Factors influencing the effects of policies and interventions to promote the appropriate use of medicines in high-income countries: A rapid realist review.

BACKGROUND: The appropriate use of medicines has long been recognized as a fundamental component of medicine policies. We aimed to extract lessons from published research on how policy contexts and mechanisms can affect the outcomes of national- or health-system level interventions to promote appropriate medicine use (defined as an increase in underutilized medications or decrease in inappropriate medication use). METHODS: We conducted a rapid realist review of published evidence concerning system-level policies to promote the appropriate use of medicines in high-income countries with universal prescription drug coverage. We searched MEDLINE and Embase to identify relevant publications. We used a realist evaluation framework to identify contexts, mechanisms, and outcomes for each intervention and to hypothesize which policy contexts and mechanisms supported successful outcomes in terms of relative changes in the prevalence of use of the specific medication classes targeted. RESULTS: From 1,318 identified studies, 18 met our inclusion criteria. 13 distinct policies were identified. Three main policy-related factors underpinned successful interventions: involving providers and patients through program interventions; central coordination through national agencies dedicated to medicine policies; and the establishment of an explicit and integrated national medicine policy strategy. CONCLUSION: Policymakers can improve coordination of national pharmaceutical policies to reduce harms from inappropriate medicines use, thus improving health outcomes through cost-effective programs.

A Family-Based Study of Inherited Genetic Risk in Lipedema.

Background: Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecular and genetic bases are poorly understood, making diagnosis and treatment difficult. Historical evaluation of individuals with lipedema indicates a positive family history in 60%-80% of cases; however, genetic investigation of larger family cohorts is required. Here, we report the largest family-based sequencing study to date, aimed at identifying genetic changes that contribute to lipedema. Methods and Results: DNA samples from 31 individuals from 9 lipedema families were analyzed to reveal genetic variants predicted to alter protein function, yielding candidate variants in 469 genes. We did not identify any individual genes that contained likely disease-causing variants across all participating families. However, gene ontology analysis highlighted vasopressin receptor activity, microfibril binding, and patched binding as statistically significantly overrepresented categories for the set of candidate variants. Conclusions: Our study suggests that lipedema is not caused by a single exomic genetic factor, providing support for the hypothesis of genetic heterogeneity in the etiology of lipedema. As the largest study of its kind in the lipedema field, the results advance our understanding of the disease and provide a roadmap for future research aimed at improving the lives of those affected by lipedema.

Displaced Geriatric Femoral Neck Fractures: A Retrospective Comparison of Total Hip Arthroplasties Versus Hemiarthroplasty.

Introduction: Controversary exists around the best surgical management for traumatic geriatric displaced femoral neck fractures. The study objective was to compare outcomes among those managed with a total hip arthroplasty (THA) to those managed with a hemiarthroplasty (HA). Methods: This retrospective matched cohort study included geriatric hip fractures (≥65 y/o) admitted 7/1/16-3/31/20. Patients were matched on having an advanced directive, pre-existing dementia, and age. Outcomes included: time to surgery, length of stay (LOS), blood loss volume, and discharge destination. THAs were compared to HAs; an alpha of <.05 indicated statistical significance. Results: There were 191 patients: 86% were treated with HA and 14% with THA. Most (40%) were 80-89 years old, 66% were female, and 92% were white. After matching, the groups were well balanced on demographics and baseline characteristics with 27 patients/arm. The median time to surgery was 23 hours for both arms, P = .38. The LOS was significantly longer for those managed with a HA when compared to those managed with a THA, 5.6 vs 4.0 days, P = .001. The median blood loss volume was significantly lower for HAs than for THAs, but the difference was small, 100 vs 120 mL, P = .02. Patients managed with a HA were less likely to be discharged home than those managed with a THA, 22% vs 70%, P = .005. Conclusions: While patients managed with a THA had significantly more blood loss than those managed with a HA, the difference in blood loss was small and not clinically relevant. Those managed with a THA experienced a significantly shorter LOS and were more likely to be discharged home than patients managed with a HA. Among a healthier, younger geriatric population, THA may lead to shortened LOS and improved discharge destinations when compared to HA for treatment of femoral neck fractures.

Propensity matched analysis examining the effect of passive reversal of direct oral anticoagulants on blood loss and the need for transfusions among traumatic geriatric hip fractures.

