Individuals With Very High Levels of Lipoprotein(a) May Benefit Most From LDL(a)-Lowering Drugs

MedicalResearch.com Interview with:

Dr. Stephen Burgess PhD Programme Leader at the Medical Research Council Biostatistics Unit University of Cambridge

Dr. Burgess

Dr. Stephen Burgess PhD
Programme Leader at the Medical Research Council Biostatistics Unit
University of Cambridge

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Lipoprotein(a) is a lipoprotein subclass, and an important biomarker for coronary heart disease. As a clinical biomarker, it has a similar story to LDL-cholesterol (“bad” cholesterol), in that it is thought to be a causal risk factor for coronary heart disease, and so is a potential target for drug development. However, while drugs that lower LDL-cholesterol, such as statins, have been successful in reducing coronary heart disease risk, drugs that lower lipoprotein(a) have not as yet been successful. New drugs are currently in development that specifically target lipoprotein(a) and can lower lipoprotein(a) concentrations by 80-90%. We performed this study to investigate whether these drugs are likely to be successful in reducing coronary heart disease risk.

We compared individuals with naturally-occurring genetic variants that predispose them to a higher or lower lifetime concentration of lipoprotein(a) as a way of mimicking a randomized controlled trial. This approach has previously been undertaken for other biomarkers, including LDL-cholesterol. We found that having 10mg/dL lower genetically-predicted concentration of lipoprotein(a) was associated with a 5.8% reduction in coronary heart disease risk.

However, associations between genetically-predicted LDL-cholesterol and coronary heart disease risk are quantitatively much stronger than the proportional effect of LDL-cholesterol lowering on coronary heart disease risk as estimated by statin trials. This is because differences in genetic variants reflect lifelong changes in LDL-cholesterol, whereas statin trials only lower LDL-cholesterol for a few years. Hence, using the ratio between the genetic and trial estimates for LDL-cholesterol, we estimate that lowering lipoprotein(a) by 10mg/dL in a short-term clinical trial would only reduce coronary heart disease risk by 2.7%. To obtain the same reduction in coronary heart disease risk of around 20% as observed in statin trials, lipoprotein(a) would have to be lowered by around 100mg/dL. This explains why previous trials of less specific and less potent lipoprotein(a)-lowering drugs have failed to demonstrate benefit.

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Stress Disorders Linked to Increase Risk of Autoimmune Disease

MedicalResearch.com Interview with:

Huan Song Associated Department of Medical Epidemiology and Biostatistics Karolinska Institutet

Huan Song

Huan Song
Associated
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet

MedicalResearch.com: What is the background for this study?

Response: Earlier findings from our group (e.g. Fang et al., NEJM 2012; Arnberg et al., Lancet Psychiatry 2015; Lu et al., JAMA Oncol 2016; Shen et al., BMJ 2016; Zhu et al., Ann Oncol 2017) have identified pathways through which stressful events contribute to deterioration in human health. With strong animal models and human data supporting a role of stress in immune dysregulation, the hypothesis linking mental distress with autoimmune is indeed plausible. However, the evidence is as yet limited to clinical observations and a few larger observational studies on US veterans, most of them on men only, and some of which have cross-sectional designs and various other methodological shortcomings.

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Trial of Antibody Immunotherapy in Parkinson’s Disease

MedicalResearch.com Interview with:

Joseph Jankovic, MD Professor of Neurology  Distinguished Chair in Movement Disorders  Director, Parkinson’s Disease Center  and Movement Disorders Clinic  Department of Neurology                                    Baylor College of Medicine  Baylor St. Luke’s Medical Center at the McNair Campus Houston, TX 77030-4202

Dr. Jankovic

Joseph Jankovic, MD
Professor of Neurology
Distinguished Chair in Movement Disorders
Director, Parkinson’s Disease Center
and Movement Disorders Clinic
Department of Neurology
Baylor College of Medicine
Baylor St. Luke’s Medical Center at the McNair Campus
Houston, TX 77030-4202

 

MedicalResearch.com: What should readers take away from your study? 

  • First demonstration of an anti-α-synuclein antibody immunotherapy in patients with Parkinson’s Disease.
  • Robust target engagement led to mean reduction of up to 97% in serum free α-synuclein levels.
  • Central Nervous System penetration is supported by a dose-dependent increase in PRX002/RG7935 levels in Cerebral Spinal Fluid.
  • All dose levels of PRX002/RG7935 had acceptable safety and tolerability profiles, meeting the primary objective of this study
  • Data support ongoing PASADENA Phase 2 clinical study of PRX002/RG7935 (NCT03100149)  

Citation:

Jankovic J, Goodman I, Safirstein B, et al. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson DiseaseA Randomized Clinical TrialJAMA Neurol. Published online June 18, 2018. doi:10.1001/jamaneurol.2018.1487 

 

 

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Severe Obesity More Common in Rural or Urban Areas in US?

