First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1ß and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development.

Telehealth Treatment of Behavior Problems in Young Children With Developmental Delay: A Randomized Clinical Trial.

Importance: Early behavior problems in children with developmental delay (DD) are prevalent and impairing, but service barriers persist. Controlled studies examining telehealth approaches are limited, particularly for children with DD. Objective: To evaluate the efficacy of a telehealth parenting intervention for behavior problems in young children with DD. Design, Setting, and Participants: A randomized clinical trial was conducted from March 17, 2016, to December 15, 2020, in which children with DD and externalizing behavior problems were recruited from early intervention and randomly assigned to a telehealth parenting intervention or control group and evaluated through a 12-month follow-up. Most children were from ethnic or racial minoritized backgrounds. Over one-half of children were in extreme poverty or low income-need ratio categories. Interventions: Internet-delivered parent-child interaction therapy (iPCIT), which leverages videoconferencing to provide live coaching of home-based caregiver-child interactions. Families received 20 weeks of iPCIT (provided in English or in Spanish) or referrals as usual (RAU). Main Outcomes and Measures: Observational and caregiver-report measures of child and caregiver behaviors and caregiving stress were examined at preintervention, midtreatment, and postintervention and at 6- and 12-month follow-ups. Results: The sample included a total of 150 children (mean [SD] age, 36.2 [1.0] months; 111 male children [74%]) and their caregivers with 75 each randomly assigned to iPCIT or RAU groups. Children receiving iPCIT relative to RAU displayed significantly lower levels of externalizing problems (postintervention Cohen d = 0.48; 6-month Cohen d = 0.49; 12-month Cohen d = 0.50) and significantly higher levels of compliance to caregiver direction after treatment. Of those children with data at postintervention, greater clinically significant change was observed at postintervention for children in the iPCIT group (50 [74%]) than for those in the RAU group (30 [42%]), which was maintained at the 6-month but not the 12-month follow-up. iPCIT did not outperform RAU in reducing caregiving stress, but caregivers receiving iPCIT, relative to RAU, showed steeper increases in proportion of observed positive parenting skills (postintervention odds ratio [OR], 1.10; 95% CI, 0.53-2.21; 6-month OR, 1.31; 95% CI, 0.61-2.55; 12-month OR, 1.64; 95% CI, 0.70-3.07) and sharper decreases in proportion of observed controlling/critical behaviors (postintervention OR, 1.40; 95% CI, 0.61-1.52; 6-month OR, 1.72; 95% CI, 0.58-1.46; 12-month OR, 2.23; 95% CI, 0.53-1.37). After treatment, iPCIT caregivers also self-reported steeper decreases in harsh and inconsistent discipline than did than RAU caregivers (postintervention Cohen d = 0.24; 6-month Cohen d = 0.26; 12-month Cohen d = 0.27). Conclusions and Relevance: Results of this randomized clinical trial provide evidence that a telehealth-delivered parenting intervention with real-time therapist coaching led to significant and maintained improvements for young children with DD and their caregivers. Findings underscore the promise of telehealth formats for expanding scope and reach of care for underserved families. Trial Registration: ClinicalTrials.gov Identifier: NCT03260816.

Operationalizing Equity-centered Implementation Through Person-centered Care Capacity-building with HIV Service Organizations: The SUSTAIN Approach.

Capacity-building in trauma-informed care and harm reduction approaches with Southern HIV service organizations must be implemented in ways that foster trust and spur organizational change. Using an equity-centered implementation science framework, this study examines implementation strategies of the SUSTAIN COMPASS Coordinating Center's person-centered care (PCC) capacity-building interventions. METHODS: Fifty-eight (58) in-depth qualitative interviews with staff (N=116) who received PCC capacity-building were analyzed using modified grounded theory. RESULTS: Analysis identified four factors of equity-centered implementation that facilitated PCC capacity-building implementation. 1) Innovation factors: SUSTAIN models PCC approaches when implementing PCC capacity-building. 2) Inner factors: SUSTAIN employs PCC approaches. 3) Outer factors: SUSTAIN highlights socio-political factors that may influence PCC implementation. 4) Bridging factors: SUSTAIN facilitates partnerships to promote PCC learning and sustainability. CONCLUSION: SUSTAIN PCC capacity-building advances health equity through operationalizing personcentered care in capacity-building implementation.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Smoking Susceptibility in Canadian Adolescent Electronic-Cigarette Users.

