Opioid dose risk, clinician and patient characteristics, and adherence to opioid prescribing recommendations in chronic non-cancer pain.

OBJECTIVE: This study aims to assess associations between morphine-equivalent daily dose (MEDD) of opioids, clinician and patient characteristics, and prescriber adherence to guidelines for long-term opioid therapy (LTOT) in chronic noncancer pain (CNCP) and to elucidate potential relationships associated with increased-risk opioid prescribing. DESIGN: Retrospective cross-sectional study. SETTING: Academic health system's 33 primary care clinics. PATIENTS: Adults (≥18 years old) prescribed LTOT (10 + outpatient prescriptions in the past year) for CNCP. MAIN OUTCOME MEASURE(S): Electronic health record data on prescribed opioids (for MEDD), clinician/patient characteristics, and adherence rates to LTOT guideline-concordant recommendations. RESULTS: A total of 2,738 patients were eligible, 61.6 percent Lower, 15.7 percent Moderate, and 22.7 percent Higher Risk MEDD (<50, 50-89, and ≥90 mg/day, respectively). Higher MEDD correlated (p < 0.001) with Medicare insurance, current cigarette smoking, higher pain intensity and interference scores, and the presence of opioid use disorder diagnoses. Male clinicians more frequently prescribed (p < 0.001) and male patients were more likely to be prescribed (p < 0.001) higher MEDD compared to their female counterparts. Higher Risk MEDD was associated with higher coprescribed benzodiazepines (p = 0.015), lower depression screening (p = 0.048), urine drug testing (p = 0.003), comparable active treatment agreement (p = 0.189), opioid misuse risk screening (p = 0.619), and prescription drug monitoring checks (p = 0.203). CONCLUSIONS: This study documented that higher MEDD was associated with risks of worse health outcomes without improved adherence to opioid prescribing guideline recommendations. Enhanced clinician awareness of factors associated with MEDD has the potential to mitigate LTOT risks and improve overall patient care.

A randomized, double-blind, placebo-controlled phase 2 study of intratympanic OTO-313 in patients with moderate to severe subjective tinnitus.

PURPOSE: This was a randomized, double-blind, placebo-controlled Phase 2 study to evaluate the efficacy and safety of intratympanic OTO-313 in patients with subjective unilateral tinnitus. METHODS: Patients with moderate to severe unilateral tinnitus of 2-12 months duration were enrolled. A single intratympanic injection of OTO-313 or placebo was administered to the affected ear and patients were evaluated during a 16-weeks follow-up period. Efficacy was assessed using the Tinnitus Functional Index (TFI), daily ratings of tinnitus loudness and annoyance, and Patient Global Impression of Change (PGIC). RESULTS: Intratympanic administration of OTO-313 and placebo produced reductions in tinnitus with a similar percentage of TFI responders at Weeks 4, 8, 12, and 16. Reductions in daily ratings of tinnitus loudness and annoyance, and PGIC scores were also similar between OTO-313 and placebo groups. No significant differences in mean TFI scores between OTO-313 and placebo were observed for pre-specified strata regarding tinnitus duration (≥ 2 to ≤ 6 months and > 6 to ≤ 12 months) and TFI baseline scores (≥ 32 to ≤ 53 points and ≥ 54 to 100 points), although the results numerically favored OTO-313 in patients in the ≥ 2 to ≤ 6 months strata. These results also demonstrated an unexpectedly high placebo response particularly amongst patients with chronic tinnitus, despite training implemented to mitigate placebo response. OTO-313 was well-tolerated with a similar incidence of adverse events compared to placebo. CONCLUSIONS: OTO-313 did not demonstrate a significant treatment benefit relative to placebo due in part to a high placebo response. OTO-313 was safe and well-tolerated.

Efficacy of Intratympanic OTO-104 for the Treatment of Ménière's Disease: The Outcome of Three Randomized, Double-Blind, Placebo-Controlled Studies.

