Most Patients Who Carry BRCA1/2 Pathogenic Variants Are Unaware

MedicalResearch.com Interview with:

Michael F. Murray, MD, FACMG, FACP Director for Clinical Operations in the Center for Genomic Health Yale School of Medicine

Dr. Murray

Michael F. Murray, MD, FACMG, FACP
Director for Clinical Operations in the Center for Genomic Health
Yale School of Medicine

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

Response: Population screening for the cancer risk associated with the BRCA1 and BRCA2 genes has been suggested by some.  We screened a cohort of about 50,000 adult patient volunteers at Geisinger Health System in Pennsylvania for this risk.  Continue reading

Single Dose of Ibalizumab Boosts Immunity in Resistant HIV

MedicalResearch.com Interview with:

Brinda Emu, MD Assistant Professor of Medicine (Infectious Diseases) Yale School of Medicine

Dr. Emu

Brinda Emu, MD
Assistant Professor of Medicine (Infectious Diseases)
Yale School of Medicine

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

Response: This was a Phase 3 study of a new antiretroviral agent, ibalizumab, for the treatment of HIV-1 infection.  Ibalizumab is a monoclonal antibody that targets the CD4 receptor on host cells.  CD4 is the receptor that HIV uses to infect CD4+ T cells.  By binding to the CD4 receptor, ibalizumab prevents viral entry.  This study recruited patients that harbor multi-drug resistant HIV and were failing their current regimen of antiretroviral agents, and thus had limited options for treatment of their HIV-1 infection using approved medications.

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Checkpoint Inhibitors Rapidly Being Incorporated Into Routine Cancer Care

MedicalResearch.com Interview with:

Jeremy O'Connor, MD Section of General Internal Medicine Department of Internal Medicine Postdoctoral Fellow, National Clinician Scholars Program Yale University

Dr. O’Connor

Jeremy O’Connor, MD
Section of General Internal Medicine
Department of Internal Medicine
Postdoctoral Fellow, National Clinician Scholars Program
Yale University

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

Response: There has been a lot of enthusiasm for the use of novel therapies in cancer care, and in particular for novel anticancer agents known as immune checkpoint inhibitors. But very little is known about how quickly providers have adopted immune checkpoint inhibitors into clinical practice. Existing studies suggest, in fact, that the process of clinical adoption is slow, with conventional wisdom holding that it takes an average of 17 years for new evidence to change practice.

Our study evaluated whether the adoption of novel therapies might be much faster in certain contexts with the early use of immune checkpoint inhibitors as a notable example.

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First Signs of Psychotic Disorder May Appear in Childhood With Drop in IQ

MedicalResearch.com Interview with:
Josephine Mollon PhD
Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience
King’s College London, London, England
Currently with the Department of Psychiatry
Yale University School of Medicine
New Haven, Connecticut

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

Response: Psychotic disorders, such as schizophrenia, are severe mental disorders that cause a range of abnormalities in perception and thinking. Individuals with psychotic disorders also experience severe impairments in IQ and there is evidence that these impairments begin many years before hallucinations and delusions first appear. Understanding how and when individuals with psychotic disorder experience a drop in IQ scores will help us better predict and treat poor cognition in these individuals, and perhaps even the disorder itself.

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Improving Adjuvant Clinical Trials By Including Only Patients For Whom Current Therapies Do Not Work Well

MedicalResearch.com Interview with:

Lajos Pusztai, M.D, D.Phil. Professor of Medicine Director of Breast Cancer Translational Research Co-Director of the Yale Cancer Center Genetics, Genomics and Epigenetics Program Yale School of Medicine New Haven, CT  06511

Dr. Pusztai

Lajos Pusztai, M.D, D.Phil.
Professor of Medicine
Director of Breast Cancer Translational Research
Co-Director of the Yale Cancer Center Genetics, Genomics and Epigenetics Program
Yale School of Medicine
New Haven, CT  06511

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

Response: Overall, about 85% of newly diagnosed stage I-III breast cancer patients will not die of their disease, and this roughly equates to an 85% cure rate. Of course cure rates are higher for stage I cancers and lower for stage III cancers. An 85% overall cure rate is good but not good enough, we continuously try to develop new therapies hoping to push these rates to 90%…,95%…etc. However, it is not possible to cure a patient twice over. For example, if surgery plus endocrine therapy cures all patients, the addition of chemotherapy cannot improve on it no matter how effective it is. If surgery plus endocrine therapy cures 95%, adding the perfect chemo to this treatment can only bring about a 5% improvement, and very good chemo that would push cure from 95% to 97%, would require a very large trial including many thousands of patients.