Background: E-cigarette use is increasing among Canadian youth, with experimentation especially prevalent among never-smoking youth. Among this group, there is concern e-cigarette use contributes to future initiation of smoking through a gateway effect. However, e-cigarette use and smoking share many common risk factors; a postulated mechanism to explain the apparent causal pathway from e-cigarette use to smoking initiation in previously smoking-naïve youth. A better understanding of the relationships between smoking susceptibility and e-cigarette use among never-smoking youth is needed. Purpose/objectives: The primary aim of this study was to gain a deeper understanding of the risk factors associated with smoking susceptibility in youth who have recently used e-cigarettes. Methods: This study used data (n = 40,363) from the 2018/2019 Canadian Student Tobacco Alcohol and Drug Use Survey (CSTADS) to compare the risk factor profiles of susceptible and non-susceptible never-smoking e-cigarette users, as well as susceptible and non-susceptible never-smoking youth who have never used an e-cigarette. Results: E-cigarette use, independent of susceptibility status, was associated with a sociodemographic and behavioral risk factor profile likely to confer a higher risk of initiating smoking. Among e-cigarette users, smoking susceptibility was associated with more smoking risk factors. Conclusions/importance: Study findings support a common risk-factor model, rather than e-cigarette use itself, to explain differences in the likelihood of smoking initiation among e-cigarette users. E-cigarette use and smoking initiation may be interchangeable outcomes amongst those with smoking risk factors. The risks of e-cigarette use, and their regulatory status, need to be balanced with their potential as harm reduction tools.

Expectations for Return to Work Predict Return to Work in Workers with Low Back Pain: An Individual Participant Data (IPD) Meta-Analysis.

Purpose Low back pain is associated with disability and lost productivity due to inability of workers to return to work. Personal recovery expectation beliefs may be associated with return to work outcomes in those with low back pain at high risk for chronic disability. We aimed to (1) assess whether workers' expectations for return to work, following a low back pain episode, are associated with subsequent return to work; and (2) explore the relationships between return to work expectations and other prognostic factors in their association with work outcomes.Methods We conducted an Individual Participant Data (IPD) meta-analysis using data from five prospective cohort studies identified by a Cochrane prognostic factor review. A one-stage IPD meta-analysis approach was applied. Multi-level mixed effects models were used to determine the unadjusted and adjusted associations between expectations and return to work (logistic regression) and time to return to work (parametric survival models with Weibull distribution).Results The final dataset included 2302 participants. Positive expectations for return to work were associated with return to work at follow-up in both unadjusted (Odds Ratio (OR) 2.95; 95% Confidence Interval (CI) 2.21, 3.95) (n = 2071) and comprehensively adjusted (OR 2.01; 95% CI 1.46, 2.77) (n = 1109) models. Similar findings were identified for shorter length of time to return to work in both unadjusted (HR 2.40; 95% CI 2.09, 2.75) (n = 1156) and minimally adjusted (HR 2.43; 95% CI 2.12, 2.79) (n = 1154) models.Conclusions Results suggest workers with low expectations for return to work are at increased risk for long-term work disability.

Measuring Irritability in Early Childhood: A Psychometric Evaluation of the Affective Reactivity Index in a Clinical Sample of 3- to 8-Year-Old Children.

The parent-report Affective Reactivity Index (ARI-P) is the most studied brief scale specifically developed to assess irritability, but relatively little is known about its performance in early childhood (i.e., ≤8 years). Support in such populations is particularly important given developmental shifts in what constitutes normative irritability across childhood. We examined the performance of the ARI-P in a diverse, treatment-seeking sample of children ages 3 to 8 years (N = 115; mean age = 5.56 years; 58.4% from ethnic/racial minority backgrounds). In this sample, confirmatory factor analysis supported the single-factor structure of the ARI-P previously identified with older youth. ARI-P scores showed large associations with another irritability index, as well as small-to-large associations with aggression, anxiety, depression, and attention problems, supporting the convergent and concurrent validity of the ARI-P when used with children in this younger age range. Findings support the ARI-P as a promising parent-report tool for assessing irritability in early childhood, particularly in clinical samples.

