An all-atom protein generative model.

Proteins mediate their functions through chemical interactions; modeling these interactions, which are typically through sidechains, is an important need in protein design. However, constructing an all-atom generative model requires an appropriate scheme for managing the jointly continuous and discrete nature of proteins encoded in the structure and sequence. We describe an all-atom diffusion model of protein structure, Protpardelle, which represents all sidechain states at once as a "superposition" state; superpositions defining a protein are collapsed into individual residue types and conformations during sample generation. When combined with sequence design methods, our model is able to codesign all-atom protein structure and sequence. Generated proteins are of good quality under the typical quality, diversity, and novelty metrics, and sidechains reproduce the chemical features and behavior of natural proteins. Finally, we explore the potential of our model to conduct all-atom protein design and scaffold functional motifs in a backbone- and rotamer-free way.

The Impact of reference pricing on prescribing patterns, costs, and health services utilization of proton pump inhibitors: A quasi-experimental study in British Columbia, Canada.

INTRODUCTION: The Reference Drug Program (RDP) was established to steer patients toward equally safe and cost-effective medication under British Columbia's public drug coverage. Each RDP class covers at least one reference drug, and non-reference drugs are reimbursed up to the cost of the reference drug. In 2016, the RDP updated to include proton pump inhibitors (PPIs). This study evaluated the impact on drug expenditures, prescription patterns, and health services utilization. METHODS: We identified a cohort of individuals covered by Fair Pharmacare who used PPIs, and a control group of H2 Blockers users. We used interrupted time series analysis on administrative data from June 2014 to December 2019 on the following outcomes: new users, day supply, expenditures, drug costs, reference drug use, and physician visits and costs. RESULTS: The RDP had little impact on overall PPI use patterns. We did not observe any changes in reference drug uptake, new users, physician visits, cost-savings, or significant changes to days supplied post-policy. Cost expenditure results were likely biased due to co-occurring changes to drug prices. CONCLUSION: Inclusion of PPIs to the RDP saw no cost-savings for the provincial drug program and had little impact on prescribing patterns. Overall, our findings are consistent with existing evidence that the RDP is safe for similar therapeutic alternatives, but the impact on PPI costs remains unclear.

Effect of a Billing Code to Reimburse Nurse-Supported Rheumatology Care on Health Care Costs and Access: An Interrupted Time Series Analysis.

OBJECTIVE: This study was undertaken to evaluate the impact of a Multidisciplinary Care Assessment (MCA) billing code on health system costs and access to care in British Columbia (BC). METHODS: Data on all people treated by rheumatologists in BC were obtained from five linked health administrative databases held by Population Data BC from April 1, 2006, to March 31, 2020. Rheumatologists were allocated to either the intervention (ever-billers) or control groups (never-billers). For the intervention group, the index date was the month of the first MCA code billing. For the control group the index dates were imputed from intervention index dates. Our analysis focused on a 48-month period (24 months before and after the index date). We evaluated the impact on two cost (costs related to rheumatoid arthritis [RA]; total health care costs) and access outcomes (rheumatology-related visits per rheumatologist; days between rheumatology visits for patients with RA) using an interrupted time series analysis. RESULTS: A total of 46 rheumatologists (31 intervention and 15 control) met our inclusion criteria. Introduction of the MCA was associated with a small but significant increase in RA-related costs that, at 2 years, translates to a net absolute change of $9.66 per patient per month, but no statistically significant changes in total health care costs. There was no statistically significant change in the number of rheumatology-related visits, but at 2 years there was a net absolute reduction in the median days between rheumatologist visits for patients with RA (6.3 days). CONCLUSION: The introduction of the MCA code was associated with a negligible increase in the RA-related costs and an improvement in access to ongoing care for patients.

Impact of the COVID-19 pandemic on prescription drug use and costs in British Columbia: a retrospective interrupted time series study.

