Accelerated Screening of Protein-Ligand Interactions via Parallel T2-Weighted 19F-MRI.

In drug discovery, ligands are sought that modulate the (mal-)function of medicinally relevant target proteins. In order to develop new drugs, typically a multitude of potential ligands are initially screened for binding and subsequently characterized for their affinity. Nuclear magnetic resonance (NMR) is a well-established and highly sensitive technology for characterizing such interactions. However, it has limited throughput, because only one sample can be measured at a time. In contrast, magnetic resonance imaging (MRI) is inherently parallel and MR parameters can conveniently be encoded in its images, potentially offering increased sample throughput. We explore this application using a custom-built 9-fold sample holder and a 19F-MRI coil. With this setup, we show that ligand binding can be detected by T2-weighted 19F-MRI using 4-(trifluoromethyl)benzamidine (TFBA) and trypsin as the reporter ligand and target protein, respectively. Furthermore, we demonstrate that the affinity of nonfluorinated ligands can be determined in a competition format by monitoring the dose-dependent displacement of TFBA. By comparing 19F-T2-weighted MR images of TFBA in the presence of different benzamidine (BA) concentrations-all recorded in parallel-the affinity of BA could be derived. Therefore, this approach promises parallel characterization of protein-ligand interactions and increased throughput of biochemical assays, with potential for increased sensitivity when combined with hyperpolarization techniques.

Lenz Lenses in a Cryoprobe: Boosting NMR Sensitivity Toward Environmental Monitoring of Mass-Limited Samples.

Nuclear magnetic resonance (NMR) spectroscopy is commonly employed in a wide range of metabolomic research. Unfortunately, due to its relatively low sensitivity, smaller samples become challenging to study by NMR. Cryoprobes can be used to increase sensitivity by cooling the coil and preamplifier, offering sensitivity improvements of ∼3 to 4x. Alternatively, microcoils can be used to increase mass sensitivity by improving sample filling and proximity, along with decreased electrical resistance. Unfortunately, combining the two approaches is not just technically challenging, but as the coil decreases, so does its thermal fingerprint, reducing the advantage of cryogenic cooling. Here, an alternative solution is proposed in the form of a Lenz lens inside a cryoprobe. Rather than replacing the detection coil, Lenz lenses allow the B1 field from a larger coil to be refocused onto a much smaller sample area. In turn, the stronger B1 field at the sample provides strong coupling to the cryocoil, improving the signal. By combining a 530 I.D. Lenz lens with a cryoprobe, sensitivity was further improved by 2.8x and 3.5x for 1H and 13C, respectively, over the cryoprobe alone for small samples. Additionally, the broadband nature of the Lenz lenses allowed multiple nuclei to be studied and heteronuclear two-dimensional (2D) NMR approaches to be employed. The sensitivity improvements and 2D capabilities are demonstrated on 430 nL of hemolymph and eight eggs (∼350 µm O.D.) from the model organismDaphnia magna. In summary, combining Lenz lenses with cryoprobes offers a relatively simple approach to boost sensitivity for tiny samples while retaining cryoprobe advantages.

Community pharmacists' naloxone counseling: A theory-informed qualitative study.

BACKGROUND: Opioid-related overdose (ORO) deaths have reached a record high in the United States. Naloxone is an opioid antagonist that can rapidly reverse an opioid overdose. Pharmacists are in an ideal position to provide naloxone and related counseling, given their accessibility and expertise. However, minimal research is available on community pharmacists' naloxone counseling. OBJECTIVES: The aim of this study was to investigate Georgia community pharmacists' naloxone counseling as well as explore their attitudes, subjective norms, and perceived behavioral control toward counseling. METHODS: Semi-structured telephone interviews were conducted to elicit pharmacists' beliefs and practices regarding naloxone counseling. The interviews were guided by open-ended questions based on the theory of planned behavior (TPB). Thematic analysis was performed to identify the modal salient beliefs expressed by the pharmacists. The Consolidated Criteria for Reporting Qualitative Research was used to report the study findings. RESULTS: A total of 12 community pharmacists participated. Pharmacists held mixed attitudes toward naloxone counseling. While they recognized it as a vital part of their profession to prevent ORO deaths, they also expressed concerns about offending patients. Regarding normative beliefs, pharmacists identified several groups, including regulatory agencies (e.g., Board of Pharmacy, CDC), managers, news/media, patients, and doctors, influencing their provision of naloxone counseling. Facilitators to counseling included receiving naloxone training and having access to counseling guidelines and resources. Reimbursement issues, high costs of naloxone, and lack of patient awareness were the most commonly cited barriers. Pharmacists reported participating in counseling and providing information on identifying signs of opioid overdose and administering naloxone. CONCLUSIONS: The TPB is a useful framework for understanding community pharmacists' beliefs and practices regarding naloxone counseling. Capitalizing on facilitators and targeting barriers related to pharmacists' reimbursement issues, high costs of naloxone, and increasing patients' awareness of naloxone use and benefits may enhance pharmacists' naloxone counseling.