BACKGROUND: Reversal of direct oral anticoagulants (DOACs) is currently recommended prior to emergent surgery, such as surgical intervention for traumatic geriatric hip fractures. However, reversal methods are expensive and timely, often delaying surgical intervention, which is a predictor of outcomes. The study objective was to examine the effect of DOAC reversal on blood loss and transfusions among geriatric patients with hip fractures. METHODS: This retrospective propensity-matched study across six level I trauma centers included geriatric patients on DOACs with isolated fragility hip fractures requiring surgical intervention (2014-2017). Outcomes included: intraoperative blood loss, intraoperative pRBCs, and hospital length of stay (HLOS). RESULTS: After matching there were 62 patients (31 reversed, 31 not reversed), 29 patients were not matched. The only reversal method utilized was passive reversal (waiting ≥ 24 hours for elimination). Passively reversed patients had a longer time to surgery (mean, 43 vs. 18 hours, p < 0.01). Most patients (92%) had blood loss (90% passively reversed, 94% not reversed); the median volume of blood loss was 100 mL for both those groups, p = 0.97. Thirteen percent had pRBCs transfused (13% passively reversed and 13% not reversed); the median volume of pRBCs transfused was 525 mL for those passively reversed and 314 mL for those not reversed, p = 0.52. The mean HLOS was significantly longer for those passively reversed (7 vs. 5 days, p = 0.001). CONCLUSIONS: Passive DOAC reversal for geriatric patients with isolated hip fracture requiring surgery may be contributing to delayed surgery and an increased HLOS without having a significant effect on blood loss or transfusions. These data suggest that passive DOAC reversal may not be necessary prior to surgical repair of isolated hip fracture.

Effect of Free Medicine Distribution on Health Care Costs in Canada Over 3 Years: A Secondary Analysis of the CLEAN Meds Randomized Clinical Trial.

Importance: Few interventions are proven to reduce total health care costs, and addressing cost-related nonadherence has the potential to do so. Objective: To determine the effect of eliminating out-of-pocket medication fees on total health care costs. Design, Setting, and Participants: This secondary analysis of a multicenter randomized clinical trial using a prespecified outcome took place across 9 primary care sites in Ontario, Canada (6 in Toronto and 3 in rural areas), where health care services are generally publicly funded. Adult patients (≥18 years old) reporting cost-related nonadherence to medicines in the past 12 months were recruited between June 1, 2016, and April 28, 2017, and followed up until April 28, 2020. Data analysis was completed in 2021. Interventions: Access to a comprehensive list of 128 medicines commonly prescribed in ambulatory care with no out-of-pocket costs for 3 years vs usual medicine access. Main Outcome and Measures: Total publicly funded health care costs over 3 years, including costs of hospitalizations. Health care costs were determined using administrative data from Ontario's single-payer health care system, and all costs are reported in Canadian dollars with adjustments for inflation. Results: A total of 747 participants from 9 primary care sites were included in the analysis (mean [SD] age, 51 [14] years; 421 [56.4%] female). Free medicine distribution was associated with a lower median total health care spending over 3 years of $1641 (95% CI, $454-$2792; P = .006). Mean total spending was $4465 (95% CI, -$944 to $9874) lower over the 3-year period. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, eliminating out-of-pocket medication expenses for patients with cost-related nonadherence in primary care was associated with lower health care spending over 3 years. These findings suggest that eliminating out-of-pocket medication costs for patients could reduce overall costs of health care. Trial Registration: ClinicalTrials.gov Identifier: NCT02744963.

Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling.

Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood. Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema. Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury. Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema.

Key signaling networks are dysregulated in patients with the adipose tissue disorder, lipedema.