OBJECTIVES: To assess the impact of the COVID-19 pandemic on prescription drug use and costs. DESIGN: Interrupted time series analysis of comprehensive administrative health data linkages in British Columbia, Canada, from 1 January 2018 to 28 March 2021. SETTING: Retrospective population-based analysis of all prescription drugs dispensed in community pharmacies and outpatient hospital pharmacies and irrespective of the drug insurance payer. PARTICIPANTS: Between 4.30 and 4.37 million individuals (52% women) actively registered with the publicly funded medical services plan. INTERVENTION: COVID-19 pandemic and associated mitigation measures. MAIN OUTCOME MEASURES: Weekly dispensing rates and costs, both overall and stratified by therapeutic groups and pharmacological subgroups, before and after the declaration of the public health emergency related to the COVID-19 pandemic. Relative changes in post-COVID-19 outcomes were expressed as ratios of observed to expected rates. RESULTS: After the onset of the pandemic and subsequent COVID-19 mitigation measures, overall medication dispensing rates dropped by 2.4% (p<0.01), followed by a sustained weekly increase to return to predicted levels by the end of January 2021. We observed abrupt level decreases in antibacterials (30.3%, p<0.01) and antivirals (22.4%, p<0.01) that remained below counterfactuals over the first year of the pandemic. In contrast, there was a week-to-week trend increase in nervous system drugs, yielding an overall increase of 7.3% (p<0.01). No trend changes in the dispensing of respiratory system agents, ACE inhibitors, antidiabetic drugs and antidepressants were detected. CONCLUSION: The COVID-19 pandemic impact on prescription drug dispensing was heterogeneous across medication subgroups. As data become available, dispensing trends in nervous system agents, antibiotics and antivirals warrant further monitoring and investigation.

The Impact of Blood Glucose Test Strips Reimbursement Limits on Utilization, Costs, and Health-care Utilization in British Columbia.

OBJECTIVE: People living with diabetes and not using insulin may not derive clinically significant benefit from routine glucose self-monitoring. As a result, in 2015, British Columbia (BC) introduced quantity restrictions for blood glucose test strips (BGTS) coverage in public plans. We studied the impact of this policy on utilization, costs, and health-care utilization. METHODS: We identified a cohort of adults (≥18 years old) with diabetes between 2013 and 2019. Using BC's administrative data, we studied utilization and costs among individuals with at least one PharmaCare-eligible BGTS claim. Using interrupted time-series analysis, we studied cost savings and determined the level of policy adherence. In addition, we investigated longitudinal changes in all-cause and diabetes-specific physician visits, all-cause hospitalizations, and health-care spending in the 3 to 5 years after policy implementation. RESULTS: Over the study period, 279.7 million BGTS were eligible for PharmaCare coverage, on which the government spent $124.3 million. After policy implementation, we observed an immediate decline in average utilization and PharmaCare expenditure on BGTS, leading to an estimated $44.6 million in savings between 2015 and 2019 (95% confidence interval $16.9 to $72.3 million). We found no association between the policy's implementation and health services utilization or overall health-care spending over the long term. CONCLUSIONS: Restricting reimbursement for BGTS in BC resulted in significant cost savings without any attendant increase in health services utilization over the subsequent 5 years. This disinvestment freed up resources that could be channeled toward other interventions.

Impact of income-based public drug coverage deductibles on adherence to asthma medications.