Highly Fluorinated Peptide Probes with Enhanced In Vivo Stability for 19 F-MRI.

A labeling strategy for in vivo 19 F-MRI (magnetic resonance imaging) based on highly fluorinated, short hydrophilic peptide probes, is developed. As dual-purpose probes, they are functionalized further by a fluorophore and an alkyne moiety for bioconjugation. High fluorination is achieved by three perfluoro-tert-butyl groups, introduced into asparagine analogues by chemically stable amide bond linkages. d-amino acids and ß-alanine in the sequences endow the peptide probes with low cytotoxicity and high serum stability. This design also yielded unstructured peptides, rendering all 27 19 F substitutions chemically equivalent, giving rise to a single 19 F-NMR resonance with <10 Hz linewidth. The resulting performance in 19 F-MRI is demonstrated for six different peptide probes. Using fluorescence microscopy, these probes are found to exhibit high stability and long circulation times in living zebrafish embryos. Furthermore, the probes can be conjugated to bovine serum albumin with only amoderate increase in 19 F-NMR linewidth to ≈30 Hz. Overall, these peptide probes are hence suitable for in vivo 19 F-MRI applications.

Continuous quality improvement regulations for community pharmacy practice in the United States.

OBJECTIVES: In the United States, medication errors are considered to be the cause of 7000 deaths annually. Continuous quality improvement (CQI) is a management process that focuses on continually and systematically evaluating the organization's work process. In community pharmacy, CQI leads to enhanced patient safety through a reduction in medication errors and quality-related events (QREs). There is limited information about the variations in CQI regulations required by State Boards of Pharmacy (SBPs) for community pharmacy across the country. The objective of this study is to comprehensively describe CQI regulations required by SBPs for community pharmacy practice in the United States. METHODS: This was a cross-sectional study. Information regarding SBPs community pharmacy CQI regulations was collected electronically by surveying a representative of each SBP. In addition, a review of State Pharmacy Laws published online complemented the survey data. The percentage of states with CQI regulations for community pharmacy was estimated. RESULTS: Of the 50 Boards, 16 require pharmacies to maintain CQI programs to monitor and prevent QREs in community pharmacy. The most common elements of CQI programs include the management of known, alleged, and suspected medication errors that reach the patient (73%) and regular reviews of the pharmacy's aggregate data of medication errors or incidents (73%). The North Dakota SBP regulation is the most comprehensive, followed by that of Iowa, Maryland, Massachusetts, and Montana. CONCLUSION: There is wide variation among SBP CQI regulations for community pharmacy practice. Standardization of CQI programs across Boards, including a national database for reporting medication errors and QREs would enhance patient safety.

Real-Time NMR Monitoring of Spatially Segregated Enzymatic Reactions in Multilayered Hydrogel Assemblies*.

Compartmentalized chemical reactions at the microscale are important in biotechnology, yet monitoring the molecular content at these small scales is challenging. To address this challenge, we integrate a compact, reconfigurable reaction cell featuring electrochemical functionality with high-resolution NMR spectroscopy. We demonstrate the operation of this system by monitoring the activity of enzymes immobilized in chemically distinct layers within a multi-layered chitosan hydrogel assembly. As a benchmark, we observed the parallel activities of urease (Urs), catalase (Cat), and glucose oxidase (GOx) by monitoring reagent and product concentrations in real-time. Simultaneous monitoring of an independent enzymatic process (Urs) together with a cooperative process (GOx + Cat) was achieved, with chemical conversion modulation of the GOx + Cat process demonstrated by varying the order in which the hydrogel was assembled.