OBJECTIVE: To determine the efficacy of intratympanic OTO-104 for the treatment of Ménière's disease. STUDY DESIGNS: Three randomized, double-blind, placebo-controlled, multicenter studies of OTO-104 in patients with Ménière's disease. SETTING: The United States and throughout Europe. PATIENTS: Individuals with Ménière's disease aged 18 to 85 years. INTERVENTIONS: All three studies were conducted according to a similar protocol, whereby after a 1-month lead-in period, eligible patients received a single intratympanic injection of either 12 mg OTO-104 (otic formulation of dexamethasone in thermosensitive poloxamer) or placebo (1:1) and were observed for 3 months. MAIN OUTCOME MEASURES: The primary efficacy endpoint was measured by the number of definitive vertigo days (DVDs) at month 3. Secondary objective was OTO-104 safety and tolerability including adverse events, audiometry, tympanometry, and otoscopic examinations. RESULTS: Although OTO-104 demonstrated numerically greater reductions in DVD compared with placebo across all three studies, statistical significance versus placebo (primary efficacy endpoint) was only achieved in one study, the AVERTS-2 study (n = 174, p = 0.029). Secondary vertigo efficacy endpoints were statistically significant at month 3 in that study including vertigo severity, the effect of vertigo on daily activity (days at home sick or bedridden), and vertigo frequency. In the AVERTS-1 study, which did not meet the primary endpoint, a subgroup analysis of the 115 patients (69.7% of study population) who did not previously receive intratympanic steroid injections demonstrated that OTO-104 patients had significantly lower mean DVD at month 3 than patients receiving placebo (1.9 for OTO-104 versus 3.0 for placebo; p = 0.045). Importantly, a significant placebo response was observed across studies in Ménière's disease patients. OTO-104 and the intratympanic injection procedure were well tolerated. CONCLUSIONS: In all three high-quality, randomized, double-blind, placebo-controlled, multicenter studies, a single intratympanic injection of 12 mg OTO-104 demonstrated numerically greater reductions in vertigo versus placebo in patients with Ménière's disease, but statistical separation from placebo was demonstrated in only one of the studies. OTO-104 was safe and well tolerated.(Otonomy, Inc. funded; NCT02717442, NCT02612337, NCT03664674).

Provider and patient sex disparities in opioid prescribing and patient outcomes.

OBJECTIVE: To assess sex disparities in opioid prescribing practices and patient outcomes. DESIGN: A retrospective cross-sectional study. SETTING: Thirty-three primary care clinics in an academic health system. PARTICIPANTS: 2,738 adults prescribed 10+ outpatient opioid prescriptions within 12 months. MAIN OUTCOME MEASURE(S): Patient and primary care provider (PCP) sexbased differences in clinical outcomes, opioid prescribing, and rates of adherence to guideline-concordant opioid prescribing practices. RESULTS: Female PCPs were more likely (p < 0.001) to prescribe lower morphineequivalent daily dose (MEDD) of opioids and complete risk assessment for opioid misuse than male PCPs. PCPs did not differ by sex in adherence rates to controlled substance agreements, urine drug, depression screening, or opioid-benzodiazepine coprescribing. Female patients were more likely (all p ≤ 0.01) to be screened for opioid misuse, treated with lower MEDD, receive opioid-benzodiazepine coprescriptions, have higher pain interference, anxiety and depression diagnoses, and have an overdose diagnosis; they were less likely (all p < 0.001) to report alcohol use or have an alcohol use disorder diagnosis and utilized health care at higher rates than male patients. CONCLUSIONS: Sex differences were found in clinician opioid-prescribing practices and adherence to opioid prescribing guidelines and patient characteristics associated with long-term opioid therapy. Strategies to identify sex-related disparities and enhance guideline-concordant opioid prescribing and monitoring could contribute to improved patient care, and clinical and safety outcomes.

Intratympanic Administration of OTO-313 Reduces Tinnitus in Patients With Moderate to Severe, Persistent Tinnitus: A Phase 1/2 Study.