BACKGROUND: Cost-related nonadherence to medications can be a barrier to asthma management. OBJECTIVE: To quantify the impact of public drug plan deductibles on adherence to asthma medications. METHODS: We used a quasi-experimental regression discontinuity analysis to determine whether thresholds in deductibles for public drug coverage, determined on the basis of annual household income, decreased medication use among lower-income children and adults with asthma in British Columbia from 2013 to 2018. Using dispensed medication records, we evaluated deductible thresholds at annual household incomes of $15,000 (a deductible increase from 0% to 2% of annual household income), and $30,000 (a deductible increase from 2% to 3% annual household income). We evaluated medication costs, use, the ratio of inhaled corticosteroids-containing controller medications to total medications, excessive use of short-acting ß-agonists, and the proportion of days covered by controller therapies. All costs are reported in 2020 Canadian dollars. RESULTS: Overall, 88,935 individuals contributed 443,847 person-years of follow-up (57% of female sex, mean age 31 years). Public drug subsidy decreased by -$41.74 (95% CI, -$28.34 to -$55.13) at the $15,000-deductible threshold, a 28% reduction, and patient costs increased by $48.45 (95% CI, $35.37-$61.53). The $30,000 deductible threshold did not affect public drug costs (P = .31), but patient costs increased by $27.65 (95% CI, $15.22-$40.09), which is an 11% increase. Asthma-related medication use, inhaled corticosteroids-to-total medication ratio, excessive use of short-acting ß-agonists, and proportion of days covered by controller therapies were not impacted by deductible thresholds. CONCLUSION: Income-based deductibles reduced public drug costs with no effect on asthma-related medication use, adherence to controller therapies, or excessive reliever therapy use in lower-income individuals with asthma.

Prevalence and predictors of primary nonadherence to medications prescribed in primary care.

BACKGROUND: Most research on medication adherence has focused on secondary nonadherence and persistence to therapy. Medication prescriptions that are never filled by patients (primary nonadherence) remain understudied in the general population. METHODS: We linked prescribing data from primary care electronic medical records to comprehensive pharmacy dispensing claims between January 2013 and April 2019 in British Columbia (BC) to estimate primary nonadherence, defined as failure to dispense a new medication or its equivalent within 6 months of the prescription date. We used hierarchical multivariable logistic regression to determine prescriber, patient and medication factors associated with primary nonadherence among community-dwelling patients in primary care. RESULTS: Among 150 565 new prescriptions to 34 243 patients, 17% of prescriptions were never filled. Primary nonadherence was highest for drugs prescribed mostly on an as-needed basis, including topical corticosteroids (35.1%) and antihistamines (23.4%). In multivariable analysis, primary nonadherence was lower for prescriptions issued by male prescribers (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.50-0.88). Primary nonadherence decreased with patient age (OR 0.91, 95% CI 0.90-0.92 for each additional 10 years) but increased with polypharmacy among patients aged 65 years or older. Patients filled more than 82% of their medication prescriptions within 2 weeks after their primary care provider visit. INTERPRETATION: The prevalence of primary nonadherence to new prescriptions was 17%. Interventions to address primary nonadherence could target older patients with multiple medication use and within the first 2 weeks of the prescription issue date.

An all-atom protein generative model.

Proteins mediate their functions through chemical interactions; modeling these interactions, which are typically through sidechains, is an important need in protein design. However, constructing an all-atom generative model requires an appropriate scheme for managing the jointly continuous and discrete nature of proteins encoded in the structure and sequence. We describe an all-atom diffusion model of protein structure, Protpardelle, which instantiates a "superposition" over the possible sidechain states, and collapses it to conduct reverse diffusion for sample generation. When combined with sequence design methods, our model is able to co-design all-atom protein structure and sequence. Generated proteins are of good quality under the typical quality, diversity, and novelty metrics, and sidechains reproduce the chemical features and behavior of natural proteins. Finally, we explore the potential of our model conduct all-atom protein design and scaffold functional motifs in a backbone- and rotamer-free way.

Uptake and Spending on Biosimilar Infliximab and Etanercept After New Start and Switching Policies in Canada: An Interrupted Time Series Analysis.