OBJECTIVES: Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema. METHODS: We compared whole-tissues, ADSCs, and adipocytes from body mass index-matched lipedema (n = 14) and unaffected (n = 10) patients using comprehensive global lipidomic and metabolomic analyses, transcriptional profiling, and functional assays. RESULTS: Transcriptional profiling revealed >4400 significant differences in lipedema tissue, with altered levels of mRNAs involved in critical signaling and cell function-regulating pathways (e.g., lipid metabolism and cell-cycle/proliferation). Functional assays showed accelerated ADSC proliferation and differentiation in lipedema. Profiling lipedema adipocytes revealed >900 changes in lipid composition and >600 differentially altered metabolites. Transcriptional profiling of lipedema ADSCs and non-lipedema ADSCs revealed significant differential expression of >3400 genes including some involved in extracellular matrix and cell-cycle/proliferation signaling pathways. One upregulated gene in lipedema ADSCs, Bub1, encodes a cell-cycle regulator, central to the kinetochore complex, which regulates several histone proteins involved in cell proliferation. Downstream signaling analysis of lipedema ADSCs demonstrated enhanced activation of histone H2A, a key cell proliferation driver and Bub1 target. Critically, hyperproliferation exhibited by lipedema ADSCs was inhibited by the small molecule Bub1 inhibitor 2OH-BNPP1 and by CRISPR/Cas9-mediated Bub1 gene depletion. CONCLUSION: We found significant differences in gene expression, and lipid and metabolite profiles, in tissue, ADSCs, and adipocytes from lipedema patients compared to non-affected controls. Functional assays demonstrated that dysregulated Bub1 signaling drives increased proliferation of lipedema ADSCs, suggesting a potential mechanism for enhanced adipogenesis in lipedema. Importantly, our characterization of signaling networks driving lipedema identifies potential molecular targets, including Bub1, for novel lipedema therapeutics.

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial.

BACKGROUND: Adherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted. METHODS AND FINDINGS: We randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI -0.25 to 0.79, p = 0.302), systolic blood pressure (-3.9; 95% CI -9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI -0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports. CONCLUSIONS: In this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT02744963.

Partial warfarin reversal prior to hip fracture surgical intervention in geriatric trauma patients effects on blood loss and transfusions.

BACKGROUND: Warfarin reversal is typically sought prior to surgery for geriatric hip fractures; however, patients often proceed to surgery with partial warfarin reversal. The effect of partial reversal (defined as having an international normalized ratio [INR] > 1.5) remains unclear. METHODS: This was a retrospective cohort study. Geriatric patients (≥65 y/o) admitted to six level I trauma centers from 01/2014-01/2018 with isolated hip fractures requiring surgery who were taking warfarin pre-injury were included. Warfarin reversal methods included: vitamin K, factor VIIa, (a)PCC, fresh frozen plasma (FFP), and the "wait and watch" method. An INR of ≤ 1.5 defined complete reversal. The primary outcome was the volume of blood loss during surgery; other outcomes included packed red blood cell (pRBC) and FFP transfusions, and time to surgery. RESULTS: There were 135 patients, 44% partially reversed and 56% completely reversed. The median volume of blood loss was 100 mL for both those completely and partially reversed, p = 0.72. There was no difference in the proportion of patients with blood loss by study arm, 95% vs. 95%, p > 0.99. Twenty-five percent of those completely reversed and 39% of those partially reversed had pRBCs transfused, p = 0.08. Of those completely reversed 5% received an FFP transfusion compared to 14% of those partially reversed, p = 0.09. There were no statistically significant differences observed for the volume of pRBC or FFP transfused, or for time to surgery. CONCLUSIONS: Partial reversal may be safe for blood loss and blood product transfusions for geriatric patients with isolated hip fractures. Complete warfarin reversal may not be necessary prior to hip fracture surgery, especially for mildly elevated INRs.

An international survey of pelvic trauma surgeons on the management of pelvic ring injuries.

