Little is understood about the incidence of sudden death, its underlying pathophysiology, or its actual relationship to subject positioning. We report data from 4828 consecutive use of force events (August 2006-March 2013) in 7 Canadian police agencies in Eastern and Western Canada. Consecutive subjects aged >18 years who were involved in a police use of force event were included regardless of outcome. Officers prospectively documented: final resting position of the subject (prone or non-prone), intoxicants and/or emotional distress, presence of features of excited delirium, and the use of all force modalities. Our outcome of interest was sudden in-custody death. Our study has 80% power to detect a difference of 0.5% in sudden death between the positions. In over 3.25 million consecutive police--public interactions; use of force occurred in 4,828 subjects (0.1% of police public interactions; 95% CI = 0.1%, 0.1%). Subjects were usually male (87.5%); median age 32 years; 81.5% exhibited alcohol and/or drug intoxication, and/or emotional distress at the scene. Significantly more subjects remained in a non-prone vs. prone position; but over 2000 subjects remained prone. One individual died suddenly and unexpectedly in the non-prone position with all 10 features of excited delirium. No subject died in the prone position. There was no significant difference in sudden in custody death, in a worst case scenario 99.8% of subjects would be expected to survive being in either the prone or non-prone position following police use of force.

Background

The Study to Assess Long-term Opioid Medication Effectiveness (SALOME) is a two-stage phase III, single site (Vancouver, Canada), randomized, double blind controlled trial designed to test if hydromorphone is as effective as diacetylmorphine for the treatment of long-term illicit opioid injection. Recruiting participants for clinical trials continues to be a challenge in medical and addiction research, with many studies not being able to reach the planned sample size in a timely manner. The aim of this study is to describe the recruitment strategies in SALOME, which offered appealing treatments but had limited clinic capacity and no guaranteed post-trial continuation of the treatments.

Methods

SALOME included chronic opioid-dependent, current illicit injection opioid users who had at least one previous episode of opioid maintenance treatment. Regulatory approvals were received in June 2011 and recruitment strategies were implemented over the next 5 months. Recruitment strategies included ongoing open communication with the community, a consistent and accessible team and participant-centered screening. All applicants completed a pre-screening checklist to assess prerequisites. Applicants meeting these prerequisites were later contacted to commence the screening process.

Results

A total of 598 applications were received over the two-year recruitment period; 130 were received on the first day of recruitment. Of these applicants, 485 met prerequisites; however, many could not be found or were not reached before recruitment ended. For the 253 candidates who initiated the screening process, the average time lapse between application and screening date was 8.3 months (standard deviation [SD] = 4.44) and for the 202 randomized to the study, the average processing time from initial screen to randomization was 25.9 days (SD = 37.48; Median = 15.0).

Conclusions

As in prior trials offering injectable diacetylmorphine within a supervised model, recruiting participants for this study took longer than planned. The recruitment challenges overcome in SALOME were due to the high number of applicants compared with the limited number that could be randomized and treated. Our study emphasizes the value of integrating these strategies into clinical addiction research to overcome study-specific barriers.

Trial registration

ClinicalTrials.gov: NCT01447212.

Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl- sn -glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). We used synchrotron small-angle x-ray scattering to determine whether PTX solubility is governed by lipid membrane structure (condensed with DNA in pellet form) or by local intermolecular interactions. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of lipid carriers for PTX delivery regardless of carrier structure.

Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). To determine whether PTX solubility is governed by lipid membrane structure or by local intermolecular interactions, we used synchrotron small-angle X-ray scattering. To increase the signal/noise ratio, we used DNA to condense the lipid formulations into lipoplex pellets. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of liposomal carriers for PTX delivery.

To measure the effect of an electronic health record (EHR) alert on chronic hepatitis B (CHB) screening among at-risk Asian and Pacific Islanders (API). API patients who had not yet completed hepatitis B surface antigen (HBsAg) testing were identified by a novel EHR-based population health tool. At-risk API patients in Cohort 1 (primarily privately insured) and Cohort 2 (includes Medicare and/or Medicaid) were randomized to alert activation in their electronic medical charts or not. In total, 8299 API were found to be deficient in HBsAg completion at baseline within our health system. In Cohort 1, 1542 patients and 1568 patients were randomized to the alert and control respectively. In Cohort 2, 2599 patients and 2590 patients were randomized to the alert and control respectively. For both cohorts combined, 389 HBsAg tests were completed in the alert group compared to 177 HBsAg tests in the control group (p < 0.0001; OR = 2.3; 95% CI 1.94-2.80), but there was no increased detection of HBsAg positivity from the alert (15 versus 13 respectively, p = 0.09; OR = 0.5; 95% CI 0.24-1.09). Our results demonstrate that personalized, automated electronic alerts increase screening for CHB, but more comprehensive measures are needed to detect HBsAg positive patients.NIH Trial Registry Number: NCT04240678.

