HTA community perspectives on the use of patient preference information: lessons learned from a survey with members of HTA bodies.

This research sought to assess whether and how patient preference (PP) data are currently used within health technology assessment (HTA) bodies and affiliated organizations involved in technology/drug appraisals and assessments. An exploratory survey was developed by the PP Project Subcommittee of the HTA International Patient and Citizen Involvement Interest Group to gain insight into the use, impact, and role of PP data in HTA, as well as the perceived barriers to its incorporation. Forty members of HTA bodies and affiliated organizations from twelve countries completed the online survey. PP data were reported to be formally considered as part of the HTA evidence review process by 82.5 percent of the respondents, while 39.4 percent reported that most of the appraisals and assessments within their organization in the past year had submitted PP data. The leading reason for why PP data were not submitted in most assessments was time/resource constraints followed by lack of clarity on PP data impact. Participants reported that PP data had a moderate level of influence on the deliberative process and outcome of the decision, but a higher level of influence on the decision's quality. Most (81.8 percent) felt patient advocacy groups should be primarily responsible for generating and submitting this type of evidence. Insights from the survey confirm the use of PP data in HTA but reveal barriers to its broader and more meaningful integration. Encouragingly, participants believe obstacles can be overcome, paving the way for a second phase of research involving in-depth collaborative workshops with HTA representatives.

Patient-centered health technology assessment: a perspective on engagement in health technology assessment by three patient organizations and a health technology assessment body.

Patient engagement in health technology assessment (HTA) has become increasingly important over the past 20 years. Academic and practitioner literature has produced numerous case studies and best practice accounts of patient involvement practices around the world. This text analyzes the experience of being involved in an Institute for Clinical and Economic Review (ICER) HTA review in the United States. The analysis comes from the joint perspective of three patient organizations: Lupus and Allied Diseases Association, Inc.; Lupus Foundation of America; and Black Women's Health Imperative, as well as ICER. We suggest that meaningful, patient-centered engagement, where patient communities are systematically integrated throughout the review, can be a way of returning to the discipline's roots focusing on technologies' societal and ethical impact. It is a process that requires robust commitment from all involved but produces assessments relevant to those directly affected by them.

Intravenous Low-Dose Ketamine Provides Greater Pain Control Compared to Fentanyl in a Civilian Prehospital Trauma System: A Propensity Matched Analysis.

Objective: A few studies report comparable analgesic efficacy between low-dose ketamine and opioids such as morphine or fentanyl; however, limited research has explored the safety and effectiveness of intravenous low-dose ketamine as a primary analgesic in a civilian prehospital setting. The objective of this study is to compare pain control between low-dose ketamine and fentanyl when administered intravenously (IV) for the indication of severe pain. Methods: This was a retrospective, observational review of prehospital adult patients (≥18 years) who presented with severe pain (numeric rating scale, 7-10) and were treated solely with either low-dose ketamine IV or fentanyl IV between January 1, 2014 and December 31, 2016. Propensity matched analysis was performed adjusting for all baseline variables with p ≤ 0.10 and for baseline pain score to match ketamine and fentanyl patients on a one-to-one ratio. The primary outcome was change in pain score from baseline to after treatment and evaluated with a paired t-test. Secondary outcomes were changes in vital signs and Glasgow coma scale (GCS) from baseline to after treatment, as well as incidence of clinically significant adverse events (AEs); AEs were followed from scene arrival through emergency department discharge. Results: Propensity matched analysis produced 79 matched pairs. Ketamine IV patients, receiving a mean (SD) dose of 0.3 (0.1) mg/kg, showed a significantly larger mean decrease in pain after treatment, compared to the fentanyl IV patients (-5.5 (3.1) vs. -2.5 (2.4), p < 0.001). A significantly greater proportion of patients receiving ketamine IV achieved at least a 50% reduction in pain compared to those receiving fentanyl IV (67% vs. 19%, p < 0.001), marking 52 ketamine IV patients as responders to treatment. Vital signs demonstrated a nonsignificant decrease in blood pressure, respiratory rate, heart rate, and GCS. No clinically significant AEs were reported for patients receiving ketamine IV. Conclusion: The significant reduction in pain, significantly high proportion of ketamine responders, and the lack of clinically significant AEs characterizing patients receiving low-dose ketamine IV compared to fentanyl IV, all provide further support for its use as an effective prehospital analgesic. Level of Evidence: Level III, therapeutic.

Comparative effectiveness analysis of two regional analgesia techniques for the pain management of isolated multiple rib fractures.

