Design and Analysis for Precision Medicine Subgroup Identification

In 2015 President Barack Obama announced the launch of the Precision Medicine Initiative, spurring an out pour of interest into research regarding patient-specific health. Precision medicine is the reproducible research from which health care professionals can provide targeted treatments to their patients. Two objectives in precision medicine include (i) identifying treatment-response subgroups and (ii) identifying disease subgroups. In this manuscript, we will consider a place for traditional study designs in the new age of precision medicine by presenting the machine learning tools and statistical theory necessary to do so. We begin with a newly proposed method for estimating the individualized treatment regime from crossover studies. This method expands generalized outcome weighted learning into the 2x2 crossover study framework by considering the difference in treatment response as the observed reward and correcting for carryover effects, estimated through regression methods. After, we propose a new technique for identifying disease subgroups by applying hierarchical clustering techniques to what can be interpreted as a set of denoised outcomes. These values are weighted averages of the observed and fitted outcomes, estimated by regressing on a set of features. Finally, we return to identifying treatment-response subgroups, but, in the realm of case-control studies. We again expand on generalized outcome weighted learning in addition to accounting for the difference in the covariate distribution between the selected study sample and the total population. Between this method and electronic health data, advancements for rare and expensive to study diseases may be closer than we think.Doctor of Philosoph

An unfolded protein-induced conformational switch activates mammalian IRE1.

The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α's ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization

Incorporating a clinical pharmacist in an outpatient palliative care team

Title: Incorporating a clinical pharmacist in an outpatient palliative care team Crystal Rim, PharmD; Sharon Leigh, PharmD, BCPS; Linda De Sitter MD, MPH; Mary Grant, ANP; Dana Nguyen, PharmD Palliative care is a growing field in medicine that focuses on delivering care that improves quality of life for patients with serious illnesses. Often, the goals of palliative care differ from traditional goals of medicine. Currently, there is limited data demonstrating the integration of pharmacists in the palliative care setting. The purpose of this quality improvement is to evaluate the clinical pharmacist’s role within an outpatient palliative care team when performing medication reconciliation and review. Medication review includes de-prescribing high-risk medications and optimizing medications in symptom management. Between January and February 2020, the clinical pharmacist interviewed patients referred to the outpatient palliative care service through three different methods: telehealth, pharmacy consult and telephone. The clinical pharmacist provided recommendations to the outpatient palliative care nurse practitioner and primary care provider for medication optimization, symptom management and de-prescribing based on STOPPFrail and Beers Criteria. Data from 19 patients were analyzed. One patient was excluded from analysis due to death. Five patients were interviewed through telehealth. Two patients were directly consulted for pharmacist review by the outpatient palliative care nurse practitioner. Seven patients were interviewed through telephone, of which 4 patients were referred to hospice following palliative care consult. Of 19 patients, 64 total recommendations (29 medication discontinuation, 30 medication optimization, 5 symptom management) were made. Six recommendations were accepted by the provider (3 medication discontinuation, 3 medication optimization). The average time spent on chart review for each patient was 1.5 hours. Pharmacist involvement in outpatient palliative care may be valuable. However, many barriers to providing meaningful interventions were identified in this study. While telehealth provided the convenience to the patient and caregivers, utilization was limited due to lack of standardization of technology. Telephone interviews allowed proper medication reconciliation prior to the palliative care visit, but non-medication related issues may be prioritized after the visit. Finally, pharmacy consult from palliative care nurse practitioners allowed more efficiency, but it did not allow formal pharmacist integration in the outpatient palliative care team. Further studies quantifying the pharmacist role in outpatient palliative care are warranted.https://digitalcommons.psjhealth.org/pharmacy_PGY1mn/1000/thumbnail.jp

