Innovative Technologies in CNS Trials: Promises and Pitfalls for Recruitment, Retention, and Representativeness.

Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption.

Appropriate controls for digital therapeutic clinical trials: A narrative review of control conditions in clinical trials of digital therapeutics (DTx) deploying psychosocial, cognitive, or behavioral content.

Digital therapeutics (DTx) are software programs that treat a disease or condition. Increasingly, DTx are part of medical care, and in the US healthcare system they are regulated by the FDA as Software as a Medical Device (SaMD). Randomized controlled trials (RCT) remain a key evidence generation step for most DTx. However, developing a unified approach to the design of appropriate control conditions has been a challenge for two main reasons: (1) inheriting control condition definitions from pharmacotherapy and medical device RCT that may not directly apply, and (2) challenges in establishing control conditions for psychosocial interventions that build the core of many DTx. In our critical review we summarize different approaches to control conditions and patient blinding in RCT evaluating DTx with psychosocial, cognitive or behavioral content. We identify control condition choices, ranging from very minimal digital controls to more complex and stringent digital applications that contain aspects of "fake" therapy, general wellness content or games. Our review of RCTs reveals room for improvement in describing and naming control conditions more consistently. We further discuss challenges in defining placebo controls for DTx and ways in which control choices may have a therapeutic effect. While no one-size-fits-all control conditions and study designs will apply to all DTx, we propose points to consider for defining appropriate digital control conditions. At the same time, given the rapid iterative development and optimization of DTx, treatments with low risk profile may be evaluated with minimal digital controls followed by extensive real-world effectiveness trials.

Pain management consultation for acute pancreatitis: impact on length of stay and opioid utilization.

Aim: The purpose of the study was to understand the impact of a pain management consult for acute pancreatitis patients on their inpatient length of stay, morphine milligram equivalences (MMEs) and pancreatitis severity. Materials & methods: Adult patient data were extracted from the electronic health records from 1 October 2016 to 31 December 2018. Results & conclusion: Of 277 patients with a single acute pancreatitis hospitalization, 23 had a pain consultation (treatment group), whereas 254 did not (control group). There were statistically significant differences in median length of stay, median MME total and median MME per day between the treatment and control groups with comparable severity and pain scores (6.8 vs 3.1 days, 196.5 vs 33.8 MMEs, 30.9 vs 12.1 MMEs, respectively, p < 0.0001). This study emphasizes the complexity of pain management and the importance of further research in the field.

A Virtual, Randomized, Control Trial of a Digital Therapeutic for Speech, Language, and Cognitive Intervention in Post-stroke Persons With Aphasia.

Background: Post-stroke aphasia is a chronic condition that impacts people's daily functioning and communication for many years after a stroke. Even though these individuals require sustained rehabilitation, they face extra burdens to access care due to shortages in qualified clinicians, insurance limitations and geographic access. There is a need to research alternative means to access intervention remotely, such as in the case of this study using a digital therapeutic. Objective: To assess the feasibility and clinical efficacy of a virtual speech, language, and cognitive digital therapeutic for individuals with post-stroke aphasia relative to standard of care. Methods: Thirty two participants completed the study (experimental: average age 59.8 years, 7 female, 10 male, average education: 15.8 years, time post-stroke: 53 months, 15 right handed, 2 left handed; control: average age 64.2 years, 7 female, 8 male, average education: 15.3 years, time post-stroke: 36.1 months, 14 right handed, 1 left handed). Patients in the experimental group received 10 weeks of treatment using a digital therapeutic, Constant Therapy-Research (CT-R), for speech, language, and cognitive therapy, which provides evidence-based, targeted therapy with immediate feedback for users that adjusts therapy difficulty based on their performance. Patients in the control group completed standard of care (SOC) speech-language pathology workbook pages. Results: This study provides Class II evidence that with the starting baseline WAB-AQ score, adjusted by -0.69 for every year of age, and by 0.122 for every month since stroke, participants in the CT-R group had WAB-AQ scores 6.43 higher than the workbook group at the end of treatment. Additionally, secondary outcome measures included the WAB-Language Quotient, WAB-Cognitive Quotient, Brief Test of Adult Cognition by Telephone (BTACT), and Stroke and Aphasia Quality of Life Scale 39 (SAQOL-39), with significant changes in BTACT verbal fluency subtest and the SAQOL-39 communication and energy scores for both groups. Conclusions: Overall, this study demonstrates the feasibility of a fully virtual trial for patients with post-stroke aphasia, especially given the ongoing COVID19 pandemic, as well as a safe, tolerable, and efficacious digital therapeutic for language/cognitive rehabilitation. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04488029.