OBJECTIVE: To evaluate the safety and exploratory efficacy of intratympanic administration of OTO-313 in patients with tinnitus. STUDY DESIGN: Single intratympanic injection of OTO-313 evaluated in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study. SETTING: Tertiary referral centers. PATIENTS: Patients with unilateral tinnitus (moderate-severe) with tinnitus duration 1 to 6 months. INTERVENTIONS: Intratympanic OTO-313. MAIN OUTCOME MEASURES: Safety and change from baseline in tinnitus functional index (TFI), daily ratings of tinnitus loudness and annoyance, and patient global impression of change (PGIC). RESULTS: OTO-313 was well-tolerated with lower incidence of adverse events than placebo. Mean TFI reduction from baseline favored OTO-313 at Week 2, 4, and 8. A clinically meaningful, 13-point improvement on the TFI was observed in 43% (6/14) of OTO-313 patients at both Weeks 4 and 8 versus 13% (2/16) of placebo patients (ad hoc responder analysis, p-value < 0.05). Reductions in daily ratings of tinnitus loudness and annoyance favored OTO-313 compared with placebo. In OTO-313 responders, a strong correlation existed between change from baseline in TFI score and changes in tinnitus loudness, tinnitus annoyance, and PGIC. CONCLUSIONS: OTO-313 was well-tolerated and demonstrated a higher proportion of responders than placebo across consecutive visits (Weeks 4 and 8) supporting further clinical development of OTO-313 for the treatment of tinnitus.

Multicenter, Double-Blind, Randomized Trial of Emricasan in Hepatitis C-Treated Liver Transplant Recipients With Residual Fibrosis or Cirrhosis.

Despite achieving sustained virologic response (SVR) to hepatitis C virus (HCV) therapy, there remains a post liver transplantation population with advanced fibrosis/cirrhosis. Emricasan is an orally active, pan-caspase inhibitor that suppresses apoptosis and inflammation, potentially decreasing hepatic inflammation and fibrosis. We aimed to determine the safety and efficacy of emricasan (IDN-6556-07) in a double-blind, randomized, placebo-controlled, multicenter study in reducing or preventing the progression of hepatic fibrosis in HCV liver transplant recipients with residual fibrosis or cirrhosis after achieving SVR. A total of 64 participants were randomly assigned to receive 25 mg twice daily of emricasan or placebo in a 2:1 ratio for 24 months. 41 participants were randomly assigned to emricasan and 23 to placebo; 32 participants in the emricasan group (78.0%) and 19 who took a placebo (82.6%) completed the study. There was no difference in the primary endpoint (Ishak fibrosis stages F2-F5, improvement in fibrosis or stability; Ishak fibrosis stage F6, improvement) between the emricasan (77.1%) and placebo groups (74.1%); P = NS. There was no difference between the emricasan (54.5%) and placebo (60.7%) arms in the rate of fibrosis improvement alone. However, those in the prespecified F3 to F5 subgroup had higher rates of stability or improvement in fibrosis in the emricasan group (95.2%) compared with placebo (54.6%) (P = 0.01). The tolerability and safety profiles were similar in both groups. In conclusion, overall stability in the Ishak fibrosis stage was similar between emricasan and placebo groups at 24 months. However, there was improvement and/or stability in fibrosis stage in the prespecified F3 to F5 subgroup with emricasan versus placebo, suggesting that patients with moderate fibrosis may benefit with emricasan.

Increasing system-wide implementation of opioid prescribing guidelines in primary care: findings from a non-randomized stepped-wedge quality improvement project.

BACKGROUND: Clinician utilization of practice guidelines can reduce inappropriate opioid prescribing and harm in chronic non-cancer pain; yet, implementation of "opioid guidelines" is subpar. We hypothesized that a multi-component quality improvement (QI) augmentation of "routine" system-level implementation efforts would increase clinician adherence to the opioid guideline-driven policy recommendations. METHODS: Opioid policy was implemented system-wide in 26 primary care clinics. A convenience sample of 9 clinics received the QI augmentation (one-hour academic detailing; 2 online educational modules; 4-6 monthly one-hour practice facilitation sessions) in this non-randomized stepped-wedge QI project. The QI participants were volunteer clinic staff. The target patient population was adults with chronic non-cancer pain treated with long-term opioids. The outcomes included the clinic-level percentage of target patients with a current treatment agreement (primary outcome), rates of opioid-benzodiazepine co-prescribing, urine drug testing, depression and opioid misuse risk screening, and prescription drug monitoring database check; additional measures included daily morphine-equivalent dose (MED), and the percentages of all target patients and patients prescribed ≥90 mg/day MED. T-test, mixed-regression and stepped-wedge-based analyses evaluated the QI impact, with significance and effect size assessed with two-tailed p < 0.05, 95% confidence intervals and/or Cohen's d. RESULTS: Two-hundred-fifteen QI participants, a subset of clinical staff, received at least one QI component; 1255 patients in the QI and 1632 patients in the 17 comparison clinics were prescribed long-term opioids. At baseline, more QI than comparison clinic patients were screened for depression (8.1% vs 1.1%, p = 0.019) and prescribed ≥90 mg/day MED (23.0% vs 15.5%, p = 0.038). The stepped-wedge analysis did not show statistically significant changes in outcomes in the QI clinics, when accounting for the comparison clinics' trends. The Cohen's d values favored the QI clinics in all outcomes except opioid-benzodiazepine co-prescribing. Subgroup analysis showed that patients prescribed ≥90 mg/day MED in the QI compared to comparison clinics improved urine drug screening rates (38.8% vs 19.1%, p = 0.02), but not other outcomes (p ≥ 0.05). CONCLUSIONS: Augmenting routine policy implementation with targeted QI intervention, delivered to volunteer clinic staff, did not additionally improve clinic-level, opioid guideline-concordant care metrics. However, the observed effect sizes suggested this approach may be effective, especially in higher-risk patients, if broadly implemented. TRIAL REGISTRATION: Not applicable.