Background: Catheter-based regional analgesia has been proposed as an alternative to systemic analgesia for patients with multiple rib fractures (MRF). This study sought to compare the efficacy of regional techniques for decreasing pain and improving clinical outcomes. Study design: This was a multi-institutional, retrospective cohort study of adult (≥18 years) patients admitted to four nonacademic trauma centers over two years (from 07/1/2014 to 06/30/2016). Study inclusion was MRF (≥3 fractures) with no other severe injuries. Two primary regional analgesia techniques were utilized and compared: continuous intercostal nerve blocks (CINB) and epidural (EPI) analgesia. The primary outcome, average pain scores on treatment, was examined using a repeated measures, linear regression mixed model. Secondary outcomes included hospital LOS, ICU LOS, ICU admission and hospital readmission, pulmonary complications, and incentive spirometry volumes during treatment, and were examined with univariate statistics. Results: There were 339 patients with isolated MRF; 85 (25%) required regional analgesia (CINB, n=41; EPI, n=44) and the remaining 75% received systemic analgesia only (IV, n=195; PO, n=59). There were demographic and clinical differences between regional analgesia and systemic analgesia groups; on the contrary, there were no demographic or clinical differences between the CINB and EPI groups. Adjusted pain scores were similar for the EPI and CINB groups (4.0 vs 4.4, p=0.49). Secondary outcomes were worse in the EPI group compared to the CINB group: less improvement in incentive spirometry volume (p=0.004), longer ICU LOS (p=0.03), longer hospital LOS (p<0.001), and more ICU admission (p<0.001). Conclusion: In patients requiring regional analgesia, pain management was equivalent with CINB and EPI, but CINB was associated with significantly better clinical outcomes. CINB might offer an efficient alternative for pain control in patients with MRF.

In session extinction and outcome in Virtual Reality Exposure Therapy for PTSD.

Recent research emphasizes emotional engagement and between-session extinction, but no longer within-session extinction, as the primary mechanisms underlying exposure therapy for the treatment of PTSD. No previous studies have examined change in subjective units of distress (SUDS) in virtual reality exposure (VRE) for PTSD despite its potential facilitation of engagement (see McLay et al., 2012; Reger & Gahm, 2008). Using in session data from Rothbaum et al. (2014) we examined patterns of within- and between-session SUDS change in veterans receiving VRE for PTSD augmented by d-cycloserine, alprazolam, or placebo. The number of treatment sessions significantly predicted SUDS rating (t = -7.74, p < 0.001). Time in session continued to serve as a significant predictor of SUDS (t = 13.44, p < 0.001). Specifically, engagement increased within session and then reduction (extinction/habituation) was apparent across sessions. Treatment group was a predictor of SUDS rating within treatment sessions (t = 2.26, p < 0.05) but not across sessions, such that participants receiving medication experienced greater increases in SUDS within-session than those receiving placebo. Responder status was a predictor of SUDS reduction across treatment sessions (t = -4.43, p < 0.001) but did not produce an overall or within-session effect on SUDS. Thus, medications impact within-session SUDS changes but do not impact between-session reductions in SUDS- the change most consistently and closely related to magnitude of therapeutic change and responder status.

Flumazenil for the Treatment of Refractory Hypersomnolence: Clinical Experience with 153 Patients.

STUDY OBJECTIVES: Patients with central disorders of hypersomnolence sometimes do not achieve satisfactory symptom control with currently available wake-promoting medications. Based on the finding that the cerebrospinal fluid from some patients with hypersomnolence demonstrates potentiation of gamma-aminobutyric acid (GABA)-A receptors in excess of that of controls, a finding that reverses with flumazenil, we initiated prescribing compounded flumazenil to carefully selected, treatment-refractory hypersomnolent patients. METHODS: This retrospective chart review evaluated the first 153 consecutive patients treated with transdermal and/or sublingual flumazenil by physicians at our center from 2013 through January 2015. RESULTS: Patients were 35.5 y old (± 14.4) and 92 (60.1%) were women. Mean Epworth Sleepiness Scale scores prior to flumazenil were 15.1 (± 4.5) despite prior or current treatment with traditional wake-promoting therapies. Symptomatic benefit was noted by 96 patients (62.8%), with a mean reduction in Epworth Sleepiness Scale score of 4.7 points (± 4.7) among responders. Of these, 59 remained on flumazenil chronically, for a mean of 7.8 mo (± 6.9 mo). Female sex and presence of reported sleep inertia differentiated flumazenil responders from nonresponders. Adverse events were common, but often did not result in treatment discontinuation. Serious adverse events included a transient ischemic attack and a lupus vasculopathy, although whether these events occurred because of flumazenil administration is unknown. CONCLUSIONS: This chart review demonstrates that sublingual and transdermal flumazenil provided sustained clinical benefit to 39% of patients with treatment-refractory hypersomnolence. Prospective, controlled studies of this GABA-A receptor antagonist for the treatment of hypersomnolence are needed. COMMENTARY: A commentary on this article appears in this issue on page 1321.

Islet amyloid polypeptide (IAPP): a second amyloid in Alzheimer's disease.

Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid ß (Aß) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aß in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aß misfolding, [3] associates with Aß plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aß in vitro, and (3) endogenous IAPP localized to Aß oligomers and plaques. For the 4th corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or "infects" Aß pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aß in the brain requires further research.