INTRODUCTION: There exists substantial variability in the management of pelvic ring injuries among pelvic trauma surgeons. The objective of this study was to perform a comprehensive survey on the management of pelvic ring injuries among an international group of pelvic trauma surgeons to determine areas of agreement and disagreement. METHODS: A 45-item questionnaire was developed using an online survey platform and distributed to 30 international pelvic trauma surgeons. The survey consisted of general questions on the acute management of pelvic ring injuries and questions regarding 5 cases: Lateral compression (LC) type 1 injury, LC-3, Anterior-posterior compression (APC) type 3 injury, a combined vertical shear (VS) injury through the sacrum, and VS injury through sacroiliac joint. Respondents were shown blinded anteroposterior pelvis radiographs and axial computed tomography (CT) images for each case and asked if the injury needed fixation, the type of fixation, the order of fixation, and postoperative weight-bearing status. The Kappa statistic was calculated to assess agreement between respondents for each question. RESULTS: Nineteen out of 30 pelvic trauma surgeons completed the survey. Respondents practiced in Brazil (n = 1), Germany (n = 1), India (n = 1), Italy (n = 1) United Kingdom (n = 1), and the United States (n = 14). Of the 45 questions in this survey, 38 (84%) had minimal to no agreement among the respondents. There was moderate agreement, for performing lumbopelvic fixation when indicated, for anterior and posterior fixation of the LC-3 injury, and on forgoing EUA or stress X-rays for the APC-3 injury. There was strong agreement for open reduction and internal fixation of the anterior pelvic ring in the APC-3 injury and the VS injury through the SI joint. In contrast, LC-1 injury and combined VS pelvic ring injury through the sacrum had no areas of moderate to strong agreement. DISCUSSION: This study identified specific areas of pelvic ring injury management with minimal to no agreement among pelvic trauma surgeons. Future research should target these areas with a lack of agreement to decrease practice variability and improve patient outcomes.

Quantifying the statistical power of monitoring programs for marine protected areas.

Marine Protected Areas (MPAs) are increasingly established globally as a spatial management tool to aid in conservation and fisheries management objectives. Assessing whether MPAs are having the desired effects on populations requires effective monitoring programs. A cornerstone of an effective monitoring program is an assessment of the statistical power of sampling designs to detect changes when they occur. We present a novel approach to power assessment that combines spatial point process models, integral projection models (IPMs) and sampling simulations to assess the power of different sample designs across a network of MPAs. We focus on the use of remotely operated vehicle (ROV) video cameras as the sampling method, though the results could be extended to other sampling methods. We use empirical data from baseline surveys of an example indicator fish species across three MPAs in California, USA as a case study. Spatial models simulated time series of spatial distributions across sites that accounted for the effects of environmental covariates, while IPMs simulated expected trends over time in abundances and sizes of fish. We tested the power of different levels of sampling effort (i.e., the number of 500-m ROV transects) and temporal replication (every 1-3 yr) to detect expected post-MPA changes in fish abundance and biomass. We found that changes in biomass are detectable earlier than changes in abundance. We also found that detectability of MPA effects was higher in sites with higher initial densities. Increasing the sampling effort had a greater effect than increasing sampling frequency on the time taken to achieve high power. High power was best achieved by combining data from multiple sites. Our approach provides a powerful tool to explore the interaction between sampling effort, spatial distributions, population dynamics, and metrics for detecting change in previously fished populations.

Failure to follow medication changes made at hospital discharge is associated with adverse events in 30 days.

OBJECTIVE: To evaluate the hypothesis that nonadherence to medication changes made at hospital discharge is associated with an increased risk of adverse events in the 30 days postdischarge. STUDY SETTING: Patients admitted to hospitals in Montreal, Quebec, between 2014 and 2016. STUDY DESIGN: Prospective cohort study. DATA COLLECTION: Nonadherence to medication changes was measured by comparing medications dispensed in the community with those prescribed at hospital discharge. Patient, health system, and drug regimen-level covariates were measured using medical services and pharmacy claims data as well as data abstracted from the patient's hospital chart. Multivariable Cox models were used to determine the association between nonadherence to medication changes and the risk of adverse events. PRINCIPAL FINDINGS: Among 2655 patients who met our inclusion criteria, mean age was 69.5 years (SD 14.7) and 1581 (60%) were males. Almost half of patients (n = 1161, 44%) were nonadherent to at least one medication change, and 860 (32%) were readmitted to hospital, visited the emergency department, or died in the 30 days postdischarge. Patients who were not adherent to any of their medication changes had a 35% higher risk of adverse events compared to those who were adherent to all medication changes (1.41 vs 1.27 events/100 person-days, adjusted hazard ratio: 1.35, 95% CI: 1.06-1.71). CONCLUSIONS: Almost half of all patients were not adherent to some or all changes made to their medications at hospital discharge. Nonadherence to all changes was associated with an increased risk of adverse events. Interventions addressing barriers to adherence should be considered moving forward.

Costs and compensation in zooplankton pigmentation under countervailing threats of ultraviolet radiation and predation.