Initial Results from Mobile Low-Dose Computerized Tomographic Lung Cancer Screening Unit: Improved Outcomes for Underserved Populations.

INTRODUCTION: The National Lung Screening Trial (NLST) demonstrated that screening high-risk patients with low-dose computed tomography (CT) of the chest reduces lung cancer mortality compared with screening with chest x-ray. Uninsured and Medicaid patients usually lack access to this hospital-based screening test because of geographic and socioeconomic factors. We hypothesized that a mobile screening unit would improve access and confer the benefits demonstrated by the NLST to this underserved group, which is most at risk of lung cancer deaths. PATIENTS AND METHODS: We created a mobile unit by building a Samsung BodyTom portable 32-slice low-dose CT scanner into a 35-foot coach; it delivers high-quality images for both soft tissue and bone and includes a waiting area and high-speed wireless internet connection for fast image transfer. The unit was extensively tested to show robustness and stability of mobile equipment. This project was designed to screen uninsured and underinsured patients, otherwise with eligibility criteria identical to that of the National Lung Screening Trial, with the only difference being exclusion of patients eligible for Medicare (which provides financial coverage for CT-based lung cancer screening). RESULTS: We screened 550 patients (20% black, 3% Hispanic, 70% rural) with a male-to-female ratio of 1.1:1, median age 61 years (range, 55-64), and found 12 lung cancers at initial screen (2.2%), including 6 at stage I-II (58% of total lung cancers early stage) and 38 Lung-RADS 4 (highly suspicious) lesions that are being followed closely. Incidental findings included nonlung cancers and coronary artery disease. DISCUSSION: In this initial pilot study, using the first mobile low-dose whole body CT screening unit in the U.S., the initial cancer detection rate is comparable to that reported in the NLST, despite excluding patients over the age of 64 years who have Medicare coverage, but with marked improvement of screening rates specifically in underserved sociodemographic, racial, and ethnic groups and with better outcomes than conventionally found in the underserved and at lower cost per case. IMPLICATIONS FOR PRACTICE: This study shows clearly that a mobile low-dose CT scanning unit allows effective lung cancer screening for underserved populations, such as impoverished African Americans, Hispanics, Native Americans, or isolated rural groups, and has a pick-up rate of 1% for early stage disease. If confirmed in a planned randomized trial, this will be policy changing, as these groups usually present with advanced disease; this approach will produce better survival data at lower cost per case.

Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension.

BACKGROUND & AIMS: Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. METHODS: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. RESULTS: There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. CONCLUSIONS: Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. LAY SUMMARY: Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02960204.

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo.

BACKGROUND & AIMS: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child-Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child-Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK-18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

Emricasan (IDN-6556) Lowers Portal Pressure in Patients With Compensated Cirrhosis and Severe Portal Hypertension.

Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect.

Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study.

