronary vessels to calculate a virtual a FFR number, similar to invasive pressure wire based FFR in the cath lab. TeraRecon’s Lesion Specific Analysis software cannot calculate FFR, but uses the same principle of tracking contrast flow in the myocardium. It uses lobular decomposition to look at each vessel segment to determine the tissue it feeds to show areas of ischemia and the expected culprit vessel segment. It shows a color contrast level maps on a 3-D model of the heart and in a coronal view of the left ventricle. Automated detection boxes highlight suspected ischemic areas of interest and identifies the vessel responsible for supplying blood to the region.

Radiation Dose Monitoring

Radiation dose monitoring solutions have been shown at previous RSNAs, but were highlighted by several companies this year as several states began implementing requirements for radiology departments to record patient dose. Dose records will have the most application with CT systems, especially for longer duration, higher dose cardiac exams, and catheter based angiography. Angiography is becoming an increasing issue due to the longer duration of more complex transcatheter interventions.

Toshiba demonstrated a work-in-progress dose tracking software for its Infinix-i angiography system. It can be displayed on a screen in the cath lab to show the approximate radiation dose that has been delivered cumulatively to specific areas of a patient. It takes into consideration the amount of time, power setting used and orientation of the C-arm to show a color-coded map of radiation delivery projected on a human figure. The colors change in real time as X-ray imaging continues. It is designed to be a visual reminder to physicians about the dose the patient has received and that they may want to change the location of the C-arm.

Sectra demonstrated 510(k)-pending Dose Track software, which radiology or cardiology departments can use to track radiation dose by patient, machine, physician, technologist, procedure type and room. The system can be set up to create alerts if a reasonable amount of dose if exceeded for a particular exam, or if certain physicians or technologists are using higher than average doses.

OLED Displays

Flat panel display technology migrated from CRT screens to LCDs over the past decade. The next major innovation in display technology is OLED, which offers even smaller components, faster response time than LCD, and the ability to display quick motion with virtually no blur. Sony showed the new PVM-2551MD OLED medical-grade monitor, which incorporates technology to achieve pure black, faithful to the source signal. By providing superb color reproduction, especially for dark images, surgeons can observe very subtle details such as the faint color difference between various tissues and blood vessels.

Aesthetically Pleasing Cath Labs

Philips Healthcare displayed video of its recent install of the Ambient Experience in a cath lab. The system uses colored lighting, subtle room design details and projected image visual effects to calm patients and make procedure rooms look less clinical. The installation highlighted allowed doctors or patients to choose a theme, such as a tropical rainforest, where diffused, indirect lighting would take a green hue and a photo projection on the ceiling of a tropical scene. Philips said at facilities that have installed these type of labs, patient satisfaction rose, as did staff morale. They say doctors and staff compete to use these rooms at some facilities.

Single Detector Spectral CT Imaging

Philips introduced an innovative work-in-progress CT system that uses new detector technology to simplify spectral imaging, offering soft tissue image quality similar to MRI. Currently, CT special imaging can be performed using systems with two X-ray tubes and two detectors. The new system in development uses a single X-ray source and a single detector that has two layers of detectors, one on top of the other, for high and low energy.

Better Transcatheter Mitral Valve Repair Guidance

Philips’ showed its new Echo Navigator system, designed to synchronize views from TEE ultrasound with the orientation on live angiography. The primary application is to aid navigation during transcatheter mitral valve procedures, which require very accurate 3-D echo navigation to deploy devices like the Abbott MitraClip.

3-D Sculptures From 3-D Datasets

Taking 3-D images shown on 2-D display screens to a true physical 3-D form, Vidar Systems/3D Systems displayed the new Z Printer 450. It takes any 3-D advanced visualization dataset and can print the image in true 3-D using gypsum powder (the same material used to make drywall), standard color ink jet printer cartridges and a binding agent. The image is saved as an STL file and sent to the printer, which prints 1/10th of a millimeter each pass, up to 2 cm per hour.

The 3-D sculptures it created can be printed in color, eliminating the need to paint the models.

The printer offers a new way to create 3-D anatomical models for medical education, complex surgical planning and cosmetic reconstruction. Another application suggested at RSNA was to print sculptures for sale to the patients, such as fetal faces taken from 3-D obstetrics ultrasound exams.

The company printed a full-sized, 3-D, color heart during the show using a cardiac CT dataset on a thumb drive provided by one of the advanced visualization vendors in the same hall.

  • Siemens unveiled the world’s first wireless ultrasound transducer at RSNA 2012.

http://www.dicardiology.com/article/latest-cardiovascular-imaging-technology

REFERENCES

1. S. Desmond-Hellmann, Toward precision medicine: A new

social contract? Sci. Transl. Med. 4, ed3 (2012).

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G. S. Ginsburg, R. S. Herbst, S. J. Nass, C. M. Streeter, J. A.

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6. G. D. Prestwich, S. Bhatia, C. K. Breuer, S. L. Dahl, C. Mason,

R. McFarland, D. J. McQuillan, J. Sackner-Bernstein, J. Schox,

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challenge in the translation of biomaterials to the clinic?

Sci. Transl. Med. 4, 60cm14 (2012).

7. Between Invention and Innovation. NIST GRC 02-841;

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8. Justin D Pearlman, MD, ME, PhD, FACC, MA; Chief Editor: Eugene C Lin, MD

Imaging in Coronary Artery Disease, Nov 13, 2012

http://emedicine.medscape.com/article/349040-overview

9. Markus Schwaiger, MD; Sibylle Ziegler, PhD; and Stephan G. Nekolla, PhD

PET/CT: Challenge for Nuclear Cardiology

THE JOURNAL OF NUCLEAR MEDICINE • Vol. 46 • No. 10 • October 2005

 

Other articles related to this topic Published on this Open Access Online Scientific Journal include the following:

New Definition of MI Unveiled, Fractional Flow Reserve (FFR) CT for Tagging Ischemia

http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

FDA: Strengthening Our National System for Medical Device Post-market Surveillance

http://pharmaceuticalintelligence.com/2012/09/07/fda-strengthening-our-national-system-for-medical-device-post-market-surveillance/

Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice

http://pharmaceuticalintelligence.com/2012/07/31/gaps-tensions-and-conflicts-in-the-fda-approval-process-implications-for-clinical-practice/

To Stent or Not? A Critical Decision

http://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/

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Gender Gap in Research Misconduct: Scientific Fraud by Male – a 25 References-based Study

Posted in Scientist: Career considerations, Statistical Methods for Research Evaluation, tagged , , , , , on January 24, 2013| Leave a Comment »

 

Reporter: Aviva Lev-Ari, PhD, RN

The Men of Misconduct

January 24, 2013
After reviewing US Office of Research Integrity misconduct reports issued since 1994, the University of Washington‘s Ferric Fang, Joan Bennett at Rutgers University, and Arturo Casadevall from the Albert Einstein College of Medicine found that 88 percent of faculty members who committed fraud were male as were 69 percent of postdocs, 58 percent of students, and 42 percent of other research personnel, as they write in mBio.

Only nine of the 72 faculty members who committed research misconduct were female, which is “one-third of the number that would have been predicted from their overall representation among life sciences faculty,” the researchers write. They note, though, that they cannot rule out that women are less likely to get caught.

But what is behind this gender difference and why people committed research misconduct is unknown. Fang, Bennett, and Casadevall say that “while not excluding a role for biological factors, recent studies suggest an important contribution of social and cultural influences in the competitive tendencies of males and females” and note that “it is generally known that men are more likely to engage in risky behaviors than women.”

 SOURCE:
 

Males Are Overrepresented among Life Science Researchers Committing Scientific Misconduct

  1. Ferric C. Fanga,
  2. Joan W. Bennettb, and
  3. Arturo Casadevallc

+Author Affiliations

  1. Departments of Laboratory Medicine and Microbiology, University of Washington, School of Medicine, Seattle, Washington, USAa;
  2. Department of Plant Biology and Pathology, Rutgers University, New Brunswick, New Jersey, USAb;
  3. Departments of Microbiology & Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USAc
  1. Address correspondence to Ferric C. Fang, fcfang@u.washington.edu.
  1. Editor Françoise Dromer, Institut Pasteur

ABSTRACT

A review of the United States Office of Research Integrity annual reports identified 228 individuals who have committed misconduct, of which 94% involved fraud. Analysis of the data by career stage and gender revealed that misconduct occurred across the entire career spectrum from trainee to senior scientist and that two-thirds of the individuals found to have committed misconduct were male. This exceeds the overall proportion of males among life science trainees and faculty. These observations underscore the need for additional efforts to understand scientific misconduct and to ensure the responsible conduct of research.