Background: Implementation of screening recommendations for chronic hepatitis B (CHB) among foreign-born persons at risk has been sub-optimal. The use of alerts and reminders in the electronic health record (EHR) has led to increased screening for other common conditions. The aim of our study was to measure the effectiveness of an EHR alert on the implementation of hepatitis B surface antigen (HBsAg) screening of foreign-born Asian and Pacific Islander (API) patients.Methods: We used a novel technique to identify API patients by self-identified ethnicity, surname, country of origin, and language preference, and who had no record of CHB screening with HBsAg within the EHR. Patients with Medicare and/or Medicaid insurance were excluded due to lack of coverage for routine HBsAg screening at the time of this study. At-risk API patients were randomized to alert activation in their EHR or not (control).Results: A total of 2,987 patients met inclusion criteria and were randomized to the alert (n = 1,484) or control group (n = 1,503). In the alert group, 119 patients were tested for HBsAg, compared with 48 in the control group (odds ratio, 2.64; 95% confidence interval, 1.88-3.73; P < 0.001). In the alert group, 4 of 119 (3.4%) tested HBsAg-positive compared with 5 of 48 (10.4%) in the control group (P = 0.12).Conclusions: An EHR alert significantly increased HBsAg testing among foreign-born APIs.Impact: Utilization of EHR alerts has the potential to improve implementation of hepatitis B-screening guidelines. Cancer Epidemiol Biomarkers Prev; 27(11); 1352-7. ©2018 AACR.

Poly(ethylene glycol) (PEG) is a polymer used widely in drug delivery to create "stealth" nanoparticles (NPs); PEG coatings suppress NP detection and clearance by the immune system and beneficially increase NP circulation time in vivo. However, NP PEGylation typically obstructs cell attachment and uptake in vitro compared to the uncoated equivalent. Here, we report on a cationic liposome (CL) NP system loaded with the hydrophobic cancer drug paclitaxel (PTX) in which PEGylation (i.e., PEG-CL_PTX NPs) unexpectedly enhances, rather than diminishes, delivery efficacy and cytotoxicity to human cancer cells. This highly unexpected enhancement occurs even when the PEG-chains coating the NP are in the transition regime between the mushroom and brush conformations. Cryogenic transmission electron microscopy (TEM) of PEG-CL_PTX NPs shows that PEG causes the proliferation of a mixture of sterically stabilized nanometer-scale vesicles and anisotropic micelles (e.g., bicelles). Remarkably, the onset of bicelles at sub-monolayer concentrations of the PEG coat has to our knowledge not been previously reported; it was previously thought that PEG-lipid in this composition regime was incorporated into vesicles but did not alter their shape. Confocal microscopy and flow cytometry reveal significantly greater PTX cell uptake from stabilized PEG-CL_PTX NPs (vesicles and bicelles) in contrast to bare CL_PTX NPs, which can aggregate in cell medium. This underscores the ability of steric stabilization to facilitate NP entry into cells via distinct size-dependent endocytic pathways, some of which cannot transport large NP aggregates into cells. This study highlights the value of understanding how PEGylation alters NP shape and structure, and thus NP efficacy, to design next-generation stealth drug carriers that integrate active cell-targeting strategies into NPs for in vivo delivery.

Objective

To evaluate the impact of implementing clinical decision support (CDS) tools for outpatient antibiotic prescribing in the emergency department (ED) and clinic settings.

Design

We performed a before-and-after, quasi-experimental study that employed an interrupted time-series analysis.

Setting

The study institution was a quaternary, academic referral center in Northern California.

Participants

We included prescriptions for patients in the ED and 21 primary-care clinics within the same health system.

Intervention

We implemented a CDS tool for azithromycin on March 1, 2020, and a CDS tool for fluoroquinolones (FQs; ie, ciprofloxacin, levofloxacin, and moxifloxacin) on November 1, 2020. The CDS added friction to inappropriate ordering workflows while adding health information technology (HIT) features to easily perform recommended actions. The primary outcome was the number of monthly prescriptions for each antibiotic type, by implementation period (before vs after).