BACKGROUND: The Coalition for Epidemic Preparedness Innovations was established in 2016, to develop vaccines that can contribute to preparedness for outbreaks of epidemic infectious diseases. Evidence on vaccine development costs for such diseases is scarce. Our goal was to estimate the minimum cost for achieving vaccine research and development preparedness targets in a portfolio of 11 epidemic infectious diseases, accounting for vaccine pipeline constraints and uncertainty in research and development preparedness outcomes. METHODS: We assembled a pipeline of 224 vaccine candidates from preclinical through to phase 2 for 11 priority epidemic infectious diseases. We used a linear regression model to identify drivers of development costs from preclinical through to end of phase 2a. Drawing from published estimates of vaccine research and development probabilities of success, we simulated costs for advancing these 224 vaccine candidates through to the end of phase 2a. We combined these findings to determine minimum costs for progressing at least one vaccine through to the end of phase 2a per epidemic infectious disease by means of a stochastic optimisation model. FINDINGS: The cost of developing a single epidemic infectious disease vaccine from preclinical trials through to end of phase 2a is US$31-68 million (US$14-159 million range), assuming no risk of failure. We found that previous licensure experience and indirect costs are upward drivers of research and development costs. Accounting for probability of success, the average cost of successfully advancing at least one epidemic infectious disease vaccine through to the end of phase 2a can vary from US$84-112 million ($23 million-$295 million range) starting from phase 2 to $319-469 million ($137 million-$1·1 billion range) starting from preclinical. This cost includes the cumulative cost of failed vaccine candidates through the research and development process. Assuming these candidates and funding were made available, progressing at least one vaccine through to the end of phase 2a for each of the 11 epidemic infectious diseases would cost a minimum of $2·8-3·7 billion ($1·2 billion-$8·4 billion range). INTERPRETATION: Our analysis provides new evidence on vaccine research and development pipelines and associated costs for 11 epidemic infectious diseases, highlighting both funding needs and research and development gaps for achieving vaccine research and development preparedness targets. FUNDING: This work was partly supported by the Research Council of Norway through the Global Health and Vaccination Programme GLOBVAC.

Assessing long-term sustainment of clinic participation in NIATx200: Results and a new methodological approach.

BACKGROUND: Sustainability frameworks differentiate between sustainability capacity and sustainment of organizational change. Multiple studies have examined sustainability capacity. Methodological approaches to assess long-term sustainment have not been explored. This study addresses this gap by describing the development of a long-term sustainment methodology and evaluating its application utilizing data from substance abuse clinics participating in a quality improvement collaborative. METHODS: The study involved clinics (n = 121) in three states (MI, NY and WA) participating in the 2007-2009 NIATx200 quality improvement (QI) intervention. It extended the primary analysis to focus on clinics' long-term sustainment of wait time, retention and admission improvements. Long-term sustainment was defined as two years post end of the active implementation period (Calendar Years 2010 and 2011). The analysis defined case exclusion criteria and spline "knot" time intervals; allowed for Cp statistic use to address clinic data volatility; established the structure of sustainment plots and explored differences between NIATx implementation strategies. RESULTS: Example spline and sustain plots highlight the application of the long-term sustainment methodology for NIATx200 clinics. In clinics with available longitudinal outcome data, 40.8% (n = 31 of 76 clinics) sustained improvements in wait time, 26.7% (n = 20 of 75 clinics) in retention, and 28.1% (n = 32 of 114 clinics) for admissions. Clinic assignment to a NIATx200 implementation strategy did not significantly influence a clinics' long-term sustainment except for lower wait time changes in the interest circle interventions. Thirty clinics (24.8%) sustained improvements for two outcomes and six clinics (5.0%) did so for all three outcomes. The clinics that sustained multiple outcome improvements were assigned to the interest circle (n = 12), learning session (n = 10), combination (n = 8), and coaching (n = 6) implementation strategies. Guidance for applying the long-term sustainment methodology in other quality improvement settings is described. CONCLUSIONS: Research about sustainability capacity and sustainment of change has become increasingly important in dissemination and implementation research. Assessment of long-term sustainment in a multi-organizational quality improvement collaborative (QIC) is needed to identify when program drift and intervention decay occurs. If "cut-points" indicate when effects diminish, specific sustainability modules could be developed and introduced within the structure of a QIC to improve organizational long-term sustainment. Coaches and change teams could be trained to focus on organizational change sustainment and strengthen the likelihood of institutionalization. ClinicalTrials.gov Identifier: NCT00934141 Registered July 6, 2009. Retrospectively registered.