This is an increasingly common scenario in modern breast cancer adjuvant trials (where the goal is to improve survival and cure); the control arm that receives the current standard of care invariably does better than expected and the experimental arm only improves outcome by 1-3% that does not reach statistical significance.  The painful conclusion from these trials is that we do not know if the new drug actually works or not because there were not enough events to demonstrate an effect.

Of course, a lot of patients in the study were also exposed to a new drug with all of its associated toxicities who could not possibly benefit from it.

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Genetic Cause and Clinical Cure Found For Rare Skin Disorder

MedicalResearch.com Interview with:

Keith Adam Choate, MD, PhD, FAAD Associate Professor of Dermatology, of Genetics and of Pathology Director of Research, Dermatology Yale University School of Medicine New Haven, CT

Dr Choate

Keith Adam Choate, MD, PhD, FAAD
Associate Professor of Dermatology,
Genetics and Pathology
Director of Research, Dermatology
Yale University School of Medicine
New Haven, CT

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

Response:  Over the last 10 years, we have systematically been examining patients with ichthyosis to identify new genetic causes of this group of disorders.  We found that autosomal recessive mutations in KDSR cause ichthyosis and that the resulting skin disease is effectively treated with isotretinoin.

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Phase 3 Studies Demonstrate Reduce Endometriosis-Associated Pain with Elagolix

MedicalResearch.com Interview with:

Hugh S. Taylor, M.D. Anitta O’keeffe Young Professor and Chair Departemnt of Obstetrics, Gynecology and Reproductive Sciences Yale School of Medicine Chief of Obstetrics and Gynecology Yale-New Haven Hospital

Dr. Taylor

Hugh S. Taylor, M.D.
Anitta O’keeffe Young Professor and Chair
Departemnt of Obstetrics, Gynecology and Reproductive Sciences
Yale School of Medicine
Chief of Obstetrics and Gynecology
Yale-New Haven Hospital

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

Response: Elagolix is an investigational, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that blocks endogenous GnRH signaling by binding competitively to GnRH receptors. Administration results in rapid, reversible, dose-dependent inhibition of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, leading to reduced ovarian production of the sex hormones, estradiol and progesterone, while on therapy.

Data from two replicate Phase 3 studies evaluating the efficacy and safety of elagolix were published in the New England Journal of Medicine. Elagolix demonstrated dose-dependent superiority in reducing daily menstrual and non-menstrual pelvic pain associated with endometriosis compared to placebo. At month three and month six, patients treated with elagolix reported statistically significant reductions in scores for menstrual pain (dysmenorrhea, DYS) and non-menstrual pelvic pain (NMPP) associated with endometriosis as measured by the Daily Assessment of Endometriosis Pain scale. The safety profile of elagolix was consistent across both Phase 3 trials and also consistent with prior elagolix studies.

Ultimately, the studies showed that both elagolix doses (150 mg QD and 200 mg BID) were effective in improving dysmenorrhea, non-menstrual pelvic pain and quality of life over 6 months in women with endometriosis-associated pain. The elagolix safety/tolerability profile was consistent with the mechanism of action.