A survey of Alberta pharmacists' attitudes, comfort and perceived barriers to a community-based naloxone program.

BACKGROUND: Community pharmacists play an important role in the wellness of patients, families and friends affected by prescription and illicit opioid drugs. They are key partners of the Community Based Naloxone (CBN) Program in Alberta and similar programs across other Canadian jurisdictions. This publicly funded program is an evidence-based response to the opioid overdose crisis, facilitating access to and distribution of naloxone kits through pharmacies. The study aimed to describe Alberta community pharmacists' practices, training, comfort levels and views in dispensing naloxone kits through the CBN program and detail potential perceived barriers to program participation. METHODS: The study was conducted as a cross-sectional online survey of Alberta pharmacists. Data collected from the survey were descriptive and evaluated using Microsoft Excel. Fisher exact tests were used to study the associations in responses among several demographic characteristics and related to dispensing practices, pharmacists' beliefs and perceived barriers. RESULTS: A total of 255 responses were included in the final analysis, with 89.8% of pharmacists replying "yes" to CBN program participation. Pharmacists on average were "comfortable" dispensing naloxone to patients for varying indications, with 85% reporting always providing education when dispensing naloxone to an individual for the first time. About 41% of pharmacists reported no barriers to the program, with the most common perceived barriers being lack of time (29%), demand (20%) and funding (19%). CONCLUSION: Most community pharmacists who responded to the survey participate in the CBN program in Alberta. They held positive beliefs about their role in screening patients for the risk of opioid overdose and are confident in their abilities to recommend and educate on naloxone kits. Proactive screening appeared lower, however, and dispensing kits were potentially variable. Addressing factors such as time, funding for services and demand may help further pharmacist uptake and success of the program. Can Pharm J (Ott) 2021;154:xx-xx.

Motion prediction enables simulated MR-imaging of freely moving model organisms.

Magnetic resonance tomography typically applies the Fourier transform to k-space signals repeatedly acquired from a frequency encoded spatial region of interest, therefore requiring a stationary object during scanning. Any movement of the object results in phase errors in the recorded signal, leading to deformed images, phantoms, and artifacts, since the encoded information does not originate from the intended region of the object. However, if the type and magnitude of movement is known instantaneously, the scanner or the reconstruction algorithm could be adjusted to compensate for the movement, directly allowing high quality imaging with non-stationary objects. This would be an enormous boon to studies that tie cell metabolomics to spontaneous organism behaviour, eliminating the stress otherwise necessitated by restraining measures such as anesthesia or clamping. In the present theoretical study, we use a phantom of the animal model C. elegans to examine the feasibility to automatically predict its movement and position, and to evaluate the impact of movement prediction, within a sufficiently long time horizon, on image reconstruction. For this purpose, we use automated image processing to annotate body parts in freely moving C. elegans, and predict their path of movement. We further introduce an MRI simulation platform based on bright field videos of the moving worm, combined with a stack of high resolution transmission electron microscope (TEM) slice images as virtual high resolution phantoms. A phantom provides an indication of the spatial distribution of signal-generating nuclei on a particular imaging slice. We show that adjustment of the scanning to the predicted movements strongly reduces distortions in the resulting image, opening the door for implementation in a high-resolution NMR scanner.

A Nuclear Magnetic Resonance (NMR) Platform for Real-Time Metabolic Monitoring of Bioprocesses.

We present a Nuclear Magnetic Resonance (NMR) compatible platform for the automated real-time monitoring of biochemical reactions using a flow shuttling configuration. This platform requires a working sample volume of ∼11 mL and it can circulate samples with a flow rate of 28 mL/min., which makes it suitable to be used for real-time monitoring of biochemical reactions. Another advantage of the proposed low-cost platform is the high spectral resolution. As a proof of concept, we acquire 1H NMR spectra of waste orange peel, bioprocessed using Trichoderma reesei fungus, and demonstrate the real-time measurement capability of the platform. The measurement is performed over more than 60 h, with a spectrum acquired every 7 min, such that over 510 data points are collected without user intervention. The designed system offers high resolution, automation, low user intervention, and, therefore, time-efficient measurement per sample.