A randomized matched-pairs study of feasibility, acceptability, and effectiveness of systems consultation: a novel implementation strategy for adopting clinical guidelines for Opioid prescribing in primary care.

BACKGROUND: This paper reports on the feasibility, acceptability, and effectiveness of an innovative implementation strategy named "systems consultation" aimed at improving adherence to clinical guidelines for opioid prescribing in primary care. While clinical guidelines for opioid prescribing have been developed, they have not been widely implemented, even as opioid abuse reaches epidemic levels. METHODS: We tested a blended implementation strategy consisting of several discrete implementation strategies, including audit and feedback, academic detailing, and external facilitation. The study compares four intervention clinics to four control clinics in a randomized matched-pairs design. Each systems consultant aided clinics on implementing the guidelines during a 6-month intervention consisting of monthly site visits and teleconferences/videoconferences. The mixed-methods evaluation employs the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Quantitative outcomes are compared using time series analysis. Qualitative methods included focus groups, structured interviews, and ethnographic field techniques. RESULTS: Seven clinics were randomly approached to recruit four intervention clinics. Each clinic designated a project team consisting of six to eight staff members, each with at least one prescriber. Attendance at intervention meetings was 83%. More than 80% of staff respondents agreed or strongly agreed with the statements: "I am more familiar with guidelines for safe opioid prescribing" and "My clinic's workflow for opioid prescribing is easier." At 6 months, statistically significant improvements were noted in intervention clinics in the percentage of patients with mental health screens, treatment agreements, urine drug tests, and opioid-benzodiazepine co-prescribing. At 12 months, morphine-equivalent daily dose was significantly reduced in intervention clinics compared to controls. The cost to deliver the strategy was $7345 per clinic. Adaptations were required to make the strategy more acceptable for primary care. Qualitatively, intervention clinics reported that chronic pain was now treated using approaches similar to those employed for other chronic conditions, such as hypertension and diabetes. CONCLUSIONS: The systems consultation implementation strategy demonstrated feasibility, acceptability, and effectiveness in a study involving eight primary care clinics. This multi-disciplinary strategy holds potential to mitigate the prevalence of opioid addiction and ultimately may help to improve implementation of clinical guidelines across healthcare. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02433496). https://clinicaltrials.gov/ct2/show/NCT02433496 Registered May 5, 2015.

The complexity and cost of vaccine manufacturing - An overview.

As companies, countries, and governments consider investments in vaccine production for routine immunization and outbreak response, understanding the complexity and cost drivers associated with vaccine production will help to inform business decisions. Leading multinational corporations have good understanding of the complex manufacturing processes, high technological and R&D barriers to entry, and the costs associated with vaccine production. However, decision makers in developing countries, donors and investors may not be aware of the factors that continue to limit the number of new manufacturers and have caused attrition and consolidation among existing manufacturers. This paper describes the processes and cost drivers in acquiring and maintaining licensure of childhood vaccines. In addition, when export is the goal, we describe the requirements to supply those vaccines at affordable prices to low-resource markets, including the process of World Health Organization (WHO) prequalification and supporting policy recommendation. By providing a generalized and consolidated view of these requirements we seek to build awareness in the global community of the benefits and costs associated with vaccine manufacturing and the challenges associated with maintaining consistent supply. We show that while vaccine manufacture may prima facie seem an economic growth opportunity, the complexity and high fixed costs of vaccine manufacturing limit potential profit. Further, for most lower and middle income countries a large majority of the equipment, personnel and consumables will need to be imported for years, further limiting benefits to the local economy.

Adaptation of the Grasha Riechman Student Learning Style Survey and Teaching Style Inventory to assess individual teaching and learning styles in a quality improvement collaborative.