OBJECTIVE: Uptake of biosimilars has been suboptimal in North America. This study was undertaken to quantify the impact of various policy interventions (namely, new start and switching policies) on uptake and spending on biosimilar infliximab and etanercept in British Columbia (BC), Canada. METHODS: We used administrative claims data to identify BC residents ≥18 years of age with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and/or plaque psoriasis who qualified for public drug coverage from January 2013 to November 2020. Using interrupted time series analysis, we studied the change in proportion spent on and prescriptions dispensed of biosimilar infliximab and etanercept out of the total amount per agent after new start and biosimilar switching policies were implemented. RESULTS: Our study included 208,984 individuals living with rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, and/or psoriatic arthritis, corresponding to 5,884 patients taking infliximab and etanercept. After the new start policy, we detected a small gradual increase in the proportion of dispensed biosimilar etanercept prescriptions of 0.65% per month (95% confidence interval [95% CI] 0.44, 0.85). The trend related to the proportion of total spending on biosimilar etanercept also increased (0.51% [95% CI 0.28, 0.73]). After the switching policy, there was a sustained increase in the proportion of dispensed biosimilar etanercept and infliximab prescriptions of 76.98% (95% CI 75.56, 78.41) and 58.43% (95% CI 52.11, 64.75), respectively. Similarly, there was a persistent increase in monthly spending on biosimilar etanercept and infliximab of 78.22% (95% CI 76.65, 79.79) and 71.23% (95% CI 66.82, 75.65), respectively. CONCLUSION: We found that mandatory switching policies were much more effective than new starting policies for increasing the use of biosimilar medications.

The impact of introducing multidisciplinary care assessments on access to rheumatology care in British Columbia: an interrupted time series analysis.

BACKGROUND: In 2011 the British Columbia (BC) Ministry of Health introduced a new fee-for-service billing code that allowed "Multidisciplinary Care Assessment" (MCA). This change has the potential to change access to and quality of care for patients. This study aimed to explore the impact on access to rheumatology services in the province. METHODS: Fee-for-service rheumatology billings were evaluated for each rheumatologist 2 years before and after use of the MCA code. Numbers of 1) unique patients and 2) services provided per month were used as proxy measures of access to care. A multiple-baseline interrupted time series model assessed the impact of the MCA on levels and trends of the access outcomes. RESULTS: Our analysis consisted of 82,360 patients cared for by 26 rheumatologists who billed for an MCA. In our primary analysis we observed a sustained increase in the mean number of unique patients of 4.9% (95% CI: 0.0% to 9.9%, p = 0.049) and the mean number of services of 7.1% (95% CI: 1.0% to 13.6%, (p = 0.021), per month provided by a rheumatologist, corresponding to the initial use of MCA. CONCLUSION: The introduction of the MCA code was associated with an initial increase in the measures of access, which was maintained but did not increase over time. Our study suggests that the use of Multidisciplinary Care Assessment can contribute to expanding and/or sustaining access to care for people with complex chronic conditions, like rheumatic diseases.

Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1.

BACKGROUND: In 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus. METHODS: We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models. RESULTS: We identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site. CONCLUSIONS: Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

The impact of the Choosing Wisely Canada campaign on the simultaneous use of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers: interrupted time-series analysis.

BACKGROUND: Choosing Wisely is a high-profile campaign seeking to reduce the use of low-value care. We investigated the impact of a Choosing Wisely Canada recommendation against using a combination of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for the management of hypertension, heart failure or diabetic nephropathy on population-level use of these medications in British Columbia, Canada. METHODS: We identified all people (any age) who were continuously registered with BC's Medical Service Plan between 2010 and 2017 with the targeted conditions. Using prescription claims data and an interrupted time-series analysis, we estimated the number of people on combination therapy per month, the proportion of days covered (PDC) by combination therapy per month and proportion of all combination prescriptions started per month in the 2 years before and after the introduction of the recommendation on Oct. 29, 2014. RESULTS: Of 1 104 593 people (mean age 65 yr, standard deviation 16 yr) in our study cohort, 4.6% were exposed to combination therapy, largely prescribed by family physicians (84%). The number of people on combination therapy and the PDC were declining before the recommendation, but the proportion of combination prescriptions started in the 2 years before the recommendation was increasing. After the recommendation, we observed no statistically significant changes in any outcome. The pre-existing downward trend of the monthly number of people decelerated (16.8, 95% confidence interval [CI] 14.0 to 19.5) and the proportion of prescriptions started increased (0.13%, 95% CI 0.08% to 0.18%). INTERPRETATION: The Choosing Wisely Canada recommendation against using a combination of ACE inhibitors and ARBs was not associated with reduced combination therapy use in the targeted conditions. The observed pre-existing declines in this practice questions the process of selecting recommendations, and the optimal implementation and value of Choosing Wisely campaigns without other reinforcing interventions.