IMPORTANCE As many of humanity’s greatest problems require scientific solutions, it is critical for the scientific enterprise to function optimally. Misconduct threatens the scientific enterprise by undermining trust in the validity of scientific findings. We have examined specific demographic characteristics of individuals found to have committed research misconduct in the life sciences. Our finding that misconduct occurs across all stages of career development suggests that attention to ethical aspects of the conduct of science should not be limited to those in training. The observation that males are overrepresented among those who commit misconduct implies a gender difference that needs to be better understood in any effort to promote research integrity.

OBSERVATION

With our colleague Grant Steen, two of us (F.F. and A.C.) recently studied all 2,047 retracted scientific articles indexed by PubMed as of 3 May 2012 (1). Unexpectedly, we found that misconduct is responsible for most retracted articles and that fraud or suspected fraud is the most common form of misconduct. Moreover, the incidence of retractions due to fraud is increasing, a trend that should be concerning to scientists and nonscientists alike. To devise effective strategies to reduce scientific misconduct, it will be essential to understand why scientists commit misconduct. However, deducing the motives for misconduct from the study of retractions alone is difficult, because retraction notices provide limited information, and many instances of misconduct do not result in retracted publications.

We therefore undertook an alternative approach by reviewing the findings of misconduct summarized in the annual reports of the U.S. Office of Research Integrity (ORI) (http://ori.hhs.gov/about-ori). The ORI is responsible for promoting the responsible conduct of research and overseeing the investigation of misconduct allegations relating to research supported by the Department of Health and Human Services. From 1994 to the present, the annual reports detail 228 individuals found by the ORI to have committed misconduct (2, 3). Fraud was involved in 215 (94%) of these cases. The total number of ORI investigations performed over this period is not known. However, data from the first ten years indicate that approximately one-half of ORI investigations conclude with a finding of misconduct (3). Although we expected most cases of misconduct to involve research trainees, we found that only 40% of instances of misconduct were attributed to a postdoctoral fellow (25%) or student (16%). Faculty members (32%) and other research personnel (28%) were responsible for the remaining instances of misconduct, and these included both junior and senior faculty members, research scientists, technicians, study coordinators, and interviewers.

We were able to determine the gender of the individual committing misconduct in all but a single case, and 149 (65%) were male. However, the gender predominance varied according to academic rank. An overwhelming 88% of faculty members committing misconduct were male, compared with 69% of postdocs, 58% of students, and 42% of other research personnel (Fig. 1). The male-female distribution of postdocs and students corresponds with the gender distribution of postdocs and students in science and engineering fields (4). However, nearly all instances of misconduct investigated by the ORI involved research in the life sciences, and the proportion of male trainees among those committing misconduct was greater than would be predicted from the gender distribution of life sciences trainees. Males also were substantially overrepresented among faculty committing misconduct in comparison to their proportion among science and engineering faculty overall, and the difference is even more pronounced for faculty in the life sciences (5). Of the 72 faculty members found to have committed misconduct, only 9 were female, or one-third of the number that would have been predicted from their overall representation among life sciences faculty. We cannot exclude the possibility that females commit research misconduct as frequently as males but are less likely to be detected.

FIG 1Gender distribution of scientists committing misconduct. The percentage of scientists sanctioned by the U.S. Office of Research Integrity who are male, stratified by rank, is compared with the percentage of males in the overall United States scientific workforce (error bars show standard deviations) (blue and green bars are from NSF data, 1999–2006 [4, 5]).

What motivates individuals to commit research misconduct? Does competition for prestige and resources disproportionately drive misconduct among male scientists? Are women more sensitive to the threat of sanctions? Is gender a correlate of integrity?

The disparity between the number of men and women in academic science fields has been considered to be evidence of biologically driven gender differences (6). Thus, it may be tempting to explain the preponderance of male fraud in terms of various evolutionary theories about Y chromosome-driven competitiveness and aggressiveness (7). For example, for more than a century the male baboon has been used to symbolize male aggression. However, stereotypes of male baboon aggression and dominance have been called into question by primatologists focusing on female social networks and competitive strategies (8). Deterministic theories based in biology have been facilely used to explain the persistent gender gap in wages and other measures in the labor market (discussed in reference 9). The pitfalls associated with such simplistic generalizations have been extensively dissected by scholars of gender in science (see, for example, references 10 and 11 and citations therein). While not excluding a role for biological factors, recent studies suggest an important contribution of social and cultural influences in the competitive tendencies of males and females (12).

Nevertheless, it is generally known that men are more likely to engage in risky behaviors than women (13) and that crime rates for men are higher than those for women. Sociologists have hypothesized that as the roles of men and women become more similar, so will their crime rates (14). There is evidence for this “convergence hypothesis” in terms of arrests for robbery, burglary, and motor vehicle theft but not for homicide (15). Similarly, while most studies show that male students cheat more frequently than female students, recent data suggest that within similar areas of study, the gender differences are small. Women majoring in engineering self-report cheating at rates comparable to those reported by men majoring in engineering (16). We did not observe a significant convergence in scientific misconduct by males and females reported by the ORI over time (Fig. 2), although the analysis was limited by the small sample size. Interestingly, we also failed to observe an overall increase in research misconduct in the ORI findings, in contrast to an increase in retractions for fraud observed in our earlier study (1), with the caveat that the present study focused on a much smaller and incompletely overlapping subset of cases.

FIG 2Gender distribution of scientists committing misconduct over time. The percentage of scientists sanctioned by the U.S. Office of Research Integrity who are male, female, or of unknown gender are shown for each reporting year. For the gender ratio in 1994–2002 (n = 120) compared with 2003–2012 (n= 108), χ2 =1.405 and P = 0.24 (calculated using the online tool athttp://www.quantpsy.org/chisq/chisq.htm).

The predominant economic system in science is “winner-take-all” (17, 18). Such a reward system has the benefit of promoting competition and the open communication of new discoveries but has many perverse effects on the scientific enterprise (19). The scientific misconduct among both male and female scientists observed in this study may well reflect a darker side of competition in science. That said, the preponderance of males committing research misconduct raises a number of interesting questions. The overrepresentation of males among scientists committing misconduct is evident, even against the backdrop of male overrepresentation among scientists, a disparity more pronounced at the highest academic ranks, a parallel with the so-called “leaky pipeline.” There are multiple factors contributing to the latter, and considerable attention has been paid to factors such as the unique challenges facing young female scientists balancing personal and career interests (20), as well as bias in hiring decisions by senior scientists, who are mostly male (21). It is quite possible that, in at least some cases, misconduct at high levels may contribute to attrition of woman from the senior ranks of academic researchers.

Our observations also raise the question of whether current efforts at ethics training are targeting the right individuals. The NIH currently mandates training in the responsible conduct of research for students and postdocs receiving support from training grants. However, these groups were responsible for only 40% of the misconduct documented in the ORI reports. The psychiatrist Donald Kornfeld has analyzed a subset of the ORI data (22) and observed “an intense fear of failure” in many trainees who committed misconduct, while some faculty members seemed to possess a “conviction that they could avoid detection.” This suggests that efforts to improve ethical conduct may also need to target faculty scientists, who in some cases are directly responsible for misconduct and in others may be unintentionally fostering a research environment in which trainees and other research personnel feel pressured to tailor results to meet expectations. Programs to help scientists become more effective mentors should be more widely implemented (23). The male predominance among senior scientists who commit misconduct also suggests that social expectations associated with gender may play a role in the likelihood of committing fraud and that the impact of culture and gender should be considered in ethics training. Curricula should become more sensitive to the heterogeneity of the target population because “one size does not fit all.”

The role of external influences on the scientific enterprise must not be ignored. With funding success rates at historically low levels, scientists are under enormous pressure to produce high-impact publications and obtain research grants. The importance of these influences is reflected in the burgeoning literature on research misconduct, including surveys that suggest that approximately 2% of scientists admit to having fabricated, falsified, or inappropriately modified results at least once (24). A substantial proportion of instances of faculty misconduct involve misrepresentation of data in publications (61%) and grant applications (72%); only 3% of faculty misconduct involved neither publications nor grant applications.