Automatic Adaptive Gain for Magnetic Resonance Sensitivity Enhancement.

The decaying nature of magnetic resonance (MR) signals results in a decreasing signal-to-quantization noise ratio (SQNR) over the acquisition time. Here we describe a method to enhance the SQNR, and thus the overall signal-to-noise ratio (SNR), by dynamically adapting the gain of the receiver before analog-to-digital conversion (ADC). This is in contrast to a standard experiment in which the gain is fixed for a single data acquisition and is thus adjusted only for the first points of the signal. The gain adjustment in our method is done automatically in a closed loop fashion by using the envelope of the MR signal as the control signal. Moreover, the method incorporates a robust mechanism that runs along with signal acquisition to monitor the gain modulation, enabling precise recovery of the signals. The automatic adaptive gain (AGAIN) method requires minimal additional hardware and is thus general and can be implemented in the signal path of any commercial spectrometer system. We demonstrate an SNR enhancement factor of 2.64 when applied to a custom spectrometer, while a factor of 1.4 was observed when applied to a commercial spectrometer.

Emergency Physicians' Perception of Barriers and Facilitators for Adopting an Opioid Prescribing Guideline in Ohio: A Qualitative Interview Study.

BACKGROUND: Ohio has the fifth highest rate of prescription opioid overdose deaths in the United States. One strategy implemented to address this concern is a state-wide opioid prescribing guideline in the emergency department (ED). OBJECTIVE: Our aim was to explore emergency physicians' perceptions on barriers and strategies for the Ohio ED opioid prescribing guideline. METHODS: Semi-structured interviews with emergency physicians in Ohio were conducted from October to December 2016. Emergency physicians were recruited through the American College of Emergency Physicians Ohio State Chapter. The interview guide explored issues related to the implementation of the guidelines. Interview data were transcribed and thematically analyzed and coded using a scheme of inductively determined labels. RESULTS: In total, we conducted 20 interviews. Of these, 11 were also the ED medical director at their institution. Main themes we identified were: 1) increased organizational responsibility, 2) improved prescription drug monitoring program (PDMP) integration, 3) concerns regarding patient satisfaction scores, and 4) increased patient involvement. In addition, some physicians wanted the guidelines to contain more clinical information and be worded more strongly against opioid prescribing. Emergency physicians felt patient satisfaction scores were perceived to negatively impact opioid prescribing guidelines, as they may encourage physicians to prescribe opioids. Furthermore, some participants reported that this is compounded if the emergency physicians' income was linked to their patient satisfaction score. CONCLUSIONS: Emergency physicians interviewed generally supported the state-wide opioid prescribing guideline but felt hospitals needed to take additional organizational responsibility for addressing inappropriate opioid prescribing.

Minding the Gap: Factors Associated With Primary Care Coordination of Adults in 11 Countries.

PURPOSE: Care coordination has been identified as a key strategy in improving the effectiveness, safety, and efficiency of the US health care system. Our objective was to determine whether population or health care system issues are associated with primary care coordination gaps in the United States and other high-income countries. METHODS: We analyzed data from the 2013 Commonwealth Fund International Health Policy (IHP) survey with multivariate logistic regression analysis. Respondents were adult primary care patients from 11 countries: Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, United Kingdom, and the United States. Poor primary care coordination was defined as participants reporting at least 3 gaps in the coordination of care out of a maximum of 5. RESULTS: Analyses were based on 13,958 respondents. The rate of poor primary care coordination was 5.2% (724/13,958 respondents) overall and highest in the United States, at 9.8% (137/1,395 respondents). Multivariate regression analysis among all respondents found that they were less likely to experience poor primary care coordination if their primary care physician often or always knew their medical history, spent sufficient time, involved them, and explained things well (odds ratio = 0.6 for each). Poor primary care coordination was more likely to occur among patients with chronic conditions (odds ratios = 1.4-2.1 depending on number) and patients younger than 65 years (odds ratios = 1.6-2.3 depending on age-group). Among US respondents, insurance status, health status, household income, and sex were not associated with poor primary care coordination. CONCLUSIONS: The United States had the highest rate of poor primary care coordination among the 11 high-income countries evaluated. An established relationship with a primary care physician was significantly associated with better care coordination, whereas being chronically ill or younger was associated with poorer care coordination.