BACKGROUND: NIATx200, a quality improvement collaborative, involved 201 substance abuse clinics. Each clinic was randomized to one of four implementation strategies: (a) interest circle calls, (b) learning sessions, (c) coach only or (d) a combination of all three. Each strategy was led by NIATx200 coaches who provided direct coaching or facilitated the interest circle and learning session interventions. METHODS: Eligibility was limited to NIATx200 coaches (N = 18), and the executive sponsor/change leader of participating clinics (N = 389). Participants were invited to complete a modified Grasha Riechmann Student Learning Style Survey and Teaching Style Inventory. Principal components analysis determined participants' preferred learning and teaching styles. RESULTS: Responses were received from 17 (94.4 %) of the coaches. Seventy-two individuals were excluded from the initial sample of change leaders and executive sponsors (N = 389). Responses were received from 80 persons (25.2 %) of the contactable individuals. Six learning profiles for the executive sponsors and change leaders were identified: Collaborative/Competitive (N = 28, 36.4 %); Collaborative/Participatory (N = 19, 24.7 %); Collaborative only (N = 17, 22.1 %); Collaborative/Dependent (N = 6, 7.8 %); Independent (N = 3, 5.2 %); and Avoidant/Dependent (N = 3, 3.9 %). NIATx200 coaches relied primarily on one of four coaching profiles: Facilitator (N = 7, 41.2 %), Facilitator/Delegator (N = 6, 35.3 %), Facilitator/Personal Model (N = 3, 17.6 %) and Delegator (N = 1, 5.9 %). Coaches also supported their primary coaching profiles with one of eight different secondary coaching profiles. CONCLUSIONS: The study is one of the first to assess teaching and learning styles within a QIC. Results indicate that individual learners (change leaders and executive sponsors) and coaches utilize multiple approaches in the teaching and practice-based learning of quality improvement (QI) processes. Identification teaching profiles could be used to tailor the collaborative structure and content delivery. Efforts to accommodate learning styles would facilitate knowledge acquisition enhancing the effectiveness of a QI collaborative to improve organizational processes and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00934141 Registered July 6, 2009. Retrospectively registered.

Systems consultation: protocol for a novel implementation strategy designed to promote evidence-based practice in primary care.

BACKGROUND: Adoption of evidence-based practices takes place at a glacial place in healthcare. This research will pilot test an innovative implementation strategy - systems consultation -intended to speed the adoption of evidence-based practice in primary care. The strategy is based on tenets of systems engineering and has been extensively tested in addiction treatment. Three innovations have been included in the strategy - translation of a clinical practice guideline into a checklist-based implementation guide, the use of physician peer coaches ('systems consultants') to help clinics implement the guide, and a focus on reducing variation in practices across prescribers and clinics. The implementation strategy will be applied to improving opioid prescribing practices in primary care, which may help ultimately mitigate the increasing prevalence of opioid abuse and addiction. METHODS/DESIGN: The pilot test will compare four intervention clinics to four control clinics in a matched-pairs design. A leading clinical guideline for opioid prescribing has been translated into a checklist-based implementation guide in a systematic process that involved experts who wrote the guideline in consultation with implementation experts and primary care physicians. Two physicians with expertise in family and addiction medicine are serving as the systems consultants. Each systems consultant will guide two intervention clinics, using two site visits and follow-up communication by phone and email, to implement the translated guideline. Mixed methods will be used to test the feasibility, acceptability, and preliminary effectiveness of the implementation strategy in an evaluation that meets standards for 'fully developed use' of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance). The clinic will be the primary unit of analysis. DISCUSSION: The systems consultation implementation strategy is intended to generalize to the adoption of other clinical guidelines. This pilot test is intended to prepare for a large randomized clinical trial that will test the strategy against other implementation strategies, such as audit/feedback and academic detailing, used to close the gap between knowledge and practice. The systems consultation approach has the potential to shorten the famously long time it takes to implement evidence-based practices and clinical guidelines in healthcare.

Which elements of improvement collaboratives are most effective? A cluster-randomized trial.