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Fewer Heart Attacks and Strokes After Trans-Fat Restriction Laws in New York

MedicalResearch.com Interview with:

Eric J. Brandt, MD Yale University Cardiovascular Disease Fellow

Dr. Eric Brandt

Eric J. Brandt, MD
Yale University
Cardiovascular Disease Fellow

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

Response: From previous studies we know that industrial trans fatty acid (trans fat) consumption is linked to elevated risk for cardiovascular disease. Even small amounts of consumption can be deleterious to cardiovascular health. In New York state, there were 11 counties that restricted the use of trans fatty acids in eateries. We compared hospitalization for heart attacks and stroke from 2002 through 2013 in counties that did and did not have restrictions.

Our study found that when comparing populations within New York state that restricted the use of trans fat, compared to those that did not, there was an associated additional decline beyond temporal trends for heart attacks and stroke events combined by 6.2%.

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End-of-Life Care Transition Patterns of Medicare Beneficiaries

MedicalResearch.com Interview with:
Shi-Yi Wang MD, PhD.

Department of Chronic Disease Epidemiology
Yale School of Public Health
New Haven, CT

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

Response: Care at the end of life is often fragmented and poorly coordinated across different health providers. Multiple transitions in care settings can be burdensome to patients and their families as well as costly to society. Despite these concerns about care transitions in the end of life, we lack contemporary data on the number, timing, and overall pattern of healthcare transitions in the last 6 months of life.

This study adds to the extant literature by understanding transition trajectories, national variation of the transitions, and factors associated with transitions. We found that more than 80% of Medicare fee-for-service decedents had at least one health care transition and approximately one-third had ≥ 4 transitions in the last 6 months of life. We produced Sankey diagrams to visualize the sequences of healthcare transitions. The most frequent transition pattern involving at least four transitions: home-hospital-home (or skilled nursing facility)-hospital-healthcare setting other than hospital. There was substantial geographic variation in healthcare transitions in the United States. We found that several factors were associated with a significantly increased risk of having multiple transitions, including female gender, blacks, residence in lower income areas, presence of heart disease or kidney disease.

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Gene Expression-based Breast Cancer Index Can Improve Decision Making For ER+ Patients

MedicalResearch.com Interview with:

Tara Sanft, MD Assistant Professor of Medicine (Medical Oncology) Medical Director of Adult Survivorship Yale Cancer Center Survivorship Clinic

Dr. Tara Sanft

Tara Sanft, MD
Assistant Professor of Medicine (Medical Oncology)
Medical Director of Adult Survivorship
Yale Cancer Center Survivorship Clinic 

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

Response: Previous studies have demonstrated the benefit of extended endocrine therapy (EET) for hormone receptor-positive (HR+) breast cancer in preventing late relapse, however that benefit is limited to 3-5% of women where late recurrence was prevented or staved off. However, EET has become common practice and as a result we are exposing many patients to risks of side effects and toxicities associated with anti-estrogen therapies when they may not be benefitting, and, conversely may not be treating the patients that might actually benefit. There is a real need to better identify the patients who are both at most risk of late distant recurrence, and most likely to benefit from EET.

This prospective study included 141 patients with a mean age of 62. In the study, 83% of patients were postmenopausal, 73% were stage I.

Breast Cancer Index (BCI) is a gene expression-based test and is the only currently available validated biomarker that is both prognostic for late distant recurrence and predictive for likelihood of benefit from EET. The purpose of this prospective study was to assess the impact of BCI on: physician EET recommendations; physician confidence; patient satisfaction, anxiety, and decision-conflict; and the cost impact of BCI.

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Racial Disparities in Genetic Testing of Women With Breast Cancer

MedicalResearch.com Interview with:

Cary P. Gross, MD Section of General Internal Medicine Yale University School of Medicine New Haven, CT

Dr. Cary Gross

Cary P. Gross, MD
Section of General Internal Medicine
Yale University School of Medicine
New Haven, CT

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

Response: Prior work has demonstrated racial and socioeconomic disparities in breast cancer diagnosis, treatment, and outcomes.  As the oncology field has progressed over the past decade, the use of genetic testing to guide treatment decisions is one of the most exciting new developments.

Our team was concerned that these new gene tests, which can offer important benefits, may have the potential to exacerbate disparities further.  That is, if there is unequal access to gene testing among patients for whom it is recommended, then our progress against cancer will not be equitably shared among people of all races and ethnicities.