In summary, we emphasize two observations from this study: first, misconduct is distributed along the continuum from trainee to senior scientist. Second, men are overrepresented among scientists committing misconduct, with a skewed gender ratio being most pronounced for senior scientists. While we acknowledge that our observations were made from a relatively small database that focuses exclusively on research supported by the U.S. Department of Health and Human Services, we note that each case was extensively documented, and this case series may represent the most reliable information currently available. From our findings, new challenges are directed to the scientific community to maintain the integrity of the scientific enterprise. The occurrence of misconduct at every level of the scientific hierarchy indicates that misconduct is not a problem limited to trainees and requires careful attention to pressures placed on scientists during different stages of their careers. Male predominance is but another example of the scientific enterprise reflecting social and cultural contexts.

In closing, the vital importance of the ORI is acknowledged. Without public access to their investigations, it would have been impossible to carry out this study. All countries should have independent agencies with the authority and resources to ensure proper conduct of scientific research. Although our findings may cause concern regarding the scientific enterprise, recognition is a first step toward solving a problem. With so many of the world’s current challenges dependent on scientific solutions, science must look for new ways to ensure the responsible conduct of scientific research (25).

FOOTNOTES

  • Citation Fang FC, Bennett JW, Casadevall A. 2013. Males are overrepresented among life science researchers committing scientific misconduct. mBio 4(1):e00640-12. doi:10.1128/mBio.00640-12.
  • Received 31 December 2012
  • Accepted 7 January 2013
  • Published 22 January 2013
  • Copyright © 2013 Fang et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    SOURCE:

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The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cerebrovascular and Neurodegenerative Diseases, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, tagged , , , , , on January 3, 2013| 17 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Tool Identifies Risk in Stenting ACS Patients

By Todd Neale, Senior Staff Writer, MedPage Today

Published: November 19, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A new, easy-to-calculate risk score developed for patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) had better prognostic accuracy than other widely used risk scores, researchers found.

The ACUITY-PCI risk score includes six variables — insulin-treated diabetes, renal insufficiency, baseline cardiac biomarker elevation or ST-segment deviation, presence of a bifurcation lesion, small vessel/diffuse coronary artery disease, and extent of coronary artery disease, according to Gregg Stone, MD, of Columbia University Medical Center in New York City, and colleagues.

The 1-year rate of death or MI significantly increased from 5.3% in the lowest risk tertile to 9.1% in the middle tertile to 19% in the highest tertile (P<0.001), the researchers reported in the November issue of JACC: Cardiovascular Interventions.

Discrimination and calibration were greater with the ACUITY-PCI score than with other established scores.

“Although the TIMI and the GRACE scores have been shown to be valuable prognostic tools at the time of hospital admission for selecting pharmacological strategies and identifying those patients most likely to benefit from an invasive strategy, they have not been optimized for patients undergoing PCI and, thus, have relatively poor prognostic power to further risk stratify acute coronary syndrome patients undergoing PCI,” Stone and colleagues wrote.

“The ACUITY-PCI score is therefore intended to supplement the TIMI and GRACE scores when an invasive strategy has been undertaken and PCI is being considered.”

The researchers created the risk score using data from 1,692 patients enrolled in the angiographic substudy of the ACUITY trial, which was a comparison of heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin (Angiomax) plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone in patients with ACS undergoing an early invasive strategy. They then validated the score using another 846 patients from the same study.

Multivariate analysis revealed six variables that were significantly associated with 1-year mortality and MI and were included in the score. The researchers assigned points based on the strength of the predictor:

  • Insulin-treated diabetes (12 points)
  • Renal insufficiency (12 points)
  • Baseline cardiac biomarker elevation or ST-segment deviation (8 points)
  • Bifurcation lesion (4 points)
  • Small vessel/diffuse coronary artery disease (2 points)
  • Extent of coronary artery disease (1 point for each 10 mm of disease)

The C-statistic for the risk score — a measure of discrimination — was 0.67 in the derivation cohort and 0.70 in the validation cohort. In the validation cohort, the chi-square statistic for calibration was 6.2 and the index of separation was 0.44.

All of those values were better than those seen for four other established risk scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX. In addition, the net reclassification improvement with the new score ranged from 9% to 38% and the integrated discrimination index varied from 1.9% to 2.7%.

The researchers noted that the ACUITY-PCI score also was a good predictor of 1-year definite or probable stent thrombosis, with a C-statistic of 0.72.

In another study in the same journal, George Dangas, MD, PhD, of Mount Sinai Medical Center in New York City, and colleagues — including Stone — reported on the development of a risk score specifically for stent thrombosis in patients with ACS undergoing PCI.

The study included 6,139 patients from the HORIZONS-AMI and ACUITY trials, which included those with ST-segment elevation MI (STEMI) in the former trial and those with non-STEMI and unstable angina in the latter. The researchers used 4,093 patients for the derivation cohort and 2,046 for the validation cohort.

The risk score included 10 variables that were significantly associated with the risk of Academic Research Consortium-defined definite or probable stent thrombosis at 1 year:

  • Type of acute coronary syndrome (4 points for STEMI, 2 points for non-ST-segment elevation ACS with ST deviation, and 1 point for non-ST-segment elevation ACS without ST changes)
  • Current smoking (1 point)
  • Insulin-dependent diabetes (2 points)
  • Prior PCI (1 point)
  • Baseline platelet count (1 point for 250 to 400 K/µL and 2 points for more than 400 K/µL)
  • Absence of pre-PCI heparin therapy (1 point)
  • Aneurysmal/ulcerated lesion (2 points)
  • Baseline TIMI flow grade 0/1 (1 point)
  • Final TIMI flow grade less than 3 (1 point)
  • Number of treated vessels (1 point for two vessels and 2 points for three vessels)

Scores from 1 to 6 are considered low risk, 7 to 9 are intermediate risk, and 10 or higher are high risk.

The rates of stent thrombosis at 1 year were 1.36%, 3.06%, and 9.18% across the three risk tertiles in the derivation cohort (P<0.001 for trend), with a similar trend seen in the validation cohort.

The C-statistics were 0.67 in the derivation cohort and 0.66 in the validation cohort. Performance was comparable for events occurring both early (within the first 30 days) and late (from 1 month to 1 year).

“We believe that the development and initial validation of this stent thrombosis risk score can be a useful tool for both clinical practice and future clinical investigation (future analyses of trials or registries), as it can be a simple way to risk stratify patients immediately following a procedure,” Dangas and colleagues wrote. “The risk score could also be used in the informed consent process to better inform patients of their individual risk of stent thrombosis.”

But Ron Waksman, MD, and Israel Barbash, MD, of MedStar Washington Hospital Center in Washington, D.C., noted some limitations of the tool, including the pooling of different types of patients, the exclusion of important variables associated with stent thrombosis risk, and the use of mostly first-generation drug-eluting stents in the trials.

“It is imperative that the user of such a prediction tool be aware of its capabilities and performance, as well as its limitations, in various clinical scenarios,” they wrote in an accompanying editorial.

“A newly developed risk score for stent thrombosis should be robust and should be tested across broad study populations, stents, and antiplatelet regimens. A new model should also be validated in a setting different from the one in which it was derived,” they wrote. “Unfortunately, this is not the case with the newly proposed model.”

“Until such an encompassing tool is developed and validated,” they wrote, “one should rely on the known stent thrombosis risk factors and tailor an appropriate treatment for each patient.”

The ACUITY trial was funded by The Medicines Company and Nycomed.

Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, and The Medicines Company. His co-authors reported relationships with Abbott, Regado, Ortho McNeil, Janssen, Merck, Maya Medical, AstraZeneca, Sanofi/Bristol-Myers Squibb, Eli Lilly, and Daiichi Sankyo.

The HORIZONS-AMI trial was supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and The Medicines Company.

Dangas has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, The Medicines Company, sanofi-aventis, and Abbott Vascular. His co-authors reported relationships with sanofi-aventis, The Medicines Company, Abbott Vascular, Bristol-Myers Squibb, Cordis, AstraZeneca, Daiichi Sankyo, Eli Lilly, Maquet, Roche, Boehringer Ingelheim, Liposcience, Merck, Pozen, Gilead Sciences, WebMD, the NIH, Pfizer, Johnson & Johnson, Schering-Plough, Merck Sharpe and Dohme, GlaxoSmithKline, Regado Biosciences, Boston Scientific, and Bristol-Myers Squibb/Sanofi.

Waksman and Barbash reported that they had no conflicts of interest.