Low Back Pain in a Nova Scotian Emergency Department: Prevalence and Patient Characteristics in the Older Adult Patient Population.

Low back pain is a major cause of disability in older adults, and results in many emergency department visits each year. Characteristics of the older back pain population are largely unknown. We conducted a retrospective study to examine the prevalence and patient characteristics for older (≥ 65 years of age) and younger (16-64 years of age) adults presenting with back pain. Study objectives were to describe the characteristics of older adults with back pain presenting to an emergency department and to identify age-group-based differences in management. Older adults were most commonly diagnosed with non-specific low back pain (49%). For older adults with this diagnosis, the length of stay was 2.1 times longer (p < 0.001), and odds of being admitted to the hospital were 5.1 times higher (p < 0.001) than for younger adults. Patterns of management are different for younger and older adults with low back pain; this information can be used to direct future resource planning.

Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial.

BACKGROUND: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. OBJECTIVE: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. METHODS: We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. RESULTS: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. CONCLUSIONS: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.

Health Care Provider Utilization of Prescription Monitoring Programs: A Systematic Review and Meta-Analysis.

OBJECTIVE: To synthesize the literature on the proportion of health care providers who access and use prescription monitoring program data in their practice, as well as associated barriers to the use of such data. DESIGN: We performed a systematic review using a standard systematic review method with meta-analysis and qualitative meta-summary. We included full-published peer-reviewed reports of study data, as well as theses and dissertations. METHODS: We identified relevant quantitative and qualitative studies. We synthesized outcomes related to prescription monitoring program data use (i.e., ever used, frequency of use). We pooled the proportion of health care providers who had ever used prescription monitoring program data by using random effects models, and we used meta-summary methodology to identify prescription monitoring program use barriers. RESULTS: Fifty-three studies were included in our review, all from the United States. Of these, 46 reported on prescription monitoring program use and 32 reported on barriers. The pooled proportion of health care providers who had ever used prescription monitoring program data was 0.57 (95% confidence interval: 0.48-0.66). Common barriers to prescription monitoring program data use included time constraints and administrative burdens, low perceived value of prescription monitoring program data, and problems with prescription monitoring program system usability. CONCLUSIONS: Our study found that health care providers underutilize prescription monitoring program data and that many barriers exist to prescription monitoring program data use.

Prescription medication use as a risk factor for motor vehicle collisions: a responsibility study.

INTRODUCTION: Previous studies on the effect of prescription medications on MVCs are sparse, not readily applicable to real-world driving and/or subject to strong selection bias. This study examines whether the presence of prescription medication in drivers' blood is associated with being responsible for MVC. METHODS: This modified case-control study with responsibility analysis compares MVC responsibility rates among drivers with detectable levels of six classes of prescription medications (anticonvulsants, antidepressants, antihistamines, antipsychotics, benzodiazepines, opioids) versus those without. Data were collected between January 2010 and July 2016 from emergency departments in British Columbia, Canada. Collision responsibility was assessed using a validated and automated scoring of police collision reports. Multivariable logistic regression was used to determine OR of responsibility (analysed in 2018-2019). RESULTS: Unadjusted regression models show a significant association between anticonvulsants (OR 1.92; 95% CI 1.20 to 3.09; p=0.007), antipsychotics (OR 5.00; 95% CI 1.16 to 21.63; p=0.03) and benzodiazepines (OR 2.99; 95% CI 1.56 to 5.75; p=0.001) with collision responsibility. Fully adjusted models show a significant association between benzodiazepines with collision responsibility (aOR 2.29; 95% CI 1.16 to 4.53; p=0.02) after controlling for driver characteristics, blood alcohol and Δ-9-tetrahydrocannabinol concentrations, and the presence of other prescription medications. Antidepressants, antihistamines and opioids exhibited no significant associations. CONCLUSION: There is a moderate increase in the risk of a responsible collision among drivers with detectable levels of benzodiazepines in blood. Physicians and pharmacists should consider collision risk when prescribing or dispensing benzodiazepines. Public education about benzodiazepine use and driving and change to traffic policy and enforcement measures are warranted.

Antibody-mediated activation of the FGFR1/Klothoß complex corrects metabolic dysfunction and alters food preference in obese humans.

Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoß (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

Embracing Their Prey at That Dark Hour: Common Cuttlefish (Sepia officinalis) Can Hunt in Nighttime Light Conditions.