Oral Contraceptives and Mood Disorders

Background information: Oral contraceptives are one of the most common types of birth control women use to prevent pregnancy. The most widely prescribed pill form contains estrogen and progesterone. Progesterone helps prevent pregnancy while estrogen controls menstrual bleeding. Today, researchers are investigating whether the use of oral contraceptives will increase the chances of developing a mood disorder such as depression or bipolar disorder. These disorders, though common, affect patients by interfering with their daily activities. Principal focus: Behavioral changes were compared to determine if there is a significant increase in the risk of being diagnosed with a mood disorder (i.e. bipolar disorder and depression) among females 13 years and older who use oral contraceptives as their main form of birth control. This was compared to women who did not use oral contraceptives or other female barrier methods such as an IUD, patch, or ring. Methodology: We systematically reviewed 70 clinical trials from UpToDate, PubMed, and the National Library of Medicine using search terms such as oral contraceptives, birth control pills, mood disorders, bipolar disorder, and depression. Limited searches to studies from 2015 to present, English, human trials, and females older than 13 years old. After further reduction, 20 studies were analyzed. Outcomes were accessed via interview assessments or surveys with clinical scores. Results: While there appears to be some supporting evidence demonstrating a correlation between the usage of oral contraceptives leading to increased risk of mood disorders, there are many outside factors that can also influence mood. Therefore, more research is still needed to further understand how oral contraceptives alone without any external influence will affect a person’s mood

Establishment of a Percutaneous Coronary Intervention Registry in Vietnam: Rationale and Methodology

Copyright: © 2020 The Author(s). Background: In lower- and middle-income countries across Asia there has been a rapid expansion and uptake of percutaneous coronary intervention (PCI). However, there has been limited routine collection of related data, particularly around quality, safety and cost. The aim of this study was to assess the viability of implementing routine collection of PCI data in a registry at a leading hospital in Hanoi, Vietnam. Method: A Vietnamese data collection form and collection strategy were developed in collaboration with the Vietnam National Heart Institute. Information on patient characteristics, treatments, and outcomes was collected through direct interviews using a standardised form and medical record abstraction, while PCI data was read and coded into paper forms by interventional cardiologists. Viability of the registry was determined by four main factors: 1) being able to collect a representative sample; 2) quality of data obtained; 3) costs and time taken for data collection by hospital staff; and 4) level of support from key stakeholders in the institute. Results: Between September 2017 and May 2018, 1,022 patients undergoing PCI were recruited from a total of 1,041 procedures conducted during that time frame. The estimated mean time to collect information from patients before discharge was 60 minutes. Of the collected data fields, 98% were successfully completed. Most hospital staff surveyed indicated support for the continuation of the activity following the implementation of the pilot study. Conclusions: The proposed methodology for establishing a PCI registry in a large hospital in Vietnam produced high quality data and was considered worthwhile by hospital staff. The model has the potential opportunity for replication in other cardiac catheterisation sites, leading to a national PCI registry in Vietnam

Clerkship Modifications for Rural and Urban Underserved Program Scholars

Clinical clerkship directors and coordinators together with the Rural and Urban Underserved Program (RUUP) have created targeted opportunities for RUUP Scholars during 3rd year clerkships. These opportunities aim to build Scholars’ clinical experience, knowledge and skills working with medically underserved groups. RUUP Scholars now have the option of spending part of their clerkships at hospitals and clinics in Shiprock, Gallup, Espanola, and Alamogordo for a portion of their OB/Gyn, Surgery, and Pediatric rotations. In addition, Scholars have options for unique outpatient experiences as part of their Pediatrics and Psychiatry clerkships, and for selected placements for Family Medicine clerkship. We will be sharing reports of experiences from the first two classes of RUUP Scholars to have these options, as well as descriptions of operational processes and hurdles. These innovative clinical experiences can be a key step to help program participants to be leaders in the care of underserved communities

In-vivo force decay of nickel-titanium closed-coil springs

Nickel-titanium (NiTi) closed coil springs are purported to deliver constant forces over extended ranges of activation and working times. In vivo studies supporting this claim are limited. The objective of this study is to evaluate changes in force decay properties of NiTi closed coil springs after clinical use