MedicalResearch.com Interview with:

Cynthia L. Ogden, PhD, MRP Chief, NHANES Analysis Branch Epidemiologist, NCHS/CDC Hyattsville, MD 20782

Dr. Ogden

Cynthia L. Ogden, PhD, MRP
Chief, NHANES Analysis Branch
Epidemiologist, NCHS/CDC
Hyattsville, MD 20782

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: 40% of adults and over 18% of youth in the US have obesity. Disparities in obesity have been reported by demographics and urbanization.

We looked at the prevalence of obesity and severe obesity by demographics and by level of urbanization – rural, small/medium metro and large urban. We also looked at trends over time in urban and rural areas.

Obesity and severe obesity rates were higher in rural areas than large urban areas among adults. Among youth, severe obesity rates were higher in rural areas compared to large urban areas.

Differences in age, smoking, education or race/ethnicity between urban and rural areas did not explain the differences we found between urban and rural areas.

Between 2001-2004 and 2013-2016 severe obesity among men in rural areas more than tripled and among women more than doubled. Increases in severe obesity also occurred in urban areas in men and women but they were not nearly as large.

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Red Meat Allergy Caused by Lone Star Tick Linked to Coronary Artery Disease

MedicalResearch.com Interview with:
“Lone Star Tick” by Katja Schulz is licensed under CC BY 2.0Jeffrey Wilson, MD, PhD

Research Fellow, Allergy & Immunology
University of Virginia 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Galactose-α-1,3-galactose (α-Gal) represents an oligosaccharide that is present in mammalian products and is the causal allergen in a syndrome of delayed red meat allergy (commonly called α-Gal syndrome). Sensitization to this allergen has been linked to tick bites, specifically the lone star tick in the United States.

Thus, sensitization to α-Gal (and the prevalence of subjects with symptomatic red meat allergy) is relatively common where the lone star tick is common, i.e- the southeast.

For a variety of reasons we hypothesized that specific immune sensitization (which relates to IgE antibody production) to α-Gal would be a risk factor for coronary artery disease. To address this possibility we measured IgE specific to α-Gal in 118 adults subjects from central Virginia who had undergone advanced cardiac imaging with a technique called intravascular ultrasound. Out of the cohort 26% of the subjects in the study had the sensitivity to α-Gal.

The main finding was that subjects with the IgE sensitization to α-Gal had greater amounts of atherosclerosis, as well as atherosclerotic plaques with more unstable characteristics. This association was significant when controlled for traditional cardiovascular risk factors such as hypertension, diabetes and lipids levels.

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PDL1 Amplification Linked To Positive Response to Checkpoint Blockers

MedicalResearch.com Interview with

Aaron Goodman, MD Hematologist/Medical Oncologist Assistant Professor of Medicine UC San Diego Health

Dr. Goodman

Aaron Goodman, MD
Hematologist/Medical Oncologist
Assistant Professor of Medicine
UC San Diego Health 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Response rates to PD-1/PD-L1 blockade in solid tumors are reported at 10-20%.  Remarkably, response rates of 65% to 87% have been reported in patients with refractory classical Hodgkin lymphoma treated with checkpoint inhibitors.

In nodular sclerosing Hodgkin lymphoma, amplification of the chromosomal region 9p24.1, which contains the genes PD-L1 (CD274)PDCD1LG2 (PD-L2)and JAK2, is directly correlated with increased expression of these proteins on Reed–Sternberg cells.

Overall, 105 of 108 (97%) biopsies from patients with newly diagnosed classical Hodgkin lymphoma have increased PD-L1 and PDCD1LG2 copy numbers.  The prevalence and utility of PD-L1amplification as a response biomarker to PD-1/PD-L1 blockade is unknown in other tumors.

We sought to determine the prevalence and utility of PD-L1 amplification as a response biomarker to PD-1/PD-L1 blockade in solid tumors.  Continue reading

African Americans Less Likely To Be Treated With Statins

MedicalResearch.com Interview with:

Michael G. Nanna, MD Fellow, Division of Cardiology Duke University Medical Center Durham, NC

Dr. Nanna

Michael G. Nanna, MD
Fellow, Division of Cardiology
Duke University Medical Center
Durham, NC

MedicalResearch.com: What is the background for this study?