Cuttlefish are highly efficient predators, which strongly rely on their anterior binocular visual field for hunting and prey capture. Their complex eyes possess adaptations for low light conditions. Recently, it was discovered that they display camouflaging behavior at night, perhaps to avoid detection by predators, or to increase their nighttime hunting success. This raises the question whether cuttlefish are capable of foraging during nighttime. In the present study, prey capture of the common cuttlefish (Sepia officinalis) was filmed with a high-speed video camera in different light conditions. Experiments were performed in daylight and with near-infrared light sources in two simulated nightlight conditions, as well as in darkness. The body of the common cuttlefish maintained a velocity of less than 0.1 m/s during prey capture, while the tentacles during the seizing phase reached velocities of up to 2.5 m/s and accelerations reached more than 450 m/s2 for single individuals. There was no significant difference between the day and nighttime trials, respectively. In complete darkness, the common cuttlefish was unable to catch any prey. Our results show that the common cuttlefish are capable of catching prey during day- and nighttime light conditions. The common cuttlefish employ similar sensory motor systems and prey capturing techniques during both day- and nighttime conditions.

Exercise treatment effect modifiers in persistent low back pain: an individual participant data meta-analysis of 3514 participants from 27 randomised controlled trials.

BACKGROUND: Low back pain is one of the leading causes of disability worldwide. Exercise therapy is widely recommended to treat persistent non-specific low back pain. While evidence suggests exercise is, on average, moderately effective, there remains uncertainty about which individuals might benefit the most from exercise. METHODS: In parallel with a Cochrane review update, we requested individual participant data (IPD) from high-quality randomised clinical trials of adults with our two primary outcomes of interest, pain and functional limitations, and calculated global recovery. We compiled a master data set including baseline participant characteristics, exercise and comparison characteristics, and outcomes at short-term, moderate-term and long-term follow-up. We conducted descriptive analyses and one-stage IPD meta-analysis using multilevel mixed-effects regression of the overall treatment effect and prespecified potential treatment effect modifiers. RESULTS: We received IPD for 27 trials (3514 participants). For studies included in this analysis, compared with no treatment/usual care, exercise therapy on average reduced pain (mean effect/100 (95% CI) -10.7 (-14.1 to -7.4)), a result compatible with a clinically important 20% smallest worthwhile effect. Exercise therapy reduced functional limitations with a clinically important 23% improvement (mean effect/100 (95% CI) -10.2 (-13.2 to -7.3)) at short-term follow-up. Not having heavy physical demands at work and medication use for low back pain were potential treatment effect modifiers-these were associated with superior exercise outcomes relative to non-exercise comparisons. Lower body mass index was also associated with better outcomes in exercise compared with no treatment/usual care. This study was limited by inconsistent availability and measurement of participant characteristics. CONCLUSIONS: This study provides potentially useful information to help treat patients and design future studies of exercise interventions that are better matched to specific subgroups. PROTOCOL PUBLICATION: https://doi.org/10.1186/2046-4053-1-64.

Acceptability and accuracy of oral fluid drug testing for patients on methadone maintenance.

BACKGROUND: Methadone maintenance is currently the predominant form of opioid substitution treatment available in the Republic of Ireland. Prescribing decisions currently involve urine testing for drug use. Urine testing may involve provision of a supervised sample in some circumstances, despite recommendations made in 2010 to abandon this practice. AIMS: This project aims to evaluate the accuracy and acceptability of oral fluid testing for patients on methadone maintenance and also gather patient views on their treatment. METHODS: Patients attending for methadone maintenance at 4 general practices were invited to take part in this study, which involved taking an additional oral fluid test and a questionnaire. RESULTS: Fifty-five patients agreed to participate. Fifty-two (95%) found the oral fluid test acceptable, and almost two-thirds would prefer to see it used instead of urine testing. Oral fluid provided similar results to urine testing for all drugs except benzodiazepines. Self-report identified cocaine and opiate use not detected by oral fluid or urine testing. CONCLUSION: This study presents evidence that oral fluid testing is acceptable to most patients. While oral fluid testing was inferior to urine testing for benzodiazepines, it may have an adjunctive role to play in methadone maintenance provision. Patients reported more negative than positive aspects of methadone maintenance.

Correction to: Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2).