Evolutionary responses to opposing directions of natural selection include trade-offs, where the phenotype balances selective forces, and compensation, where other traits reduce the impact of one selective force. Zooplankton pigmentation protects from ultraviolet radiation (UVR) but attracts visual predators. This trade-off is understudied in the ocean where planktonic larvae in surface waters face ubiquitous UVR and visual predation threats. We tested whether crab larvae can behaviorally reduce UVR risk through downward swimming or expansion of photoprotective chromatophores. Then we examined whether more pigmented larvae are more heavily predated by silverside fish under natural sunlight in the tropics in three UVR treatments (visible light, visible + UVA, visible + UVA + UVB). Lastly, we tested the behavioral chromatophore response of larvae to predation threats in two light treatments. Armases ricordi avoided surface waters after exposure to sunlight with UVR. Armases ricordi, Armases americanum, and Eurypanopeus sp. consistently expanded chromatophores in UVR or visible light, while Mithraculus sculptus and Mithraculus coryphe showed no response. Fish preferred pigmented larvae on sunnier days in visible light lacking UVR. Lastly, both M. coryphe and M. sculptus unexpectedly expanded chromatophores in fish cues, but responses were inconsistent over trials and across light treatments. The more consistent larval responses to UVR than to predator cues and the lack of predator preferences in natural light conditions suggest that UVR may have a stronger influence on pigmentation than predation. This study improves our understanding of planktonic adaptation to countervailing selection caused by visual predation and exposure to UVR.

Both New and Chronic Potentially Inappropriate Medications Continued at Hospital Discharge Are Associated With Increased Risk of Adverse Events.

BACKGROUND: Admission to hospital provides the opportunity to review patient medications; however, the extent to which the safety of drug regimens changes after hospitalization is unclear. OBJECTIVE: To estimate the number of potentially inappropriate medications (PIMs) prescribed to patients at hospital discharge and their association with the risk of adverse events 30 days after discharge. DESIGN: Prospective cohort study. SETTING: Tertiary care hospitals within the McGill University Health Centre Network in Montreal, Quebec, Canada. PARTICIPANTS: Patients from internal medicine, cardiac, and thoracic surgery, aged 65 years and older, admitted between October 2014 and November 2016. MEASURES: Abstracted chart data were linked to provincial health databases. PIMs were identified using AGS (American Geriatrics Society) Beers Criteria®, STOPP, and Choosing Wisely statements. Multivariable logistic regression and Cox models were used to assess the association between PIMs and adverse events. RESULTS: Of 2,402 included patients, 1,381 (57%) were male; median age was 76 years (interquartile range [IQR] = 70-82 years); and eight discharge medications were prescribed (IQR = 2-8). A total of 1,576 (66%) patients were prescribed at least one PIM at discharge; 1,176 (49%) continued a PIM from prior to admission, and 755 (31%) were prescribed at least one new PIM. In the 30 days after discharge, 218 (9%) experienced an adverse drug event (ADE) and 862 (36%) visited the emergency department (ED), were rehospitalized, or died. After adjustment, each additional new PIM and continued community PIM were respectively associated with a 21% (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 1.01-1.45) and a 10% (OR = 1.10; 95% CI = 1.01-1.21) increased odds of ADEs. They were also respectively associated with a 13% (hazard ratio [HR] = 1.13; 95% CI = 1.03-1.26) and a 5% (HR = 1.05; 95% CI = 1.00-1.10) increased risk of ED visits, rehospitalization, and death. CONCLUSIONS: Two in three hospitalized patients were prescribed a PIM at discharge, and increasing numbers of PIMs were associated with an increased risk of ADEs and all-cause adverse events. Improving hospital prescribing practices may reduce the frequency of PIMs and associated adverse events. J Am Geriatr Soc 68:1184-1192, 2020.

Variation in the prescription drugs covered by health systems across high-income countries: A review of and recommendations for the academic literature.