Homeoprotein SIX1 compromises antitumor immunity through TGF-ß-mediated regulation of collagens.

The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.

Does early intervention improve outcomes for patients with acute ureteral colic?

OBJECTIVES: Early surgical intervention is increasingly employed for patients with ureteral colic, but guidelines and current practice are variable. We compared 60-day outcomes for matched patients undergoing early intervention vs. spontaneous passage. METHODS: This multicentre propensity-matched cohort analysis used administrative data and chart review to study all eligible emergency department (ED) patients with confirmed 2.0-9.9 mm ureteral stones. Those having planned stone intervention within 5 days comprised the intervention cohort. Controls attempting spontaneous passage were matched to intervention patients based on age, sex, stone width, stone location, hydronephrosis, ED site, ambulance arrival and acuity level. The primary outcome was treatment failure, defined as rescue intervention or hospitalization within 60 days, using a time to event analysis. Secondary outcome was ED revisit rate. RESULTS: Among 1154 matched patients, early intervention did not reduce the risk of treatment failure (adjusted hazard ratio 0.94; P = 0.61). By 60 days, 21.8% of patients in both groups experienced the composite primary outcome (difference 0.0%; 95% confidence interval - 4.8 to 4.8%). Intervention patients required more hospitalizations (20.1% vs. 12.8%; difference 7.3%; 95% CI 3.0-11.5%) and ED revisits (36.1% vs. 25.5%; difference 10.6%; 95% CI 5.3-15.9%), but (insignificantly) fewer rescue interventions (18.9% vs. 21.3%; difference - 2.4%; 95% CI - 7.0 to 2.2%). CONCLUSIONS: In matched patients with 2.0-9.9 mm ureteral stones, early intervention was associated with similar rates of treatment failure but greater patient morbidity, evidenced by hospitalizations and emergency revisits. Physicians should adopt a selective approach to interventional referral and consider that spontaneous passage probably provides better outcomes for many low-risk patients.

RéSUMé: OBJECTIFS: L'intervention chirurgicale précoce est de plus en plus utilisée pour les patients atteints de coliques urétérales, mais les lignes directrices et la pratique actuelle sont variables. Nous avons comparé les résultats à 60 jours pour les patients appariés subissant une intervention précoce par rapport au passage spontané. LES MéTHODES: Cette analyse de cohorte multicentrique par appariement de propension a utilisé des données administratives et l'examen des dossiers pour étudier tous les patients admissibles des services d'urgence (ED) ayant des calculs urétéraux confirmés de 2,0-9,9 mm Ceux qui avaient planifié une intervention de calcul dans les cinq jours constituaient la cohorte d'intervention. Les témoins tentant de passer spontanément ont été appariés aux patients d'intervention en fonction de l'âge, du sexe, de la largeur du calcul, de l'emplacement du calcul, de l'hydronéphrose, du site de l'urgence, de l'arrivée de l'ambulance et du niveau d'acuité. Le résultat principal était l'échec de traitement, défini comme l'intervention de sauvetage ou l'hospitalisation dans les 60 jours, utilisant un temps à l'analyse d'événement. Le résultat secondaire était le taux de revisite à l'urgence RéSULTATS: Sur 1154 patients appariés, une intervention précoce n'a pas réduit le risque d'échec du traitement (ratio de risque ajusté = 0,94 ; P = 0,61). Au bout de 60 jours, 21,8 % des patients des deux groupes avaient atteint le résultat primaire composite (différence = 0,0 % ; intervalle de confiance à 95 % -4,8 % à 4,8 %). Les patients d'intervention ont nécessité plus d'hospitalisations (20,1 % contre 12,8 % ; différence = 7,3 % ; IC 95 %, 3,0 à 11,5 %) et de nouvelles visites à l'urgence (36,1 % contre 25,5 % ; différence = 10,6 % ; IC 95 %, 5,3 à 15,9 %), mais (de manière non significative) moins d'interventions de sauvetage (18,9 % contre 21,3 % ; différence = 2,4 % ; IC 95 %, -7,0 à 2,2 %). CONCLUSIONS: Chez des patients appariés présentant des calculs urétéraux de 2,0 à 9,9 mm, l'intervention précoce a été associée à des taux similaires d'échec du traitement mais à une morbidité plus importante des patients, comme en témoignent les hospitalisations et les revisites aux urgences. Les médecins devraient adopter une approche sélective de l'orientation interventionnelle et considérer que le passage spontané offre probablement de meilleurs résultats pour de nombreux patients à faible risque.