Response: We know that African Americans are at higher risk for cardiovascular disease than white patients. We also know that African American individuals have been less likely to receive statin therapy compared to white individuals in the past. However, the reasons underlying these racial differences in statin treatment are poorly understood. We set out to determine if African American individuals in contemporary practice are treated less aggressively than whites and, if so, we wanted to investigate potential reasons why this might be the case.

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What Causes Failures in Personal Protective Equipment Use in Hospitals?

MedicalResearch.com Interview with:

Sarah L. Krein, PhD, RN Research Career Scientist VA Ann Arbor Healthcare System Ann Arbor, MI 

Sarah L. Krein, PhD, RN
Research Career Scientist
VA Ann Arbor Healthcare System
Ann Arbor, MI

MedicalResearch.com: What is the background for this study?

Response: We conducted this study to better understand the challenges faced by health care personnel when trying to follow transmission based precaution practices while providing care for hospitalized patients.  We already know from other studies that there are breaches in practice but our team was interested in better understanding why and how those breaches (or failures) occur so we can develop better strategies to ensure the safety of patients and health care personnel.

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Study Finds No Link Between Fluconazole During Pregnancy and Stillbirth or Neonatal Death

MedicalResearch.com Interview with:

Björn Pasternak,

Dr. Pasternak

Björn Pasternak, MD, PhD
Associate Professor,Clinical Epidemiology Division
Department of Medicine Solna
Karolinska Institutet
Stockholm, Sweden

MedicalResearch.com: What is the background for this study?

Response: To summarize the background for this study, there have been animal studies suggesting that oral fluconazole may give rise to fetal death. Given this background and the paucity of controlled human studies, we previously conducted a nationwide register-based study in Denmark, which was published in JAMA in 2016. In that study, we observed an increased risk of spontaneous abortion associated with fluconazole use in pregnancy. This prompted the European Medicines Agency to update the European label of fluconazole, warning about this potential adverse event. Further, findings in that study indicated that there could be an increased risk of stillbirth. We wanted to investigate this outcome further, in an independent data material, and also to investigate the outcome of neonatal death.

Here, we report the results of a bi-national study conducted on the basis of nationwide health care registers in Sweden and Norway. From a background cohort of close to 1.5 million deliveries, we identified more than 10,000 pregnancies exposed to oral fluconazole and matched these to more than 100,000 unexposed pregnancies.

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No Link Found Between Caesarean Delivery and Childhood Obesity

MedicalResearch.com Interview with:
Sheryl L. Rifas-Shiman, MPH
Lead Research Analyst
Department of Population Medicine
Harvard Medical School and Harvard Pilgrim Health Care Institute
Landmark Center
Boston, MA 02215 

MedicalResearch.com: What is the background for this study?

Response: Caesarean delivery rates remain high and variable across hospitals, regions, and countries.
Caesarean delivery may be a risk factor for childhood obesity, possibly because delivery route can influence the intestinal microbiomes, which may influence energy regulation.

Previously reported associations of caesarean delivery with childhood obesity may be confounded by maternal BMI and sociocultural factors. To address this possibility, we studied sibling pairs from the Linked CENTURY Study, a longitudinal clinical database of well-child visits in Massachusetts linked to each child’s birth certificate, to isolate the effect of caesarean delivery from most other factors. Continue reading

Amyloid PET Scan Useful in Memory Evaluation

MedicalResearch.com Interview with:
Arno de Wilde, MD / PhD candidate

Department of Neurology & Alzheimer Center
Amsterdam Neuroscience
VU University Medical Center
Amsterdam, the Netherlands

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous studies assessing the clinical utility of amyloid imaging used very selected research populations, limiting the translatability to clinical practice. In contrast, we used an unselected memory clinic cohort, offering amyloid PET to ALL patients visiting our memory clinic, and for the purpose of this study, we implemented amyloid PET in our routine diagnostic work-up. Our results demonstrate that amyloid PET has important consequences, in terms of diagnosis and treatment changes, for a significant number of patients within a situation that closely resembles clinical practice. I think that these results are an important step in ‘bridging the gap’ between using amyloid PET in a research setting versus daily clinical practice.