After publication of our article [1] we were notified that the data presented in the upper row of Fig. 7 was inadvertently the least square mean change from baseline (standard error) at Month 6 rather than the overall average of Month 3 and Month 6. The figure legend and discussion of the data in the text were and are correct. The error was only in the upper row of Fig. 7. The legend for Fig. 7 did not require revision.

The effectiveness of prescription drug monitoring programs at reducing opioid-related harms and consequences: a systematic review.

BACKGROUND: In order to address the opioid crisis in North America, many regions have adopted preventative strategies, such as prescription drug monitoring programs (PDMPs). PDMPs aim to increase patient safety by certifying that opioids are prescribed in appropriate quantities. We aimed to synthesize the literature on changes in opioid-related harms and consequences, an important measure of PDMP effectiveness. METHODS: We completed a systematic review. We conducted a narrative synthesis of opioid-related harms and consequences from PDMP implementation. Outcomes were grouped into categories by theme: opioid dependence, opioid-related care outcomes, opioid-related adverse events, and opioid-related legal and crime outcomes. RESULTS: We included a total of 22 studies (49 PDMPs) in our review. Two studies reported on illicit and problematic use but found no significant associations with PDMP status. Eight studies examined the association between PDMP status and opioid-related care outcomes, of which two found that treatment admissions for prescriptions opioids were lower in states with PDMP programs (p < 0.05). Of the thirteen studies that reported on opioid-related adverse events, two found significant (p < 0.001 and p < 0.05) but conflicting results with one finding a decrease in opioid-related overdose deaths after PDMP implementation and the other an increase. Lastly, two studies found no statistically significant association between PDMP status and opioid-related legal and crime outcomes (crime rates, identification of potential dealers, and diversion). CONCLUSION: Our study found limited evidence to support overall associations between PDMPs and reductions in opioid-related consequences. However, this should not detract from the value of PDMPs' larger role of improving opioid prescribing.

Individual recovery expectations and prognosis of outcomes in non-specific low back pain: prognostic factor review.

BACKGROUND: Low back pain is costly and disabling. Prognostic factor evidence can help healthcare providers and patients understand likely prognosis, inform the development of prediction models to identify subgroups, and may inform new treatment strategies. Recent studies have suggested that people who have poor expectations for recovery experience more back pain disability, but study results have differed. OBJECTIVES: To synthesise evidence on the association between recovery expectations and disability outcomes in adults with low back pain, and explore sources of heterogeneity. SEARCH METHODS: The search strategy included broad and focused electronic searches of MEDLINE, Embase, CINAHL, and PsycINFO to 12 March 2019, reference list searches of relevant reviews and included studies, and citation searches of relevant expectation measurement tools. SELECTION CRITERIA: We included low back pain prognosis studies from any setting assessing general, self-efficacy, and treatment expectations (measured dichotomously and continuously on a 0 - 10 scale), and their association with work participation, clinically important recovery, functional limitations, or pain intensity outcomes at short (3 months), medium (6 months), long (12 months), and very long (> 16 months) follow-up. DATA COLLECTION AND ANALYSIS: We extracted study characteristics and all reported estimates of unadjusted and adjusted associations between expectations and related outcomes. Two review authors independently assessed risks of bias using the Quality in Prognosis Studies (QUIPS) tool. We conducted narrative syntheses and meta-analyses when appropriate unadjusted or adjusted estimates were available. Two review authors independently graded and reported the overall quality of evidence. MAIN RESULTS: We screened 4635 unique citations to include 60 studies (30,530 participants). Thirty-five studies were conducted in Europe, 21 in North America, and four in Australia. Study populations were mostly chronic (37%), from healthcare (62%) or occupational settings (26%). General expectation was the most common type of recovery expectation measured (70%); 16 studies measured more than one type of expectation. Usable data for syntheses were available for 52 studies (87% of studies; 28,885 participants). We found moderate-quality evidence that positive recovery expectations are strongly associated with better work participation (narrative synthesis: 21 studies; meta-analysis: 12 studies, 4777 participants: odds ratio (OR) 2.43, 95% confidence interval (CI) 1.64 to 3.62), and low-quality evidence for clinically important recovery outcomes (narrative synthesis: 12 studies; meta-analysis: 5 studies, 1820 participants: OR 1.89, 95% CI 1.49 to 2.41), both at follow-up times closest to 12 months, using adjusted data. The association of recovery expectations with other outcomes of interest, including functional limitations (narrative synthesis: 10 studies; meta-analysis: 3 studies, 1435 participants: OR 1.40, 95% CI 0.85 to 2.31) and pain intensity (narrative synthesis: 9 studies; meta-analysis: 3 studies, 1555 participants: OR 1.15, 95% CI 1.08 to 1.23) outcomes at follow-up times closest to 12 months using adjusted data, is less certain, achieving very low- and low-quality evidence, respectively. No studies reported statistically significant or clinically important negative associations between recovery expectations and any low back pain outcome. AUTHORS' CONCLUSIONS: We found that individual recovery expectations are probably strongly associated with future work participation (moderate-quality evidence) and may be associated with clinically important recovery outcomes (low-quality evidence). The association of recovery expectations with other outcomes of interest is less certain. Our findings suggest that recovery expectations should be considered in future studies, to improve prognosis and management of low back pain.

Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2).

BACKGROUND: Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM. METHODS: Data were pooled from two double-blind, placebo-controlled phase 3 trials; EVOLVE-1 and EVOLVE-2. Patients were 18-65 years old, experienced 4-14 monthly migraine headache days (MHDs) for ≥1 year prior, with onset at < 50 years of age. Migraine headaches were tracked via electronic patient-reported outcome system and randomization was stratified by low (LFEM; 4-7 monthly MHDs) or high (HFEM; 8-14 monthly MHDs) frequency. Subgroup analysis compared the HFEM and LFEM subgroups with a linear or generalized linear mixed model repeated measures approach. RESULTS: The intent-to-treat patients (N = 1773) had a mean age of 41.3 years, were mostly white (75%), female (85%), and 66% of patients had HFEM. In both the LFEM and HFEM subgroups, the overall (Months 1-6) and monthly changes from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg. Galcanezumab (120-mg and 240-mg) significantly decreased the overall and monthly MHDs with nausea and/or vomiting, and with photophobia and phonophobia versus placebo in patients with LFEM or HFEM. In both subgroups, the mean overall (Months 1-6) and monthly percentages of patients with ≥50%, ≥75%, and 100% reduction in monthly MHDs from baseline were statistically significantly greater in patients receiving either dose of galcanezumab versus placebo. Galcanezumab (120-mg and 240-mg) significantly improved the Migraine-Specific Quality of Life Questionnaire role function-restrictive domain score as well as the Migraine Disability Assessment total score versus placebo for patients with LFEM or HFEM. There were no significant subgroup-by-treatment interactions. CONCLUSIONS: Galcanezumab was as effective in patients with HFEM as in those with LFEM. Associated symptoms, quality of life, and disability were similarly improved in patients with HFEM or LFEM. TRIAL REGISTRATION: NCT02614183 , NCT02614196 .

Effectiveness of Prescription Monitoring Programs in Reducing Opioid Prescribing, Dispensing, and Use Outcomes: A Systematic Review.

Prescription monitoring programs (PMPs) house and monitor data about the prescribing practices of health care providers, as well as medications received by patients. PMPs aim to promote the appropriate use of prescription opioids by providing this information to prescribers and dispensers. Our objective in this systematic review was to comprehensively identify and assess the available evidence about the impact of PMPs on opioid prescribing and dispensing, multiple provider use for obtaining opioids, inappropriate opioid prescribing, and the extent of nonmedical prescription opioid use. We used a comprehensive search strategy and included study designs that could determine changes in outcomes with the implementation of a PMP. We included 24 studies; 75% of studies were conducted in the United States, and studies encompassed data years from 1993 to 2014. Overall, we did not find evidence to support an association between PMPs and decreased opioid prescribing and dispensing. We found limited, but inconsistent, evidence that PMPs were associated with reduced schedule II opioid prescribing and dispensing, as well as multiple provider use. Covariate adjustment was often inadequate in analyses, as was the timing of outcome and PMP measurement. Future studies should broaden their geographic scope to other countries and use more recent data with standard measurement. PERSPECTIVE: This systematic review aimed to determine the effectiveness of PMPs in changing prescribing practices and prescription opioid use. The findings from this review will inform policymakers and PMP administrators about the current state of the evidence on program effectiveness.