From the American Heart Association:

Primary source: JACC: Cardiovascular Interventions
Source reference:
Palmerini T, et al “A new score for risk stratification of patients with acute coronary syndromes undergoing percutaneous coronary intervention: the ACUITY-PCI (Acute Catheterization and Urgent Intervention Triage Strategy-Percutaneous Coronary Intervention) risk score” JACC Cardiovasc Interv 2012; 5: 1108-1116.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Dangas G, et al “Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes” JACC Cardiovasc Interv 2012; 5: 1097-1105.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Waksman R, Barbash I “The appropriate use of risk scores” JACC Cardiovasc Interv 2012; 5: 1106-1107.

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University. He is based atMedPage Today headquarters in Little Falls, N.J.

SOURCE:

http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/36010

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Big Data in Genomic Medicine

Posted in Bio Instrumentation in Experimental Life Sciences Research, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , on December 17, 2012| 9 Comments »

Reporter: Larry H Bernstein, MD, FCAP

Big Data in Genomic Medicine

Image Source: Created by Noam Steiner Tomer 7/31/2020

Pathologists May Be Healthcare’s Rock Stars of Big Data in Genomic Medicine’s ’Third Wave’

Published: December 17 2012

Pathologists are positioned to be the primary interpreters of big data as genomic medicine further evolves

Pathologists and clinical laboratory managers may be surprised to learn that at least one data scientist has proclaimed pathologists the real big data rock stars of healthcare. The reason has to do with the shift in focus of genomic medicine from therapeutics and presymptomatic disease assessment to big data analytics.

In a recent posting published at Forbes.com, data scientist Jim Golden heralded the pronouncement of Harvard pathologist Mark S. Boguski, M.D., Ph.D., FACM. He declared that “The time of the $1,000 genome meme is over!”

DNA Sequencing Systems and the $1,000 Genome

Golden has designed, built, and programmed DNA sequencing devices. He apprenticed under the Human Genome program and spent 15 years working towards the $1,000 genome. “I’m a believer,” he blogged. “[That’s] why I was so intrigued [by Boguski’s remarks].

Boguski is Associate Professor of Pathology at the Center for Biomedical Informatics at Harvard Medical School and the Department of Pathology at Beth Israel Deaconess Medical Center. It was in a presentation at a healthcare conference in Boston that Boguski pronounced that it is time for the $1,000 genome to go.

“Big data analytics” will be required for translational medicine to succeed in the Third Wave of Genetic Medicine. That’s the opinion of Mark S. Boguski, M.D., Ph.D., who is a pathologist-informatist at Harvard Medical School and Beth Israel Deaconess Medical Center. Boguski predicts that pathologists are positioned to become the “rock stars” of big data analytics. For pathologists and clinical laboratory administrators, that means that big computer power will become increasingly important for all medical laboratories. (Photo by Medicine20Congress.com.)

Both Golden and Boguski acknowledged the benefits generated by the race to the $1,000 genome. Competition to be first to achieve this milestone motivated scientists and engineers to swiftly drive down the cost of decoding DNA. The result was a series of advances in instrumentation, chemistry, and biology.

Pathologists and Big Data Analytics

“Our notions about how genome science and technology would improve health and healthcare have changed,” Boguski wrote in an editorial published at Future Medicine. He then noted that the focus has shifted to big data analytics.

In the editorial, Boguski described the phases of development of genomic medicine as “waves.” The first wave occurred during the mid- to late-1990s. It focused on single- nucleotide polymorphisms (SNP) and therapeutics.

Medical Laboratories Have Opportunity to Perform Presymptomatic Testing

The second wave focused on presymptomatic testing for disease risk assessment and Genome Wide Association Studies (GWAS). Researchers expected this data to help manage common diseases.

The first two waves of medical genomics were conducted largely by the pharmaceutical industry, as well as with  primary care and public health communities, according to Boguski. Considerable optimism accompanied each wave of medical genomics.

“Despite the earlier optimism, progress in improving human health has been modest and incremental, rather than paradigm-shifting,” noted Boguski, who wrote that,to date, only a handful of genome-derived drugs have reached the market. He further observed that products such as direct-to-consumer genomic testing have proved more educational and recreational than medical.

“Third Wave” of Genomic Medicine

It was rapid declines in the cost of next-generation DNA sequencing technologies that now has triggered the third wave of genomic medicine. Its focus is postsymptomatic genotyping for individualized and optimized disease management.

“This is where genomics is likely to bring the most direct and sustained impact on healthcare for several reasons,” stated Boguski. “Genomics technologies enable disease diagnosis of sufficient precision to drive both cost-effective [patient] management and better patient outcomes. Thus, they are an essential part of the prescription for disruptive healthcare reform.”

Boguski reiterated the case for the value of laboratory medicine. He stated the following critical—but often overlooked—points, each of which is familiar to pathologists and clinical laboratory managers:

1. Pathologist-directed, licensed clinical laboratory testing has a major effect on clinical decision-making.

2. Medical laboratory testing services account for only about 2% of healthcare expenditures in the United States.

3. Medical laboratory services strongly influence the remaining 98% of costs through the information they provide on the prevention, diagnosis, treatment, and management of disease.

Molecular Diagnostics Reaching Maturity for Clinical Laboratory Testing

“Genome analytics are just another technology in the evolution of molecular diagnostics,” Boguski declared in his editorial.

Read more: Pathologists May Be Healthcare’s Rock Stars of Big Data in Genomic Medicine’s ’Third Wave’ | Dark Daily http://www.darkdaily.com/pathologists-may-be-healthcare%e2%80%99s-rock-stars-of-big-data-in-genomic-medicines-third-wave-1217#ixzz2FL24IRAA

English: Created by Abizar Lakdawalla.

English: Created by Abizar Lakdawalla. (Photo credit: Wikipedia)

English: Workflow for DNA nanoball sequencing

English: Workflow for DNA nanoball sequencing (Photo credit: Wikipedia)

DNA sequence

DNA sequence (Photo credit: Wikipedia)

Big Data: water wordscape

Big Data: water wordscape (Photo credit: Marius B)

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Comment & Response

Right now the cost of the testing and the turnaround times are not favorable. It is going to take a decade or more for clinical labs to catch up. For some time it will be send out tests to Quest, LabCorp, and State or University lab consortia.

The power of the research technology is pushing this along, but for Personalized Medicine the testing should be coincident with the patient visit, and the best list of probable issues should be accessible on the report screen. The EHR industry is dominated by 2 companies that I see have no interest in meeting the needs of the physicians. The payback has to be on efficient workflow, accurate assessment of the record, and timely information. The focus for 25 years has been on billing structure. But even the revised billing codes (ICD10) can’t be less than 5 years out-of-date because of improvements in the knowledge base and improvements in applied math algorithms.

The medical record still may have information buried min a word heap, and the laboratory work is a go-to-you know where sheet with perhaps 15 variables on a page, with chemistry and hematology, immunology, blood bank, and microbiology on separate pages. The ability of the physician to fully digest the information with “errorless” discrimination is tested, and the stress imposed by the time for each patient compromises performance. There is work going on in moving proteomics along to a high throughput system for improved commercial viability, that was reported by Leigh Anderson a few years ago. The genomics is more difficult, but the genomics is partly moving to rapid micropanel tools.

In summary, there are 3 factors:

1. Automation and interpretation
2. Integration into the EHR in real time and usable by a physician.
3. The sorting out of the highest feature “predictors” and classifying them into clinically meaningful sets and subsets.

When this is done, then the next generation of recoding will be in demand.
The Automated Malnutrition Assessment
Gil David1, Larry Bernstein2, Ronald R. Coifman1

1Department of Mathematics, Program in Applied Mathematics,
Yale University, New Haven, CT 06510, USA,
2Triplex Consulting, Trumbull, CT 06611

Abstract

Introduction: We propose an automated nutritional assessment (ANA) algorithm that provides a method for malnutrition risk prediction with high accuracy and reliability.

Materials and Methods: The database used for this study is a file of 432 patients, where each patient is described by 4 laboratory parameters and 11 clinical parameters. A malnutrition risk assessment of low (1), moderate (2) or high (3) was assigned by a dietitian for each patient. An algorithm for data organization and classification via characteristic metrics is proposed. For each patient, the algorithm characterizes its unique profile and builds a characteristic metric to identify similar patients who are mapped into a classification.

Results: The algorithm assigned a malnutrition risk level for each patient based on different training sizes that were taken out of the data.

Our method resulted in an average error (distance between the automated score and the real score) of 0.386, 0.3507, 0.3454, 0.34 and 0.2907 for 10%, 30%, 50%, 70% and 90% training sizes, respectively.