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Membership In Medical Schools’ Honor Society Skews Toward White Students

MedicalResearch.com Interview with:

Dowin Boatright, MD, MBA</strong> Department of Emergency Medicine Yale School of Medicine New Haven, Connecticut Fellow, Robert Wood Johnson Clinical Scholars Program Veterans Affairs Scholar

Dr. Dowin Boatright

Dowin Boatright, MD, MBA
Department of Emergency Medicine
Yale School of Medicine
New Haven, Connecticut
Fellow, Robert Wood Johnson Clinical Scholars Program
Veterans Affairs Scholar

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

Response: Studies have demonstrated racial and ethnic inequities in medicine, including disparities in the receipt of awards, research funding, and promotions. Yet few studies have examined the link between race and ethnicity and opportunities for medical school students.

Our results show that black and Asian medical school students are less likely to be selected for membership in a prestigious medical honor society, Alpha Omega Alpha (AΩA), than white medical school students.

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Antidepressants Have Variable Effects On Symptom Clusters

MedicalResearch.com Interview with:

Adam Chekroud PhD Candidate Human Neuroscience Lab

Adam Chekroud

Adam Chekroud
PhD Candidate
Human Neuroscience Lab
Department of Psychology
Yale University

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

Response: We know that depression includes a wide range of symptoms, from low mood and feeling worthless, to problems sleeping, slowed thinking, and suicidal ideation.

We wanted to know whether antidepressants work well in treating all of these symptoms, or whether they are primarily effective on certain kinds of symptoms.

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Hospital Readmissions Fell After Penalties Instituted But Then Plateaued

MedicalResearch.com Interview with:
Nihar R. Desai, MD, MPH

Assistant Professor of Medicine
Section of Cardiovascular Medicine, Yale School of Medicine
Center for Outcomes Research and Evaluation
Yale New Haven Health System

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

Response: Reducing rates of readmissions after hospitalization has been a major focus for patients, providers, payers, and policymakers because they reflect, at least partially, the quality of care and care transitions, and account for substantial costs. The Hospital Readmission Reduction Program (HRRP) was enacted under Section 3025 of the Patient Protection and Affordable Care Act (ACA) in March 2010 and imposed financial penalties beginning in October 2012 for hospitals with higher than expected readmissions for acute myocardial infarction (AMI), congestive heart failure (HF), and pneumonia among their fee-for-service Medicare beneficiaries. In recent years, readmission rates have fallen nationally, and for both target (AMI, HF, pneumonia) and non-target conditions.

We were interested in determining whether the Hospital Readmission Reduction Program (HRRP) associated with different changes in readmission rates for targeted and non-targeted conditions for penalized vs non-penalized hospitals?

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Neuroanatomy Accounts for Age-Related Changes in Risk Preferences.

MedicalResearch.com Interview with:
Ifat Levy, PhD

Associate Professor
Comparative Med and Neuroscience
Yale School of Medicine

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

Response: The proportion of older adults in the population is rapidly rising. These older adults need to make many important decisions, including medical and financial ones, and therefore understanding age-related changes in decision making is of high importance. Prior research has shown that older adults tend to be more risk averse than their younger counterparts when making choices between sure gains and lotteries. For example, asked to choose between receiving $5 for sure and playing a lottery with 50% of gaining $12 (but also 50% of gaining nothing), older adults are more likely than young adults to prefer the safe $5. We were interested in understanding the neurobiological mechanisms that are involved in these age-related shifts in preferences.

An earlier study that we have conducted in young adults provided a clue. In that study, we measured the risk preference of each participant (based on a series of choices they made between safe and risky options), and also used MRI to obtain a 3D image of their brain. Comparing the behavioral and anatomical measures, we found an association between individual risk preferences and the gray-matter volume of a particular brain area, known as “right posterior parietal cortex” (rPPC), which is located at the back of the right side of the brain. Participants with more gray matter in that brain area were, on average, more tolerant of risk (or less risk averse).