BACKGROUND: Because not all medicines are equally safe, effective, and affordable, health systems often use formularies to define explicitly which medicines will be included and excluded from coverage. OBJECTIVE: We sought to synthesize methods and findings from published studies of formulary variation across health systems in high-income countries. METHODS: We conducted a systematic review of peer-reviewed research papers published from 2000 to 2017, inclusively. Because of the heterogeneous nature of the literature, we used an inductive approach to summarize methods and findings. RESULTS: Nine studies met our study inclusion criteria. Included studies used a variety of methods for selecting medicines for analysis, for measuring coverage levels, and for measuring concordance between formularies. Studies assessing variations in coverage of all licensed medicines and found lower rates of cross-national coverage variation than studies of coverage for selected specialty drugs and indications. The one study that focused on coverage of high-volume medicines found the most complete and consistent levels of formulary listings across countries. CONCLUSION: Although published studies contain interesting findings that likely have prompted discussions about their policy implications, the literature can be improved with greater transparency concerning the overarching objective of work in this area and more rigor concerning the selection, analysis, and reporting of data.

Assessing an intervention to improve the safety of automatic stop orders for inpatient antimicrobials.

BACKGROUND: Automatic stop orders (ASOs) for antimicrobials have been recommended as a component of antimicrobial stewardship programs, but may result in unintentional treatment interruption due to failure of providers to re-order an antimicrobial medication. We examined the impact of a multifaceted intervention designed to reduce the potential harms of interrupting antimicrobial treatment due to ASOs. METHODS: An intervention was implemented that included pharmacist review of expiring antimicrobials as well as provider education to encourage use of a long-term antimicrobial order set for commonly used prophylactic antimicrobials. Pharmacist interventions and antimicrobial re-ordering was recorded. Percent of missed doses of a commonly used prophylactic antimicrobial, single strength co-trimoxazole, was compared pre- and post-intervention using a chi-squared test. RESULTS: From November 1, 2015 to November 30, 2016, there were 401 individual pharmacist interventions for antimicrobial ASOs, resulting in 295 instances of antimicrobial re-ordering. The total percent of presumed missed single strength co-trimoxazole doses was reduced from 8.4% to 6.2% post-intervention (P<0.001). CONCLUSIONS: This study found that a targeted intervention was associated with a reduction in unintended antimicrobial treatment interruption related to ASOs.

Effect on Treatment Adherence of Distributing Essential Medicines at No Charge: The CLEAN Meds Randomized Clinical Trial.

Importance: Nonadherence to treatment with medicines is common globally, even for life-saving treatments. Cost is one important barrier to access, and only some jurisdictions provide medicines at no charge to patients. Objective: To determine whether providing essential medicines at no charge to outpatients who reported not being able to afford medicines improves adherence. Design, Setting, and Participants: A multicenter, unblinded, parallel, 2-group, superiority, outcomes assessor-blinded, individually randomized clinical trial conducted at 9 primary care sites in Ontario, Canada, enrolled 786 patients between June 1, 2016, and April 28, 2017, who reported cost-related nonadherence. Follow-up occurred at 12 months. The primary analysis was performed using an intention-to-treat principle. Interventions: Patients were randomly allocated to receive free medicines on a list of essential medicines in addition to otherwise usual care (n = 395) or usual medicine access and usual care (n = 391). Main Outcomes and Measures: The primary outcome was adherence to treatment with all medicines that were appropriately prescribed for 1 year. Secondary outcomes were hemoglobin A1c level, blood pressure, and low-density lipoprotein cholesterol levels 1 year after randomization in participants taking corresponding medicines. Results: Among the 786 participants analyzed (439 women and 347 men; mean [SD] age, 51.7 [14.3] years), 764 completed the trial. Adherence to treatment with all medicines was higher in those randomized to receive free distribution (151 of 395 [38.2%]) compared with usual access (104 of 391 [26.6%]; difference, 11.6%; 95% CI, 4.9%-18.4%). Control of type 1 and 2 diabetes was not significantly improved by free distribution (hemoglobin A1c, -0.38%; 95% CI, -0.76% to 0.00%), systolic blood pressure was reduced (-7.2 mm Hg; 95% CI, -11.7 to -2.8 mm Hg), and low-density lipoprotein cholesterol levels were not affected (-2.3 mg/dL; 95% CI, -14.7 to 10.0 mg/dL). Conclusions and Relevance: The distribution of essential medicines at no charge for 1 year increased adherence to treatment with medicines and improved some, but not other, disease-specific surrogate health outcomes. These findings could help inform changes to medicine access policies such as publicly funding essential medicines. Trial Registration: ClinicalTrials.gov identifier: NCT02744963.