How long does it take patients to find a new primary care physician when theirs retires: a population-based, longitudinal study.

BACKGROUND: The retirement of a family physician can represent a challenge in accessibility and continuity of care for patients. In this population-based, longitudinal cohort study, we assess whether and how long it takes for patients to find a new majority source of primary care (MSOC) when theirs retires, and we investigate the effect of demographic and clinical characteristics on this process. METHODS: We used provincial health insurance records to identify the complete cohort of patients whose majority source of care left clinical practice in either 2007/2008 or 2008/2009 and then calculated the number of days between their last visit with their original MSOC and their first visit with their new one. We compared the clinical and sociodemographic characteristics of patients who did and did not find a new MSOC in the three years following their original physician's retirement using Chi-square and Fisher's exact test. We also used Cox proportional hazards models to determine the adjusted association between patient age, sex, socioeconomic status, location and morbidity level (measured using Johns Hopkins' Aggregated Diagnostic Groupings), and time to finding a new primary care physician. We produce survival curves stratified by patient age, sex, income and morbidity. RESULTS: Fifty-four percent of patients found a new MSOC within the first 12 months following their physician's retirement. Six percent of patients still had not found a new physician after 36 months. Patients who were older and had higher levels of morbidity were more likely to find a new MSOC and found one faster than younger, healthier patients. Patients located in more urban regional health authorities also took longer to find a new MSOC compared to those in rural areas. CONCLUSIONS: Primary care physician retirements represent a potential threat to accessibility; patients followed in this study took more than a year on average to find a new MSOC after their physician retired. Providing programmatic support to retiring physicians and their patients, as well as addressing shortages of longitudinal primary care more broadly could help to ensure smoother retirement transitions.

Impact of a free care policy on the utilisation of health services during an Ebola outbreak in the Democratic Republic of Congo: an interrupted time-series analysis.