Strategies and policies to address the opioid epidemic: A case study of Ohio.

OBJECTIVE: To describe the strategies and policies implemented in Ohio to improve opioid safety and to discuss the role that pharmacists can play in implementing, promoting, and enhancing the effectiveness of these policies. SETTING: Ohio has the fifth highest rate of drug overdose deaths (24.6 deaths per 100,000) in the United States. Unintentional drug overdose has become the leading cause of injury-related death in Ohio. In 2015, there were 3050 overdose deaths in Ohio, and in 2014 there were an estimated 12,847 overdose events reversed by emergency medical services with naloxone. PRACTICE DESCRIPTION: Not applicable. PRACTICE POLICY INNOVATION: In 2011, the Governor's Cabinet Opiate Action Team was created to implement a multifaceted strategy, in part (1) to promote the responsible use of opioids, (2) to reduce the supply of opioids, and (3) to support overdose prevention and expand access to naloxone. Innovations to assist these goals include the development of Ohio guidelines on the responsible use of opioids, mandatory use of Ohio's prescription drug monitoring program, closing pill mills, promotion of drug take-back programs and increased access to naloxone and public health campaigns. EVALUATION: Not applicable. RESULTS: Since the development of the Governor's Cabinet Opiate Action Team, there were 81 million fewer doses of opioids dispensed to Ohio patients in 2015 compared with 782 million doses dispensed in 2011. As such, the proportion of unintentional drug overdose deaths involving prescription opioids has reduced from 45% in 2011 to 22% in 2015. CONCLUSION: Strong political support was crucial in Ohio to facilitate the rapid implementation opioid overdose prevention programs and the promotion of public awareness campaigns. However, the misuse and abuse of prescription opioids are complex problems requiring a comprehensive and multifaceted approach. Pharmacists are identified as a crucial component of the state strategy to addressing opioid abuse by promoting responsible prescribing and adopting prevention practices.

Development of clinical pharmacy key performance indicators for hospital pharmacists using a modified Delphi approach.

BACKGROUND: Key performance indicators (KPIs) are quantifiable measures of quality. There are no published, systematically derived clinical pharmacy KPIs (cpKPIs). OBJECTIVE: A group of hospital pharmacists aimed to develop national cpKPIs to advance clinical pharmacy practice and improve patient care. METHODS: A cpKPI working group established a cpKPI definition, 8 evidence-derived cpKPI critical activity areas, 26 candidate cpKPIs, and 11 cpKPI ideal attributes in addition to 1 overall consensus criterion. Twenty-six clinical pharmacists and hospital pharmacy leaders participated in an internet-based 3-round modified Delphi survey. Panelists rated 26 candidate cpKPIs using 11 cpKPI ideal attributes and 1 overall consensus criterion on a 9-point Likert scale. A meeting was facilitated between rounds 2 and 3 to debate the merits and wording of candidate cpKPIs. Consensus was reached if 75% or more of panelists assigned a score of 7 to 9 on the consensus criterion during the third Delphi round. RESULTS: All panelists completed the 3 Delphi rounds, and 25/26 (96%) attended the meeting. Eight candidate cpKPIs met the consensus definition: (1) performing admission medication reconciliation (including best-possible medication history), (2) participating in interprofessional patient care rounds, (3) completing pharmaceutical care plans, (4) resolving drug therapy problems, (5) providing in-person disease and medication education to patients, (6) providing discharge patient medication education, (7) performing discharge medication reconciliation, and (8) providing bundled, proactive direct patient care activities. CONCLUSIONS: A Delphi panel of hospital pharmacists was successful in determining 8 consensus cpKPIs. Measurement and assessment of these cpKPIs will serve to advance clinical pharmacy practice and improve patient care.