Our method outperformed the compared method even when our method used a smaller training set then the compared method. In addition, we show that the laboratory parameters themselves are sufficient for the automated risk prediction and organize the patients into clusters that correspond to low, low-moderate, moderate, moderate-high and high risk areas.

Discussion: The problem of rapidly identifying risk and severity of malnutrition is crucial for minimizing medical and surgical complications. These are not easily performed or adequately expedited. We characterize for each patient a unique profile and map similar patients into a classification. We also find that the laboratory parameters themselves are sufficient for the automated risk prediction.

Keywords: Network Algorithm, unsupervised classification, malnutrition screening, protein energy malnutrition (PEM), malnutrition risk, characteristic metric, characteristic profile, data characterization, non-linear differential diagnosis.

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15 Novel Risk Loci for Coronary Artery Disease: found by International Consortium

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics, Resident-cell-based, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , , on December 3, 2012| 3 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

International Consortium Finds 15 Novel Risk Loci for Coronary Artery Disease

“lipid metabolism and inflammation as key biological pathways involved in the genetic pathogenesis of CAD”

Themistocles Assimes from Stanford University Medical Center said in a statement that these findings begin to clear up its role. “Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause,” he said.

On this Open Access Online Scientific Journal, lipid metabolism and inflammation were researched and exposed in the following entries.

However, it is ONLY,  these 15 Novel Risk Loci for Coronary Artery Disease published on 12/3/2012 that provides the genomics loci and the genetic explanation for the following empirical results obtained in the recent research on Cardiovascular diseases, as present in the second half of this post, below.

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

http://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

What is the role of plasma viscosity in hemostasis and vascular disease risk?

http://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

http://pharmaceuticalintelligence.com/2012/11/28/pik3ca-mutation-in-colorectal-cancer-may-serve-as-a-predictive-molecular-biomarker-for-adjuvant-aspirin-therapy/

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

http://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

http://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

http://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy

http://pharmaceuticalintelligence.com/2012/11/26/the-essential-role-of-nitric-oxide-and-therapeutic-no-donor-targets-in-renal-pharmacotherapy/

Nitric Oxide Function in Coagulation

http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/Nitric Oxide Function in Coagulation

15 Novel Risk Loci for Coronary Artery Disease

December 03, 2012

NEW YORK (GenomeWeb News) – A large-scale association analysis of coronary artery disease has detected 15 new loci associated with risk of the disease, bringing the total number of known risk alleles to 46. As the international CARDIoGRAMplusC4D Consortium reported in Nature Genetics yesterday, the study also found that lipid metabolism and inflammation pathways may play a part in coronary artery disease pathogenesis.

“The number of genetic variations that contribute to heart disease continues to grow with the publication of each new study,” Peter Weissberg from the British Heart Foundation, a co-sponsor of the study, said in a statement. “This latest research further confirms that blood lipids and inflammation are at the heart of the development of atherosclerosis, the process that leads to heart attacks and strokes.”

For its study, the consortium, which was comprised of more than 180 researchers, performed a meta-analysis of data from the 22,233 cases and 64,762 controls of the CARDIoGRAM genome-wide association study and of the 41,513 cases and 65,919 controls from 34 additional studies of people of European and South Asian descent. Using the custom Metabochip array from Illumina, the team tested SNPs for disease association in those populations. The SNPs that reached significance in that stage of the study were then replicated using data from a further four studies.

From this, the team identified 15 new loci with genome-wide significance for risk of coronary artery disease, in addition to known risk loci.

The consortium also reported an additional 104 SNPs that appeared to be associated with coronary artery disease but did not meet the cut-off for genome-wide significance.

Then looking to other known risk factors for coronary artery disease, like blood pressure and diabetes, the researchers assessed whether any of those risk factors were associated with the risk loci. Of the 45 known risk loci, 12 were associated with blood lipid content and five with blood pressure. And while people with type 2 diabetes have a higher risk of developing coronary artery disease, none of the known risk loci were linked to diabetic traits.

An analysis of the pathways that SNPs linked to coronary artery disease fall in revealed that many of them are involved in lipid metabolism and inflammation pathways — 10 risk loci were found to be involved in lipid metabolism. “Our network analysis identified lipid metabolism and inflammation as key biological pathways involved in the genetic pathogenesis of CAD,” the researchers wrote in the paper. “Indeed, there was significant crosstalk between the lipid metabolism and inflammation pathways identified.”

The role of inflammation in coronary artery disease has been up for debate — a debate centering on whether it is a cause or a consequence of the disease — and study author Themistocles Assimes from Stanford University Medical Center said in a statement that these findings begin to clear up its role. “Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause,” he said.

Related Stories

SOURCE:

http://www.genomeweb.com//node/1159041?hq_e=el&hq_m=1424172&hq_l=3&hq_v=09187c3305

 

GWAS, Meta-Analyses Uncover New Coronary Artery Disease Risk Loci

March 07, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Three new studies — including the largest meta-analysis yet of coronary artery disease — have identified dozens of coronary artery disease risk loci in European, South Asian, and Han Chinese populations. All three papers appeared online yesterday in Nature Genetics.

For the first meta-analysis, members of a large international consortium known as the Coronary Artery Disease Genome-wide Replication and Meta-Analysis study, or CARDIoGRAM, sifted through data on more than 135,000 individuals from the UK, US, Europe, Iceland, and Canada. In so doing, they tracked down nearly two-dozen new and previously reported coronary artery disease risk loci.

Because only a few of these loci have been linked to other heart disease-related risk factors such as high blood pressure, those involved say the work points to yet unexplored heart disease pathways.

“[W]e have discovered several new genes not previously known to be involved in the development of coronary heart disease, which is the main cause of heart attacks,” co-corresponding author Nilesh Samani, a cardiology researcher affiliated with the University of Leicester and Glenfield Hospital, said in a statement. “Understanding how these genes work, which is the next step, will vastly improve our knowledge of how the disease develops, and could ultimately help to develop new treatments.”

Samani and his co-workers identified the loci by bringing together data on 22,233 individuals with coronary artery disease and 64,762 unaffected controls. The participants, all of European descent, had been sampled through 14 previous genome-wide association studies and genotyped at an average of about 2.5 million SNPs each. The team then assessed the top candidate SNPs found in this initial analysis in another 56,582 individuals (roughly half of whom had coronary artery disease).

The search not only confirmed associations between coronary artery disease and 10 known loci, but also uncovered associations with 13 other loci. All but three of these were distinct from loci previously implicated in other heart disease risk factors such as hypertension or cholesterol levels, researchers noted.

Consequently, those involved in the study say that exploring the biological functions of the newly detected genes could offer biological clues about how heart disease develops — along with strategies for preventing and treating it.

The genetic complexity of coronary artery disease being revealed by such studies has diagnostic implications as well, according to some.

“Each new gene identified brings us a small step closer to understanding the biological mechanisms of cardiovascular disease development and potential new treatments,” British Heart Foundation Medical Director Peter Weissberg, who was not directly involved in the new studies, said in a statement. “However, as the number of genes grows, it takes us further away from the likelihood that a simple genetic test will identify those most of risk of suffering a heart attack or a stroke.”

Meanwhile, researchers involved with Coronary Artery Disease Genetics Consortium did their own meta-analysis using data collected from four GWAS to find five coronary artery-associated loci in European and South Asian populations.

The group initially looked at 15,420 individuals with coronary artery disease — including 6,996 individuals from South Asia and 8,424 from Europe — and 15,062 unaffected controls. Participants were genotyped at nearly 575,000 SNPs using Illumina BeadChips. Most South Asian individuals tested came from India and Pakistan, researchers noted, while European samples came from the UK, Italy, Sweden, and Germany.

For the validation phase of the study, the team focused in on 59 SNPs at 50 loci from the discovery group that seemed most likely to yield authentic new disease associations. These variants were assessed in 10 replication groups comprised of 21,408 individuals with coronary artery disease and 19,185 individuals without coronary artery disease.

All told, researchers found five loci that seem to influence coronary artery disease risk in the European and South Asian populations: one locus each on chromosomes 7, 11, and 15, along with a pair of loci on chromosome 10.

The team didn’t see significant differences in the frequency or effect sizes of these newly identified variants between the European and South Asian populations, though they emphasized that their approach may have missed some potential risk variants, particularly in those of South Asian descent.

“[C]urrent genome-wide arrays may not capture all important variants in South Asians,” they explained, “Nevertheless, all of the known and new variants were significantly associated with [coronary artery disease] risk in both the European and South Asian populations in the current study, indicating the importance of genes associated with [coronary artery disease] beyond the European ancestry groups in which they were first defined.”