This suggested a very interesting possibility – that perhaps the increase in risk aversion observed in older adults is linked to the thinning of gray matter which is also observed in elders. In the current study we set out to test this hypothesis, by measuring risk preference and gray matter density in a group of 52 participants between the ages of 18 and 88. We found that, as expected, older participants were more risk averse than younger ones, and also had less gray matter in their rPPC. We also replicated our previous finding – that less gray matter was associated with higher risk aversion. The critical finding, however, was that the gray matter volume was a better predictor of increased risk aversion than age itself.  Essentially, if both age and the gray matter volume of rPPC were used in the same statistical model, rPPC volume predicted risk preferences, while age did not. Moreover, the predictive power was specific to the rPPC – when we added the total gray matter volume to the model, it did not show such predictive power.

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Predictors of Chemosensitivity in Triple Negative Breast Cancer

MedicalResearch.com Interview with:

Christos Hatzis, PhD Assistant Professor of Medicine Director of Bioinformatics, Breast Medical Oncology Yale Comprehensive Cancer Center Yale School of Medicine New Haven, CT

Dr. Christos Hatzis,

Christos Hatzis, PhD
Assistant Professor of Medicine
Director of Bioinformatics, Breast Medical Oncology
Yale Comprehensive Cancer Center
Yale School of Medicine
New Haven, CT

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

Response: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.

Identifying chemosensitive triple negative breast cancers could significantly impact
the survival of patients with these difficult to treat cancers until novel targeted
therapies become available. We hypothesized that genomic somatic aberrations may
provide important molecular clues about chemosensitivity in TNBC. Our study used
a carefully selected cohort of 29 uniformly treated TNBC patients who either achieved
pathologic complete response (pCR) or had extensive residual disease after neoadjuvant
anthracycline/taxane chemotherapy.

MedicalResearch.com: What are the main findings?

Response: We sequenced the coding genomic DNA of TNBC tumors and compared the somatic mutations found in the two groups at the two extremes of the chemosensitivity spectrum.

Our analysis revealed that, although mutations in single genes were not individually predictive, TNBC tumors bearing mutations in genes involved in the androgen receptor
(AR) and FOXA1 pathways were much more sensitive to chemotherapy.
We also found that mutations that lowered the levels of functional BRCA1 or BRCA2 RNA
were associated with significantly better survival outcomes; we derived a BRCA
deficiency signature to define this new, highly chemosensitive subtype of TNBC.
BRCA-deficient TNBC tumors have a higher rate of clonal mutation burden, defined as
more clonal tumors with a higher number of mutations per clone, and are also associated
with a higher level of immune activation, which may explain their greater chemosensitivity.

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

Response: Mutations in the AR/FOXA1 pathway provide a novel marker for identifying chemosensitive TNBC patients who may benefit from current standard-of-care chemotherapy regimens.

The newly defined RNA-based BRCA-deficient subtype includes up to 50% of the
Triple negative breast cancer tumors that appear to be immune primed, and it would be of interest to investigate combinations of chemotherapy with immunotherapies, which could provide clinical benefit for these patients. Although our study showed concordant results in three different datasets, our key findings need to be further validated in a larger, prospectively designed study with archival samples.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in Triple negative breast cancer and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. Our results suggest that the combination of immunotherapies with ACT chemotherapy or PARP inhibitors might be an effective strategy for treating BRCA-D tumors.

The strong connection of ACT chemosensitivity and immune activity with a new transcriptionally defined BRCA-D phenotype could help inform future therapeutic strategies for TNBC patients.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic AnalysisTingting Jiang,Weiwei Shi,Vikram B. Wali,Lőrinc S. Pongor,Charles Li,Rosanna Lau,Balázs Győrffy,Richard P. Lifton,William F. Symmans,Lajos Pusztai,Christos Hatzis

PLOS Medicine Published: December 13, 2016http://dx.doi.org/10.1371/journal.pmed.1002193

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Cranberry Juice Capsules Ineffective in Reducing UTIs in Older Women