Using the Health Belief Model to explain patient involvement in patient safety.

BACKGROUND: With the knowledge that patient safety incidents can significantly impact patients, providers and health-care organizations, greater emphasis on patient involvement as a means to mitigate risks warrants further research. OBJECTIVE: To understand whether patient perceptions of patient safety play a role in patient involvement in factual and challenging patient safety practices and whether the constructs of the Health Belief Model (HBM) help to explain such perceptions. DESIGN: Partial least squares (PLS) analysis of survey data. SETTING AND PARTICIPANTS: Four inpatient units located in two tertiary hospitals in Atlantic Canada. Patients discharged from participating units between November 2010 and January 2011. INTERVENTION: None. RESULTS: A total of 217 of the 587 patient surveys were returned for a final response rate of 37.0%. The PLS analysis revealed relationships between patient perceptions of threat and self-efficacy and the performance of factual and challenging patient safety practices, explaining 46 and 42% of the variance, respectively. DISCUSSION: The results from this study provide evidence for the constructs and relationships set forth by the HBM. Perceptions of patient safety were shown to influence patient likelihood for engaging in selected patient safety practices. While perceptions of barriers and benefits and threats were found to be a contributing factor to patient involvement in patient safety practices, self-efficacy plays an important role as a mediating factor. CONCLUSIONS: Overall, the use of the HBM within patient safety provides for increased understanding of how such perceptions can be influenced to improve patient engagement in promoting safer health care.

Seniors managing multiple medications: using mixed methods to view the home care safety lens.

BACKGROUND: Patient safety is a national and international priority with medication safety earmarked as both a prevalent and high-risk area of concern. To date, medication safety research has focused overwhelmingly on institutional based care provided by paid healthcare professionals, which often has little applicability to the home care setting. This critical gap in our current understanding of medication safety in the home care sector is particularly evident with the elderly who often manage more than one chronic illness and a complex palette of medications, along with other care needs. This study addresses the medication management issues faced by seniors with chronic illnesses, their family, caregivers, and paid providers within Canadian publicly funded home care programs in Alberta (AB), Ontario (ON), Quebec (QC) and Nova Scotia (NS). METHODS: Informed by a socio-ecological perspective, this study utilized Interpretive Description (ID) methodology and participatory photographic methods to capture and analyze a range of visual and textual data. Three successive phases of data collection and analysis were conducted in a concurrent, iterative fashion in eight urban and/or rural households in each province. A total of 94 participants (i.e., seniors receiving home care services, their family/caregivers, and paid providers) were interviewed individually. In addition, 69 providers took part in focus groups. Analysis was iterative and concurrent with data collection in that each interview was compared with subsequent interviews for converging as well as diverging patterns. RESULTS: Six patterns were identified that provide a rich portrayal of the complexity of medication management safety in home care: vulnerabilities that impact the safe management and storage of medication, sustaining adequate supports, degrees of shared accountability for care, systems of variable effectiveness, poly-literacy required to navigate the system, and systemic challenges to maintaining medication safety in the home. CONCLUSIONS: There is a need for policy makers, health system leaders, care providers, researchers, and educators to work with home care clients and caregivers on three key messages for improvement: adapt care delivery models to the home care landscape; develop a palette of user-centered tools to support medication safety in the home; and strengthen health systems integration.

Confirming delivery: understanding the role of the hospitalized patient in medication administration safety.

The purpose of our study was to gain an understanding of current patient involvement in medication administration safety from the perspectives of both patients and nursing staff members. Administering medication is taken for granted and therefore suited to the development of theory to enhance its understanding. We conducted a constructivist, grounded theory study involving 24 patients and 26 nursing staff members and found that patients had the role of confirming delivery in the administration of medication. Confirming delivery was characterized by three interdependent subprocesses: engaging in the medication administration process, being "half out of it" (patient mental status), and perceiving time. We believe that ours is one of the first qualitative studies on the role of hospitalized patients in administering medication. Medication administration and nursing care systems, as well as patient mental status, impose limitations on patient involvement in safe medication administration.