Finally, using a three-stage discovery, validation, and replication GWAS approach, Chinese researchers identified a single coronary artery disease risk variant in the Han Chinese population.

In this first phase of that study, researchers tested samples from 230 cases and 230 controls from populations in Beijing and in China’s Hubei province that were genotyped at Genentech and CapitalBio using Affymetrix Human SNP5.0 arrays.

From the nearly three-dozen SNPs identified in the first stage of the study, they narrowed in on nine suspect variants. After finding linkage disequilibrium between two of the variants, they did validation testing on eight of these in 572 individuals with coronary artery disease and 436 unaffected controls, all from Hubei province.

That analysis implicated a single chromosome 6 SNP called rs6903956 in coronary artery disease — a finding the team ultimately replicated in another group of 2,668 coronary artery disease cases and 3,917 controls from three independent populations in Hubei, Shandong province, and northern China.

The team’s subsequent experiments suggest that the newly detected polymorphism, which falls within a putative gene called C6orf105 on chromosome 6, curbs the expression of this gene. The functional consequences of this shift in expression, if any, are yet to be determined.

Because C6orf105 shares some identity and homology with an androgen hormone inducible gene known as AIG1, those involved in the study argue that it may be worthwhile to investigate possible ties between C6orf105 expression, androgen signaling, and coronary artery disease.

“Androgen has previously been reported to be associated the pathogenesis of atherosclerosis,” they wrote. “Future studies are needed to explore whether C6orf105 expression can be induced by androgen and to further determine the potential mechanism of [coronary artery disease] associated with decreased C6orf105 expression.”

 SOURCE:

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Computational Genomics Center: New Unification of Computational Technologies at Stanford

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Scientist: Career considerations, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , on December 3, 2012| 3 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Computational Genomics Center: New Unification of Computational Technologies at Stanford

Word Cloud by Zach Day

Stanford Launches Computational Genomics Center

December 03, 2012

NEW YORK (GenomeWeb News) – Stanford University has launched a new genomics research center that will foster collaboration across its seven schools and harness new computational technologies, it said today.

The Stanford Center for Computational, Evolutionary and Human Genomics, headed by the university’s School of Medicine and School of Humanities and Sciences, has been authorized for five years of funding, the university said.

Created with the goal of spurring and nurturing cross-cutting research collaborations, the new center will be open to all university faculty and labs. It will provide support for small project grants and computational genomics analysis services for member labs, faculty, students, and staff.

The center also will consult with academic institutions, industry, government, and research organizations on collaborations, will support graduate and postdoctoral students, and in its first year will launch public outreach programs in three areas – genomics and social systems, medical genomics, and agricultural, ecological, and environmental genomics. The center’s focus, regardless of the particulars of the project at hand, will be on using expertise and methods for sorting through, integrating, and analyzing large-scale data sets.

Stanford Professor Carlos Bustamante, who also is one of the center’s two founding directors, told GenomeWeb Daily News today that the university has not yet set the funding amount for the center but has committed to five years and will be “sufficient to catalyze all of the programs that we want to get started.” Ultimately, the center will seek funding from beyond the university, he noted.

“The incredible thing about a place like Stanford is that we’ve got the medical school co-located with the main campus, the traditional arts and sciences and humanities programs, and an exceptional engineering school, so we really are looking to create interdisciplinary programs that cut across traditional academic boundaries,” Bustamante said.

He explained that the new center will pursue and support projects that cut a broad swath across Stanford’s academic research areas, including paleo-anthropology, population genetics, agriculture, climate science, and biomedicine, as well as pursue bioethical questions that have arisen alongside human genomic science.

For example, Bustamante said, the research may involve integrating genetics and history studies.

“How can we use technologies from genomics to improve our understanding of the great human diaspora? That’s an area that [Founding Director and Stanford Biology Professor] Mark Feldman and I have been interested in for years.

“But now we can begin to do things that are cross-cutting in, say, funding archaeology students that want to study ancient DNA, or beginning to do projects that have to do with race, genetics, and ethnicity,” he said. “Now we can fund graduate students and post-docs to really work on interdisciplinary issues that are very hard to fund through traditional mechanisms.”

Bustamante pointed out that Stanford has “a tremendous amount of expertise in machine learning and statistical learning,” and the center will try to bring people and projects together with clinicians who are pursuing cutting-edge projects in a wide array of fields, such as cancer genomics.

“Traditionally, these people would know about each other but they haven’t necessarily had the mechanisms to initiative [joint] pilot projects and collaborations,” Bustamante said, and that is where the new center might fit in.

One of the key aims of the center also is to forge collaborations between biomedical researchers with those in the humanities and social sciences.

For example, one of the center’s executive committee members, Stanford Biology Professor Noah Rosenberg, is co-directing a program focused on Jewish genetics and Jewish history. Another executive member, Professor Dmitri Petrov, will head a year-long project focused on ecological genetics.

Bustamante, who previously was a researcher at Cornell University, said he expects that the center will branch out into agricultural genomics as well.

“Genomics is transforming agriculture. It is probably where genomics is having some of its biggest impacts,” he said.

Aside from the wide range of research areas that the new center may support, it will have one core mission, Bustamante told GWDN.

“It really is, first and foremost, a center focused on computational analysis, both in terms of developing methods and computing on big data. That is a particular expertise of those of us involved in launching the center.”

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Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Liver & Digestive Diseases Research, Metabolomics, Origins of Cardiovascular Disease, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , , on November 15, 2012| 10 Comments »

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Reporter: Aviva Lev-Ari, PhD, RN

Updated 3/5/2013

Genetic Associations with Valvular Calcification and Aortic Stenosis

N Engl J Med 2013; 368:503-512

February 7, 2013DOI: 10.1056/NEJMoa1109034

METHODS

We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.

CONCLUSIONS

Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

SOURCE:

N Engl J Med 2013; 368:503-512

HDL is more than an eNOS Agonist

 In addition to the modulation of NO production by signaling events that rapidly dictate the level of enzymatic activity, important control of eNOS involves changes in the abundance of the enzyme. In a clinical trial by the Karas laboratory of niacin therapy in patients with low HDL levels (nine males and two females), flow-mediated dilation of the brachial artery was improved in association with a rise in HDL of 33% over 3 months (Kuvin et al., 2002).

Am. Heart J., 144:165–172.

They also demonstrated that eNOS expression in cultured human endothelial cells is increased by HDL exposure for 24 hours. They further showed that the increase in eNOS is related to an increase in the half-life of the protein, and that this is mediated by PI3K–Akt kinase and MAPK (Ramet et al., 2003).

J. Am. Coll. Cardiol., 41:2288–2297.

Thus, the same mechanisms that underlie the acute activation of eNOS by HDL appear to be operative in upregulating the expression of the enzyme.

The current understanding of the mechanism by which HDL enhances endothelial NO production is summarized in Shaul & Mineo (2004), Figure 1.

J Clin Invest., 15; 113(4): 509–513.

It describes the mechanism of action for HDL enhancement of NO production by eNOS in vascular endothelium.

(a)   HDL causes membrane-initiated signaling, which stimulates eNOS activity. The eNOS protein is localized in cholesterol-enriched (orange circles) plasma membrane caveolae as a result of the myristoylation and palmitoylation of the protein. Binding of HDL to SR-BI via apoAI causes rapid activation of the nonreceptor tyrosine kinase src, leading to PI3K activation and downstream activation of Akt kinase and MAPK. Akt enhances eNOS activity by phosphorylation, and independent MAPK-mediated processes are additionally required (Duarte, et al., 1997). Eur J Pharmacol, 338:25–33.

HDL also causes an increase in intracellular Ca2+ concentration (intracellular Ca2+ store shown in blue; Ca2+ channel shown in pink), which enhances binding of calmodulin (CM) to eNOS. HDL-induced signaling is mediated at least partially by the HDL-associated lysophospholipids SPC, S1P, and LSF acting through the G protein–coupled lysophospholipid receptor S1P3. HDL-associated estradiol (E2) may also activate signaling by binding to plasma membrane–associated estrogen receptors (ERs), which are also G protein coupled. It remains to be determined if signaling events are also directly mediated by SR-BI (Yuhanna et al., 2001), (Nofer et al., 2004), (Gong et al., 2003), (Mineo et al., 2003).

Nat. Med., 7:853–857.