MedicalResearch.com Interview with:

Manisha Juthani-Mehta, MD, FACP, FIDSA, FSHE</strong>A Associate Professor, Section of Infectious Diseases Infectious Diseases Fellowship Program Director Yale University School of Medicine

Dr. Manisha Juthani-Mehta

Manisha Juthani-Mehta, MD, FACP, FIDSA, FSHEA
Associate Professor, Section of Infectious Diseases
Infectious Diseases Fellowship Program Director
Yale University School of Medicine

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

Response: One of the first studies that showed that cranberry juice was effective in older women living in nursing homes and assisted living facilities was published in 1994. Since that time, there have been multiple conflicting studies as to the effect of cranberry juice or capsules. We started our study in 2012. Shortly thereafter, a Cochrane review suggested that the vast body of evidence did not suggest that cranberry products work for UTI prevention, but questions still existed as to whether the appropriate dose of cranberry was being tested. Since cranberry juice is hard for older women to drink (taste, sugar load, volume), capsules at a high dose of the active ingredient (72mg type A proanthocyanidin [PAC}) was worthwhile to test.

This study was a clinical trial of two cranberry capsules with a total of 72mg of proanthocyanidin (pac) vs two placebo capsules to prevent bacteria in the urine of older women who live in nursing homes.

Unfortunately, it didn’t work. It also didn’t reduce the number of hospitalizations, deaths, antibiotics used, or antibiotic resistant bugs in the urine.

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US Task Force Recommends Primary Care Interventions to Support Breastfeeding

MedicalResearch.com Interview with:

Ann Kurth, Ph.D., C.N.M., R.N. USPSTF Task Force member Dean of the Yale School of Nursing

Dr. Ann Kurth

Ann Kurth, Ph.D., C.N.M., R.N.
USPSTF Task Force member
Dean of the Yale School of Nursing

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

Response: Breastfeeding is beneficial for both mothers and their babies, with the evidence showing that babies who are breastfed are less likely to get infections such as ear infections, or to develop chronic conditions such as asthma, obesity, and diabetes. For mothers, breastfeeding is associated with a lower risk for breast and ovarian cancer and type 2 diabetes. While breastfeeding rates have been rising in recent decades—with 80 percent of women starting to breastfeed and just over half still doing so at six months—they are still lower than the Healthy People 2020 targets and the Task Force wanted to review the latest evidence around how clinicians can best support breastfeeding.”

After balancing the potential benefits and harms, the Task Force found sufficient evidence to continue to recommend interventions during pregnancy and after birth to support breastfeeding. This recommendation includes the same types of interventions the Task Force recommended in 2008, such as education about the benefits of breastfeeding, guidance and encouragement, and practical help for how to breastfeed.

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Mibefradil Dihydrochoride with Hypofractionated Radiation for Recurrent Glioblastoma

MedicalResearch.com Interview with:

Nataniel Lester-Coll, MD Chief Resident in Radiation Oncology at Yale New Haven, Connecticut

Dr. Nataniel Lester-Coll

Nataniel Lester-Coll, MD
Chief Resident in Radiation Oncology at Yale
New Haven, Connecticut 

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

Response: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Mibefradil diydrochloride was identified using a high-throughput compound screen for DNA double stranded break repair inhibitors. Mibefradil was found to radiosensitize GBM tumor cells in vitro and in vivo. Based on these findings, we sought to determine the maximum tolerated dose of mibefradil and radiation therapy in a Phase I recurrent GBM study. Eligible patients with recurrent  Glioblastoma Multiforme received Mibefradil over a 17 day period, with hypofractionated radiation (600 cGy x 5 fractions). There are 18 patients currently enrolled who have completed treatment. Thus far, there is no clear evidence of radionecrosis. A final dose level of 200 mg/day was reached as the maximum tolerated dose. The drug was very well tolerated at this dose. We saw intriguing evidence of enhanced local control in selected cases. Patients enrolled in a translational substudy who received Mibefradil prior to surgery were found to have adequate levels of Mibefradil in resected brain tumor tissue.