BACKGROUND: During past outbreaks of Ebola virus disease (EVD) and other infectious diseases, health service utilisation declined among the general public, delaying health seeking behaviour and affecting population health. From May to July 2018, the Democratic Republic of Congo experienced an outbreak of EVD in Equateur province. The Ministry of Public Health introduced a free care policy (FCP) in both affected and neighbouring health zones. We evaluated the impact of this policy on health service utilisation. METHODS: Using monthly data from the national Health Management Information System from January 2017 to January 2019, we examined rates of the use of nine health services at primary health facilities: total visits; first and fourth antenatal care visits; institutional deliveries; postnatal care visits; diphtheria, pertussis and tetanus (DTP) vaccinations and visits for uncomplicated malaria, pneumonia and diarrhoea. We used controlled interrupted time series analysis with a mixed effects model to estimate changes in the rates of services use during the policy (June-September 2018) and afterwards. FINDINGS: Overall, use of most services increased compared to control health zones, including EVD affected areas. Total visits and visits for pneumonia and diarrhoea initially increased more than two-fold relative to the control areas (p<0.001), while institutional deliveries and first antenatal care increased between 20% and 50% (p<0.01). Visits for DTP, fourth antenatal care visits and postnatal care visits were not significantly affected. During the FCP period, visit rates followed a downward trend. Most increases did not persist after the policy ended. INTERPRETATION: The FCP was effective at rapidly increasing the use of some health services both EVD affected and not affected health zones, but this effect was not sustained post FCP. Such policies may mitigate the adverse impact of infectious disease outbreaks on population health.

What happens to drug use and expenditure when cost sharing is completely removed? Evidence from a Canadian provincial public drug plan.

OBJECTIVES: The role of cost-sharing for medicines is under active policy discussion, including in proposals for value-based insurance design. To inform this debate, we estimated the impact of completely removing cost-sharing on medication use and expenditure using a quasi-experimental approach. METHODS: Fair PharmaCare, British Columbia's income-based public drug plan, includes a household out-of-pocket limit. Therefore, when one household member starts a long-term high-cost drug surpassing this maximum, cost-sharing is completely removed for other family members. We used an interrupted time series design to estimate monthly prescriptions and expenditures of other household members, 24 months before and after cost-sharing removal. RESULTS: We studied 2191 household members newly free of cost-sharing requirements, most of whom had lower incomes. R emoving cost-sharing increased the level of drug expenditure and prescription numbers by 16 and 19%, respectively (i.e. $2659.43 (95%$1507.27-$3811.59, p < 0.001); 50.0 (95%CI 25.1-74.9, p < 0.001)) relative to prior expenditures and utilization without changing pre-existing trends. Much of this change was driven by 533 individuals initiating medication for the first time after cost-sharing removal. This initiation substantially increased average expenditure, especially for antiviral agents. CONCLUSIONS: Completely removing cost-sharing, independent of health status, significantly increased medication use and expenditure particularly due to medicine initiation by new users. While costs may be preventing use, the appropriateness of additional use, especially among new users, is unclear.

Cost-related nonadherence to medicines in people with multiple chronic conditions.

BACKGROUND: Multimorbidity is common and frequently associated with medicine nonadherence. Although cost is a common reason for nonadherence, very little research has quantified cost-related nonadherence (CRNA) to medicines specifically in people with multimorbidity, the prevalence of CRNA for different conditions nor the impact of cost when prioritising treatment between conditions. OBJECTIVE: To determine the extent of CRNA in people with multimorbidity and the patient characteristics associated with these behaviours. DESIGN AND SETTING: People reporting two or more chronic conditions responding to a rapid response module regarding prescription drug affordability fielded between January 1 and June 30 2016 in the Canadian Community Health Survey, a cross-sectional household survey. METHODS: Ordinal logistic regression, adjusted for key sociodemographic, clinical and treatment related variables, of weighted population estimates of self-reported CRNA within one group of conditions, across multiple groups of conditions, or no CRNA. RESULTS: 10.2% of 8420 Canadians with multimorbidity reported CRNA. The majority (61%) reported CRNA within one group of conditions, especially respiratory (16%) and mental health disorders (17%). CRNA was more common in younger adults, people without employer or association drug insurance plans, poorer health status, more chronic conditions, and increased out-of-pocket prescription costs. Having no prescription insurance was associated with a higher probability of CRNA across multiple groups of conditions. CONCLUSIONS: People with multimorbidity primarily forego medicines because of cost within one group of conditions. However, those without drug insurance extended these behaviours to multiple condition groups. Further work is needed to determine how people prioritise the conditions and treatments that are foregone because of cost, and how to best incorporate this information into treatment plans.