AIMS: Improvement collaboratives consisting of various components are used throughout health care to improve quality, but no study has identified which components work best. This study tested the effectiveness of different components in addiction treatment services, hypothesizing that a combination of all components would be most effective. DESIGN: An unblinded cluster-randomized trial assigned clinics to one of four groups: interest circle calls (group teleconferences), clinic-level coaching, learning sessions (large face-to-face meetings) and a combination of all three. Interest circle calls functioned as a minimal intervention comparison group. SETTING: Out-patient addiction treatment clinics in the United States. PARTICIPANTS: Two hundred and one clinics in five states. MEASUREMENTS: Clinic data managers submitted data on three primary outcomes: waiting-time (mean days between first contact and first treatment), retention (percentage of patients retained from first to fourth treatment session) and annual number of new patients. State and group costs were collected for a cost-effectiveness analysis. FINDINGS: Waiting-time declined significantly for three groups: coaching (an average of 4.6 days/clinic, P = 0.001), learning sessions (3.5 days/clinic, P = 0.012) and the combination (4.7 days/clinic, P = 0.001). The coaching and combination groups increased significantly the number of new patients (19.5%, P = 0.028; 8.9%, P = 0.029; respectively). Interest circle calls showed no significant effect on outcomes. None of the groups improved retention significantly. The estimated cost per clinic was $2878 for coaching versus $7930 for the combination. Coaching and the combination of collaborative components were about equally effective in achieving study aims, but coaching was substantially more cost-effective. CONCLUSIONS: When trying to improve the effectiveness of addiction treatment services, clinic-level coaching appears to help improve waiting-time and number of new patients while other components of improvement collaboratives (interest circles calls and learning sessions) do not seem to add further value.

Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations.

BACKGROUND: Quinolone-resistant Neisseria gonorrhoeae (QRNG) arise from mutations in gyrA (intermediate resistance) or gyrA and parC (resistance). Here we tested the consequence of commonly isolated gyrA(91/95) and parC86 mutations on gonococcal fitness. METHODS: Mutant gyrA(91/95) and parC86 alleles were introduced into wild-type gonococci or an isogenic mutant that is resistant to macrolides due to an mtrR(-79) mutation. Wild-type and mutant bacteria were compared for growth in vitro and in competitive murine infection. RESULTS: In vitro growth was reduced with increasing numbers of mutations. Interestingly, the gyrA(91/95) mutation conferred an in vivo fitness benefit to wild-type and mtrR(-79) mutant gonococci. The gyrA(91/95), parC86 mutant, in contrast, showed a slight fitness defect in vivo, and the gyrA(91/95), parC86, mtrR(-79) mutant was markedly less fit relative to the parent strains. A ciprofloxacin-resistant (Cip(R)) mutant was selected during infection with the gyrA(91/95), parC86, mtrR(-79) mutant in which the mtrR(-79) mutation was repaired and the gyrA(91) mutation was altered. This in vivo-selected mutant grew as well as the wild-type strain in vitro. CONCLUSIONS: gyrA(91/95) mutations may contribute to the spread of QRNG. Further acquisition of a parC86 mutation abrogates this fitness advantage; however, compensatory mutations can occur that restore in vivo fitness and maintain Cip(R).

To divide or manipulate the chorda tympani in stapedotomy.

The objective of this study is to determine the nature, duration and severity of chorda tympani symptoms in post-stapedotomy patients when the nerve has been known to have either sustained surgical manipulation or division. The study design was retrospective and blind, based at a tertiary Otology Referral Center (Gloucestershire Royal Hospital). All successive patients undergoing stapedotomy operated upon by the senior author (JMR) between November 1991 and October 1998 were included. The main outcome measures were postoperative graded dysgeusia (questionnaire) and post operative electrogustometry score, comparing the chorda tympani cut group and the chorda tympani preserved group. Sixty stapedotomies were performed in the study period. After a minimum interval of 8 months, questionnaire data were obtained in 55/60 (92%), and electrogustometry studies were carried out in 48/60 (80%). Symptoms of dysgeusia were experienced in the chorda tympani nerve cut (CC) group in 95% and in the chorda preserved (CP) group in 52%. For those with symptoms, duration was 6.7 months (+/-4.9 SD) and 3.4 months (+/-3.7 SD) for the CC and CP groups, respectively. From the electrogustometry data, after 8 months, the risk of total loss of response is significantly higher in CC patients (94%) than in CP patients (25%) (P = 0.0001). Also at 8 months, 54% of CP patients had normal ipsilateral electrogustometry responses compared with 6% in the CC group. In conclusion, cutting the chorda tympani results in significantly greater symptoms than when subjected to manipulation only, and these symptoms are likely to be more long lasting. Therefore, it is our recommendation that where possible the chorda be preserved. The risk of severe chorda symptoms when the chorda is cut is small (<5%). Preoperative consent to include dysgeusia is advised.