J. Clin. Invest.,113:569–581.

J. Clin. Invest., 111:1579–1587.

J. Biol. Chem., 278:9142–9149.

(b)   HDL regulates eNOS abundance and subcellular distribution. In addition to modulating the acute response, the activation of the PI3K–Akt kinase pathway and MAPK by HDL upregulates eNOS expression (open arrows). HDL also regulates the lipid environment in caveolae (dashed arrows). Oxidized LDL (OxLDL) can serve as a cholesterol acceptor (orange circles), thereby disrupting caveolae and eNOS function. However, in the presence of OxLDL, HDL maintains the total cholesterol content of caveolae by the provision of cholesterol ester (blue circles), resulting in preservation of the eNOS signaling module (Ramet et al., 2003), (Blair et al., 1999), (Uittenbogaard et al., 2000).

J. Am. Coll. Cardiol., 41:2288–2297.

J. Biol. Chem., 274:32512–32519.

J. Biol. Chem., 275:11278–11283.

SOURCE:

Shaul, PW and Mineo, C, (2004). HDL action on the vascular wall: is the answer NO? J Clin Invest., 15; 113(4): 509–513.

Are Additional Lipid Measures Useful?

Ryan D. Bradley, ND; and Erica B. Oberg, ND, MPH

http://www.imjournal.com/resources/web_pdfs/recent/1208_bradley.pdf

Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are the well-established standards by which clinicians identify individuals at risk for coronary artery disease (CAD), yet nearly 50% of people who have a myocardial infarction have normal cholesterol levels. Measurement of additional biomarkers may be useful to more fully stratify patients according to disease risk. The typical lipid panel includes TC, LDL-C, high-density lipoprotein cholesterol  (HDL-C), and triglycerides (TGs). Emerging biomarkers for cardiovascular risk include measures of LDL-C pattern, size,  and density; LDL particle number; lipoprotein(a); apolipoproteins  (apoA1 and apoB100 being the most useful);  C-reactive protein; and lipoprotein-associated phospholipase

Some of these emerging biomarkers have been proven to add to, or be more accurate than, traditional risk factors in predicting coronary artery disease and, thus, may be useful for clinical decision-making in high-risk patients and in patients with borderline traditional risk factors.  However, we still believe that until treatment strategies can uniquely address these added risk factors—ie, until protocols to rectify unhealthy findings are shown to improve cardiovascular outcomes—healthcare providers should continue to focus primarily on helping patients reach optimal LDL-C, HDL-C, and TG levels

Table 1. Traditional Lipid Panel and Recommended Treatment

Goals for Cardiovascular Disease Prevention34

  • Total Cholesterol Desirable (low) < 200 mg/dL
  • Borderline high 200-239 mg/dL
  • High 240 mg/dL or greater
  • HDL Cholesterol Desirable (high) > 60 mg/dL
  • Acceptable 40-60 mg/dL
  • Low < 40 mg/dL
  • LDL Cholesterol Desirable (low) < 100 mg/dL
  • Acceptable 100-129 mg/dL
  • Borderline high 130-159 mg/dL
  • High 160-189 mg/dL
  • Very high 190 mg/dL or greater
  • Triglycerides Desirable (low) < 150 mg/dL
  • Borderline high 150-199 mg/dL
  • High 200-499 mg/dL
  • Very high 500 mg/dL or greater

LDL-C and HDL-C: Pattern, Size, and Density

Two patterns predominate and are used to describe the average size of LDL particles. Pattern A refers to a preponderance of large LDL particles, while Pattern B refers to a preponderance of small LDL particles; a minority of individuals displays an intermediate or mixed pattern. Some commercially available assays further subdivide LDL-C into 7 distinct designations based on particle size.9,10

LDL Lipoprotein Particle Number

LDL particle number (LDL-P) is a measure of the number of lipoprotein particles independent of the quantity of lipid within the cholesterol particle; ie, LDL-P measures the number of individual particles, not a concentration like LDL-C. It is measured using nuclear magnetic resonance technology and is unaffected by fasting status.21 Higher LDL-P measures have been associated with a higher risk of CAD. This might simply be because there are more particles susceptible to oxidation in circulation.

There are suggestions, but not definitive proof, that reducing LDL-P increases intra-LDL antioxidant capacity.  The European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, a study that has followed 25 663 participants  (men and women aged 45-79 years) over 6 years, evaluated associations between LDL-P and risk of CAD. Compared to controls,  cases of CAD had a higher number of LDL particles (LDL-P P<.0001), smaller average LDL-particle size (P=.002), and higher concentrations of small LDL particles (P<.0001).22

Once again,  small, dense LDL-C were positively associated with TG and negatively associated with HDL.  In another study investigating incident angina and MI with LDL-P, females, but not males, had a significantly increased odds ratio for incident MI and angina for higher LDL-P—but not for LDL size—after adjustment for LDL, age, and race.  Males had increased (but not significant) point estimates showing the same relationship.23 Of note, LDL-P and non-HDL-C (ie,  TC minus HDL-C, or, specifically, LDL-C plus VLDLs), added equivalently to Framingham-predicted CAD risk stratification, thus reducing our enthusiasm for this additional measurement when TC and HDL-C are routinely available.22 Based on these results, LDL-P is becoming recognized as a more-precise measure of LDL-related risk and, as it becomes more available, is likely to replace LDL-C in risk-stratification tools. Clinical availability is currently limited; however, Medicare recently began reimbursing for regular testing of LDL-P in highrisk patients, so we should see availability increase soon. There are no novel treatments based on LDL-P at this time, and data shows therapies that lower LDL-C lower LDL-P as well.

 Apolipoproteins

Apolipoproteins are the protein components of plasma lipoproteins. Several different apolipoproteins have been identified and numbered; however, apoB48, apoB100, and apoA are the most commonly referenced.  ApoB48 is associated with LDL particles that transport dietary cholesterol to the liver for processing. ApoB100 is found in lipoproteins originating from the liver (eg, LDL and VLDL); it transports these lipoproteins and, also, TGs to the periphery. In addition, ApoB100 is involved with the binding of LDL particles to the vascular wall, implicating itself as a key player in the development of atherogenic plaques. Importantly, there is one apoB100 molecule per hepatic-derived lipoprotein. Hence, it is possible to quantify the number of LDL/VLDL particles by noting the total apoB100 concentration.

Measurement of apoB100 has been shown in nearly all studies to outperform LDL-C and non-HDL-C as a predictor of CAD events and as an index of residual CAD risk, perhaps due to differences in measurement sensitivity between measurement methodologies. Direct measurement of apolipoproteins is superior to calculated lipid measurements. Yet, currently, apoB100 measurement is more costly than routine measurements and,  because apoB100 is so closely associated with non-HDL-C (which,  as mentioned previously, can be estimated by TC minus HDL-C),  our enthusiasm for the clinical use of this test is limited.24 For its part, apoA is associated with HDL particles; the 2 major proteins in HDL are apoAI and apoAII. Of these, apoAI has more frequently been used to estimate HDL-C, but, in contrast to apoB100, apoAI is not unique to HDL and so the ratio of apoAI to HDL is not 1 to 1.24

Lipoprotein(a)

Lipoprotein(a)—Lp(a)—is attached to apoB. The association of Lp(a) with CAD and its ability to act as a biomarker of risk appears to be strongest in patients with hypercholesterolemia and, in particular, in young patients with premature atherosclerosis (males younger than 55 and females younger than 65). Part of the reason for this is the observation that there seem to be important threshold effects such that only very high Lp(a) levels (> 30 mg/dL) are associated with elevated vascular risk; in this regard, these increased plasma levels of Lp(a) independently predict the presence of CAD, particularly in patients with elevated LDL-C levels.28

In the Cardiovascular Health Study, a relative risk of approximately 3-fold for death from vascular events and stroke was seen in the highest quintile compared to the lowest quintile of Lp(a) but for males only, whereas no such relation existed for women.29 Lp(a) is commonly considered a marker for familial hypercholesterolemia. Lp(a) may best be used in assessing the risk of younger males with strong family histories of CVD but  should not be used more generally.

