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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