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bpMRI Can Be Used to Improve Prostate Cancer Risk

MedicalResearch.com Interview with:

Lars Boesen MD PhD Department of Urology Herlev Gentofte University Hospital Herlev

Dr. Boessen

Dr. Lars Boesen MD PhD
Department of Urology
Herlev Hospital

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: The current standard of care in prostate cancer diagnosis includes untargeted transrectal ultrasound-guided biopsies for all biopsy-naïve men with clinically suspicion of prostate cancer. However, this strategy that practically has remained unchanged for decades has limited diagnostic accuracy as significant cancers are missed or under-graded and insignificant cancers are unintendedly detected by the random sampling leading to possible overtreatment.

Multiparametric MRI in the diagnosis of prostate cancer has been studied extensively in recent years and has improved detection, localization, staging and risk stratification. It has been suggested that if multiparametric MRIs were used as a triage test prior to biopsies, a significant proportion of men might safely avoid prostate biopsies and the diagnostic ratio of significant vs. insignificant cancer could be improved compared to performing standard biopsies in all men. However, multiparametric MRIs are generally time-consuming (~40 min scan time), expensive and include intravenous contrast media. This reduces its feasibility for widespread clinical implementation in larger patient populations in the western community with its high PCa prevalence.

The development of a simpler and faster (~15 min) biparametric MRI protocol using less scan sequences and circumvents intravenous contrast-media seems to preserve adequate diagnostic accuracy in a detection setting and could facilitate dissemination of prostate MRI as a triage test before any biopsy.

Here we present a large prospective study that assesses the diagnostic accuracy of a novel biparametric MRI to rule out significant prostate cancer in N=1020 biopsy-naive men with clinically suspicion of prostate cancer.

We found that a low suspicion biparametric MRI had a very high negative predictive value (97%) for ruling out significant cancer on confirmatory biopsies. Furthermore, bpMRI suspicion scores were strongly associated with prostate cancer detection rates and restricting biopsies (targeted plus standard) to men with suspicious biparametric MRIs meant 30% could avoid prostate biopsies, improved significant prostate cancer diagnosis by 11%, and reduced insignificant prostate cancer diagnosis by 40% compared to our current diagnostic approach – standard biopsies for all men with clinically suspicion of prostate cancer.  Continue reading

Food Allergies More Common in Children With ASD

MedicalResearch.com Interview with:

Wei Bao, MD, PhD Assistant Professor, Epidemiology College of Public Health University of Iowa

Dr. Wei Bao

Wei Bao, MD, PhD
Assistant Professor, Epidemiology
College of Public Health
University of Iowa

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous studies indicated a possible link between immunologic dysfunction and autism. The current study, based on nationally representative large-scale surveys, showed that food allergy, respiratory allergy, and skin allergy, all relevant to immunological dysfunction, were associated with autism spectrum disorder among US children.

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Panitumumab (Vectibix) For Primary HER2-Negative Inflammatory Breast Cancer

MedicalResearch.com Interview with:

Naoto Tada Ueno, M.D., Ph.D., F.A.C.P. Executive Director, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic Section Chief, Section of Translational Breast Cancer Research, Department of Breast Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TXNaoto Tada Ueno, M.D., Ph.D., F.A.C.P.
Executive Director, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic
Section Chief, Section of Translational Breast Cancer Research, Department of Breast Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The best outcome of inflammatory breast cancer (IBC) is dependent on achieving a pathological completed response after neoadjuvant chemotherapy for primary inflammatory breast cancer, which is the most aggressive type of breast cancer.

We have conducted extensive preclinical work, which showed that EGFR is a potential therapeutic targets of IBC.

Based on this preclinical data, we have conducted a phase II study to determine the pathological complete response rate of panitumumab plus neoadjuvant chemotherapy for HER2 negative primary inflammatory breast cancer.  Continue reading

Hypertension Disorders in Pregnancy Associated With Increase in ASD and ADHD in Offspring

MedicalResearch.com Interview with:
“Blood Pressure” by Bernard Goldbach is licensed under CC BY 2.0Ali Khashan, PhD
Senior Lecturer in Epidemiology
School of Public Health & INFANT Centre
University College Cork
Cork, Ireland

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There is some evidence to suggest an increased likelihood of neurodevelopmental disorders in relation to hypertensive disorders in pregnancy, however consensus is lacking. Considering hypertensive disorders in pregnancy are among the most common prenatal complication, we decided to synthesise the published literature on this topic by conducting a comprehensive systematic review and meta-analysis.

Our main findings suggest that hypertensive disorders in pregnancy are associated with about 30% increase in the likelihood of autism spectrum disorders (ASD) and ADHD in the offspring, compared to offspring not exposed to hypertensive disorders in pregnancy. Continue reading