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Intestinal Microbiome Linked to Obesity and Fat Storage in Children

MedicalResearch.com Interview with:

Nicola Santoro, MD, PhD Associate Research Scientist in Pediatrics (Endocrinology) Yale University

Dr. Nicola Santoro

Nicola Santoro, MD, PhD
Associate Research Scientist in Pediatrics (Endocrinology)
Yale University

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

Response: The study start from previous observations showing an association between the gut microbiota and obesity.

Similarly to what previously described in adults and in children, we found an association between the gut microbiota and obesity. We took a step further and also observed that the gut flora is associated to body fat partitioning (amount of fat in the abdomen). Moreover, we observed that the effect of microbiota could be mediated by the short chain fatty acids a product of gut flora.

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Declining Admission Rates and 30-Day Readmissions Linked

MedicalResearch.com Interview with:

Kumar Dharmarajan, MD, MBA Assistant Professor of Medicine (Cardiology) Cardiovascular Medicine: Center for Outcomes Research & Evaluation (CORE) Yale School of Medicine

Dr. Kumar Dharmarajan

Kumar Dharmarajan, MD, MBA
Assistant Professor of Medicine (Cardiology)
Cardiovascular Medicine: Center for Outcomes Research & Evaluation (CORE)
Yale School of Medicine

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

Response: Programs from the Centers for Medicare and Medicaid Services simultaneously promote strategies to lower hospital admissions and readmissions. However, there is concern that hospitals in communities that successfully reduce admissions may be penalized, as patients that are ultimately hospitalized may be sicker and at higher risk of readmission. We therefore examined the relationship between changes from 2010 to 2013 in admission rates and thirty-day readmission rates for elderly Medicare beneficiaries.

We found that communities with the greatest decline in admission rates also had the greatest decline in thirty-day readmission rates, even though hospitalized patients did grow sicker as admission rates declined. The relationship between changing admission and readmission rates persisted in models that measured observed readmission rates, risk-standardized readmission rates, and the combined rate of readmission and death.

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WATCHMAN Device to Control Atrial Fibrillation May Be More Cost Effective than Anticoagulation

MedicalResearch.com Interview with:

Dr. James V. Freeman MD Assistant professor of cardiology and Assistant Clinical Professor of Nursing Internal Medicine Yale School of Medicine

Dr. James Freeman

Dr. James V. Freeman MD
Assistant professor of cardiology and
Assistant Clinical Professor of Nursing
Internal Medicine
Yale School of Medicine

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

Dr. Freeman: Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown varying results, and its cost-effectiveness compared to anticoagulation has not been evaluated using all available contemporary trial data.

We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost-effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of PROTECT AF and PREVAIL randomized trials. Using data from PROTECT AF, the incremental cost-effectiveness ratios (ICER) compared to warfarin and dabigatran were $20,486 and $23,422 per quality adjusted life year (QALY), respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (8.44, 8.54, and 8.59 QALYs, respectively) and more costly.

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Newly Discovered Phages Can Target Antibiotic Resistance

MedicalResearch.com Interview with:

Paul E. Turner Chair of Ecology and Evolutionary Biology, Yale University Microbiology Faculty, Yale School of Medicine New Haven, CT 06520

Dr. Paul Turner

Paul E. Turner Ph.D
Chair of Ecology and Evolutionary Biology,
Yale University
Microbiology Faculty,
Yale School of Medicine
New Haven, CT 06520

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

Dr. Turner:  Our study concerned the problem of multi-drug resistance in the opportunistic pathogen Pseudomonas aeruginosa, especially the search for promising bacteriophage candidates with biological properties to effectively target these bacteria. We tested whether the binding of phage to outer membrane proteins of multidrug efflux pumps would exert selection for bacteria to avoid virus attack by compromising pump performance – thus suffering increased sensitivity to traditional antibiotics. We discovered a naturally occurring phage that forced the desired evolutionary trade-off; we showed that clinical isolates of P. aeruginosa gained phage resistance, while simultaneously becoming susceptible to several antibiotics that are ordinarily useless in controlling these MDR pathogens.