Risk Factors for Cardiovascular Disease

(Exclusive of LDL Cholesterol)34

  • Cigarette smoking
  • Hypertension (BP > 140/90 mmHg or on antihypertensive medication)
  • Low HDL cholesterol (< 40 mg/dL)
  • Family history of premature CHD (CHD in first-degree male relative <
  • 55 years; CHD in first-degree female relative < 65 years)
  • Age (men > 44 years; women > 54 years

In addition,

  • Clinical coronary heart disease,
  • symptomatic carotid artery disease,
  • peripheral arterial disease, or
  • abdominal aortic aneurysm

Conclusion

In the United States, treatment guidelines for high CVD risk factors are set by the National Cholesterol Education Program (NCEP) Expert Panel, which developed the third report of the Adult Treatment Panel (ATPIII).34 Treatment goals are determined according to risk stratification by LDL-C and by known additional risk factors such as smoking, low HDL, hypertension,  family history, and age. Yet, clinically, decision-making is always more complex than this. Additional risk stratification can be accomplished by measuring the biomarkers discussed above, and this may potentially provide additive benefit beyond NCEP guidelines. However, we always encourage clinicians to treat known risks to goal levels before adding additional goals for treatment. In a future article we will provide further detail on treatment options for novel biomarkers.

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2. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood

biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol.

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3. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol,

and regression of coronary atherosclerosis. JAMA. 2007;297(5):499-508.

4. Hausenloy DJ, Yellon DM. Targeting residual cardiovascular risk: raising high-density

lipoprotein cholesterol levels. JAMA. 2007;297(5):499-508.

5. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with

nonfasting triglycerides and risk of cardiovascular events in women. JAMA.

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6. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides

and risk of myocardial infarction, ischemic heart disease, and death in men and

women. JAMA. 2007;298(3):299-308.

7. Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, lowdensity

lipoprotein particle diameter, and risk of myocardial infarction. JAMA.

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8. Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes

mellitus. Diabetes Metab Res Rev. 2000;16(2):125-132.

9. Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in artherosclerosis.

Circulation. 2004;109(23 Suppl 1):III2-III7.

10. Dormans TP, Swinkels DW, de Graaf J, Hendriks JC, Stalenhoef AF, Demacker PN.

Single-spin density-gradient ultracentrifugation vs gradient gel electrophoresis: two

methods for detecting low-density-lipoprotein heterogeneity compared. Clin Chem.

1991;37(6):853-858.

11. Roheim PS, Asztalos BF. Clinical significance of lipoprotein size and risk for coronary

atherosclerosis. Clin Chem. 1995;41(1):147-152.

12. Swinkels DW, Demacker PN, Hendriks JC, van ‘t Laar A. Low density lipoprotein

subfractions and relationship to other risk factors for coronary artery disease in

healthy individuals. Arteriosclerosis. 1989;9(5):604-613.

13. Tan CE, Chew LS, Chio LF, et al. Cardiovascular risk factors and LDL subfraction

profile in Type 2 diabetes mellitus subjects with good glycaemic control. Diabetes Res

Clin Pract. 2001;51(2):107-114.

14. Lamarche B, Tchernof A, Mauriège P, et al. Fasting insulin and apolipoprotein B levels

and low-density lipoprotein particle size as risk factors for ischemic heart disease.

JAMA. 1998;279(24):1955-1961.

15. St-Pierre AC, Ruel IL, Cantin B, et al. Comparison of various electrophoretic characteristics

of LDL particles and their relationship to the risk of ischemic heart disease.

Circulation. 2001;104(19):2295-2299.

16. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and

carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA).

Atherosclerosis. 2007;192(1):211-217.

17. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target:

a systematic review. JAMA. 2007;298(7):786-798.

18. Lewis GF. Determinants of plasma HDL concentrations and reverse cholesterol

transport. Curr Opin Cardiol. 2006;21(4):345-352.

19. Kontush A, de Faria EC, Chantepie S, Chapman MJ. A normotriglyceridemic, low

HDL-cholesterol phenotype is characterised by elevated oxidative stress and HDL

particles with attenuated antioxidative activity. Atherosclerosis. 2005;182(2):277-285.

20. Nobécourt E, Jacqueminet S, Hansel B, et al. Defective antioxidative activity of small

dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and

hyperglycaemia. Diabetologia. 2005;48(3):529-538.

21. Dungan KM, Guster T, DeWalt DA, Buse JB. A comparison of lipid and lipoprotein

measurements in the fasting and nonfasting states in patients with type 2 diabetes.

Curr Med Res Opin. 2007;23(11):2689-2695.

22. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein

particle number and size as predictors of coronary artery disease in apparently

healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll

Cardiol. 2007;49(5):547-553.

23. Kuller L, Arnold A, Tracy R, et al. Nuclear magnetic resonance spectroscopy of lipoproteins

and risk of coronary heart disease in the cardiovascular health study.

Arterioscler Thromb Vasc Biol. 2002;22(7):1175-1180.

24. Olofsson SO, Wiklund O, Borén J. Apolipoproteins A-I and B: biosynthesis, role in

the development of atherosclerosis and targets for intervention against cardiovascular

disease. Vasc Health Risk Manag. 2007;3(4):491-502.

25. Walldius G, Jungner I. Is there a better marker of cardiovascular risk than LDL cholesterol?

Apolipoproteins B and A-I—new risk factors and targets for therapy. Nutr

Metab Cardiovasc Dis. 2007;17(8):565-571.

26. Anand SS, Islam S, Rosengren A, et al. Risk factors for myocardial infarction in

women and men: insights from the INTERHEART study. Eur Heart J.

2008;29(7):932-940.

27. McQueen MJ, Hawken S, Wang X, et al. Lipids, lipoproteins, and apolipoproteins as

risk markers of myocardial infarction in 52 countries (the INTERHEART study): a

case-control study. Lancet. 2008;372(9634):224-233.

28. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Metaanalysis

of prospective studies. Circulation. 2000;102(10):1082-1085.

29. Ariyo AA, Thach C, Tracy R; Cardiovascular Health Study Investigators. Lp(a) lipoprotein,

vascular disease, and mortality in the elderly. N Engl J Med.

2003;349(22):2108-2115.

30. Retterstol L, Eikvar L, Bohn M, Bakken A, Erikssen J, Berg K. C-reactive protein predicts

death in patients with previous premature myocardial infarction—a 10 year

follow-up study. Atherosclerosis. 2002;160(2):433-440.

31. Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-

associated phospholipase A2 activity, and 10-year cardiovascular outcomes:

prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol.

2007;27(8):1788-1795.

32. Kolko M, Rodriguez de Turco EB, Diemer NH, Bazan NG. Neuronal damage by

secretory phospholipase A2: modulation by cytosolic phospholipase A2, plateletactivating

factor, and cyclooxygenase-2 in neuronal cells in culture. Neurosci Lett.

2003;338(2):164-168.

33. Robins SJ, Collins D, Nelson JJ, Bloomfield HE, Asztalos BF. Cardiovascular events

with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-

cholesterol: the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb

Vasc Biol. 2008;28(6):1172-1178.

34. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in

Adults. Executive Summary of The Third Report of The National Cholesterol

Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment

of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA.

2001;285(19):2486-2497.

Other related articles on this Open Access Online Scientific Journal include the following:

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

 

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Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , on November 5, 2012| 5 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Genomics: The single life

Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

31 October 2012

The tendency of sperm to swim alone makes the cells ideal for single-cell genomics. Adam Auton, a statistical geneticist at Albert Einstein College of Medicine in New York is using sperm to study recombination, the process that shuffles genes during the formation of germ cells and therefore influences which genes are inherited. “Recombination is one of the fundamental forces that shapes genetic diversity,” he says. “In recent years we’ve learned that there is considerable variation in the recombination rate between different populations, between the sexes and even between individuals.” But pinning down the rate in people once seemed impossible because it would have required finding individuals with hundreds of children and sequencing their genomes.

The ability to sequence single cells meant that researchers could take another approach. Working with a team at the Chinese sequencing powerhouse BGI, Auton sequenced nearly 200 sperm cells and was able to estimate the recombination rate for the man who had donated them. The work is not yet published, but Auton says that the group found an average of 24.5 recombination events per sperm cell, which is in line with estimates from indirect experiments2. Stephen Quake, a bioengineer at Stanford University in California, has performed similar experiments in 100 sperm cells and identified several places in the genome in which recombination is more likely to occur. The location of these recombination ‘hotspots’ could help population biologists to map the position of genetic variants associated with disease.

Quake also sequenced half a dozen of those 100 sperm in greater depth, and was able to determine the rate at which new mutations arise: about 30 mutations per billion bases per generation3, which is slightly higher than what others have found. “It’s basically the population biology of a sperm sample,” Quake says, and it will allow researchers to study meiosis and recombination in greater detail.

SOURCE:  

VIEW ARTICLE IN NATURE

http://www.nature.com/news/genomics-the-single-life-1.11710#/genome

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