Results

Immediately after azithromycin-CDS implementation, monthly rates of azithromycin prescribing decreased significantly in both the ED (-24%; 95% CI, -37% to -10%; P < .001) and outpatient clinics (-47%; 95% CI, -56% to -37%; P < .001). In the first month after FQ-CDS implementation in the clinics, there was no significant drop in ciprofloxacin prescriptions; however, there was a significant decrease in ciprofloxacin prescriptions over time (-5% per month; 95% CI, -6% to -3%; P < .001), suggesting a delayed effect of the CDS.

Conclusion

Implementing CDS tools was associated with an immediate decrease in azithromycin prescriptions, in both the ED and clinics. CDS may serve as a valuable adjunct to existing antimicrobial stewardship programs.

Background

Proactive referrals through electronic orders (eReferrals) can increase patient connection with tobacco quitlines. More information is needed on "real-world" implementation of electronic health record tools to promote tobacco cessation while minimizing provider burden.

Objectives

This paper examines the health system implementation of an eReferral to a tobacco quitline without best practice alerts in primary care, specialty, and hospital settings in an academic health system.

Methods

This is a prospective implementation study of a health system tobacco eReferral to a state quitline that was completed with an approach to minimize provider cognitive burden. Data are drawn from electronic health record data at University of California, Davis Health Systems (March 2013-February 2016).

Results

Over 3 years, 16,083 encounters with smokers resulted in 1,137 eReferral orders (7.1%). Treatment reach was 1.6% for quitline services and 2.3% for outpatient group classes. While the group classes were offered to outpatient smokers, the eReferral order was included in an outpatient order set and eventually an automated inpatient discharge order set; no provider alerts were implemented. Referrals were sustained and doubled after inpatient order set implementation. Among all first time eReferral patients, 12.2% had a 6 to 12 month follow-up visit at which they were documented as nonsmoking.

Conclusion

This study demonstrates a quitline eReferral order can be successfully implemented and sustained with minimal promotion, without provider alerts and in conjunction with group classes. Reach and effectiveness were similar to previously described literature.

Importance

Individually designed single-patient multi-crossover (n-of-1) trials can facilitate tailoring of treatments directed at various conditions, including chronic musculoskeletal pain (CMSP) but are potentially burdensome, which may limit uptake in research and practice.

Objectives

To determine whether patients randomized to participate in an n-of-1 trial supported by a mobile health (mHealth) app would experience less pain and improved global health, adherence, satisfaction, and shared decision making compared with patients assigned to usual care.

Design, setting, and participants

This randomized clinical trial compared participation in an individualized, mHealth-supported n-of-1 trial vs usual care. The participating 215 patients had CMSP for at least 6 weeks, had a smartphone or tablet with a data plan, were enrolled in northern California from July 2014 through July 2016, and were followed for up to 1 year by 48 clinicians in academic, community, Veterans Affairs, and military settings.

Interventions

Intervention patients met with their clinicians and used a desktop interface to select treatments and trial parameters for an n-of-1 trial comparing 2 pain-management regimens. The mHealth app provided reminders to take designated treatments on assigned days and to upload responses to daily questions on pain and treatment-associated adverse effects. Control patients received care as usual.

Main outcomes and measures

The primary outcome was change in the PROMIS (Patient-Reported Outcomes Measurement Information System) pain-related interference 8-item short-form scale (full scale range, 41-78) from baseline to 6 months. Secondary outcomes included patient-reported pain intensity, overall health, analgesic adherence, trust in clinician, satisfaction with care, medication-related shared decision making, and, for the n-of-1 group only, participant engagement and experience.

Results

Among 215 patients (108 randomized to the n-of-1 intervention and 107 to control), 102 (47%) were women, and the mean (SD) age was 55.5 (11.1) years. At the 6-month follow-up, pain interference was reduced in both groups, though there was no difference between the intervention and control groups (-1.36 points; 95% CI, -2.91 to 0.19 points; P = .09). There were no advantages in secondary outcomes for intervention patients vs control patients except for higher medication-related shared decision making at 6 months (between-group difference, 11.9 points; 95% CI, 2.6-21.2 points; P = .01). Among patients assigned to the n-of-1 group, 88% (n = 86) affirmed that the mHealth app could help people like them manage their pain.

Conclusions and relevance

In this population of patients with CMSP, mHealth-supported n-of-1 trials were feasible and associated with a satisfactory user experience, but n-of-1 trial participation did not significantly improve pain interference at 6 months vs usual care.

Trial registration

ClinicalTrials.gov identifier: NCT02116621.