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

Dr. Turner: Newly discovered phages can be highly effective at targeting antibiotic resistance mechanisms in MDR bacteria, causing these pathogens to become antibiotic sensitive. Medical use of such resistance targeting phages could greatly improve clinical outcomes by reversing antibiotic resistance in MDR bacterial pathogens.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Turner: We recommend utilizing a ‘rational drug design’ approach to combating antibiotic resistance, especially use of phages to target efflux pump systems in MDR bacteria. This approach could greatly reduce the burden to rely on drugs of last resort and would extend the lifetime of our current antibiotic library.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Benjamin K. Chan, Mark Sistrom, John E. Wertz, Kaitlyn E. Kortright, Deepak Narayan, Paul E. Turner. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Scientific Reports, 2016; 6: 26717 DOI:10.1038/srep26717

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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IVC Filters Widely Used in Attempt To Prevent Pulmonary Embolism

MedicalResearch.com Interview with:

Behnood Bikdeli MD Department of Internal Medicine and Center for Outcomes Research and Evaluation (CORE) Yale University School of Medicine New Haven, CT 06510

Dr. Behnood Bikdeli

Behnood Bikdeli MD
Department of Internal Medicine and Center for Outcomes Research and Evaluation (CORE)
Yale University School of Medicine
New Haven, CT 06510 

Medical Research: What is the background for this study? What are the main findings?

Response: The idea of closing the path of inferior vena cava (IVC) to prevent blood clots migrating to the pulmonary circulation and causing a pulmonary embolism (PE) has been around for over 150 years. We were aware than many practitioners might think of IVC filters for that reason, and specifically with the introduction of retrievable filters in recent years; that have made it more palatable for referring physicians.

However, there is a paucity of high-quality data to suggest the efficacy of IVC filters. The two existing large trials did not show a mortality benefit from use of filters, and the guidelines have very narrow indications for use of IVC filters in patients who have already had a pulmonary embolism.

Having said that, we wondered whether despite the absence of high-quality comparative effectiveness data, filters might be commonly used in patients with PE, particularly among older adults who are a vulnerable population (at higher risk of PE, at higher risk of PE complications; but also less likely to receive other advanced therapies for PE).

Our study common use of IVC filters among older adults in the US; with over 75% relative increase in use of IVC filters from 1999 to 2010 (from ~5000 patients with PE in 1999 to ~9000 patients with PE in 2010). We also noted wide regional variations in the use of IVC filters (e.g. highest in the South Atlantic and lowest in the Mountain region). Such differences fundamentally persisted over time. In addition, we noted declining short-term and 1-year mortality rates in patients with pulmonary embolism over time, irrespective of whether or not they received an IVC filter.

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Brain Neurons That Detect Blood Glucose Identified

MedicalResearch.com Interview with:

Sabrina Diano, Ph.D. Professor Depts. Ob/Gyn, Neuroscience and Comparative Medicine Associate Chair for Faculty Development Dept Ob/Gyn and Reproductive Sciences Program in Cell Signaling and Neurobiology of Metabolism Yale University School of Medicine and Graduate School

Dr. Sabrina Diano

Sabrina Diano, Ph.D.
Professor, Depts. Ob/Gyn, Neuroscience and Comparative Medicine
Associate Chair for Faculty Development
Dept Ob/Gyn and Reproductive Sciences
Program in Cell Signaling and Neurobiology of Metabolism
Yale University School of Medicine and Graduate School 

Medical Research: What is the background for this study? What are the main findings?

Dr. Diano: We have been studying the intracellular mechanisms that regulate glucose sensing by the brain. We found that in a specific area of the brain (called ventromedial nucleus of the hypothalamus) a small group of neurons (the brain cells) are able to sense increased glucose levels in the blood via their mitochondria, the energy powerhouse of the cells. This mitochondrial change enables these neurons to get activated, which in turn, results in a reduction of  glucose levels in the blood due to an increased muscles glucose utilization.

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