Efficacy and safety of tocilizumab in treatment of Takayasu arteritis: A systematic review of randomized controlled trials.

BACKGROUND: Takayasu arteritis (TAK) is a chronic immune vasculitis in which Interleukin-6 (IL-6) receptors play a key role in pathogenesis. Tocilizumab (TCZ), an IL-6 receptor antagonist with a favorable safety and efficacy profile, has been tried as an option for patients with TAK. This systematic review analyzed the evidence from randomized control trials (RCT) assessing the safety and efficacy of TCZ in patients with TAK. METHODS: MEDLINE, Embase, the Cochrane Library, and clinical trial registries were searched from inception to July 2018. We included RCT assessing the efficacy and safety of TCZ versus placebo/other comparators for the treatment of patients with TAK. The risk of bias (RoB) was assessed using Cochrane RoB tool. RESULTS: 2799 identified articles were screened as per abstract and title; 42 selected full-texts articles were assessed for the potential inclusion. One trial, reported in two publications, comparing subcutaneous TCZ (162 mg/week) versus matching placebo in 36 patients with TAK was included. The relapse-free rate at 24 weeks was 50.6% and 22.9% in TCZ and placebo arm, respectively. The hazard ratio (HR) for time to first relapse was statistically significant in the per-protocol population (HR 0.34 [95.41% CI, 0.11-1.00]; p = .0345), while non-significant in the intention-to-treat population (HR 0.41 [95.41% CI, 0.15-1.10]; p = .0596). The serious adverse events were higher in the placebo arm. CONCLUSIONS: This systematic review finds the existing evidence from RCT on efficacy and safety profile of TCZ in TAK to be promising but limited. Additional evidence is required to draw a stronger conclusion.

New Media, Technology and Neurology Education.

The use of technology in neurology education has revolutionized many aspects of medical teaching, addressing some important challenges of modern education such as information overload and the unique needs of millennial learners. However, it also has inherent problems, such as depersonalization and high development costs. Due to the heterogeneity of different applications, it is difficult to establish general principles to guide front line educators, but it may be possible to describe "minimum" best practice elements. In this article, we examine commonalities of some of the most successful uses of technology in neurology education. We suggest the following for effective application of technology: (1) match technology to predetermined educational objectives, (2) characterize learners in relationship to technology, (3) optimize how technological components fit into the learning environment, (4) monitor and manage learner engagement with technology, (5) perform cost analyses, and (6) explore opportunities for educational scholarship and research.

Curriculum mapping as a tool to facilitate curriculum development: a new School of Medicine experience.

BACKGROUND: Every curriculum needs to be reviewed, implemented and evaluated; it must also comply with the regulatory standards. This report demonstrates the value of curriculum mapping (CM), which shows the spatial relationships of a curriculum, in developing and managing an integrated medical curriculum. METHODS: A new medical school developed a clinical presentation driven integrated curriculum that incorporates the active-learning pedagogical practices of many educational institutions worldwide while adhering to the mandated requirements of the accreditation bodies. A centralized CM process was run in parallel as the curriculum was being developed. A searchable database, created after the CM data was uploaded into an electronic curriculum management system, was used to ensure placing, integrating, evaluating and revising the curricular content appropriately. RESULTS: CM facilitated in a) appraising the content integration, b) identifying gaps and redundancies, c) linking learning outcomes across all educational levels (i.e. session to course to program), c) organizing the teaching schedules, instruction methods, and assessment tools and d) documenting compliance with accreditation standards. CONCLUSIONS: CM is an essential tool to develop, review, improve and refine any integrated curriculum however complex. Our experience, with appropriate modifications, should help other medical schools efficiently manage their curricula and fulfill the accreditation requirements at the same time.

Corrigendum: Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke.

[This corrects the article on p. 32 in vol. 4, PMID: 23565108.].

Neurotransmitters in hiccups.

Hiccups are the sudden involuntary contractions of the diaphragm and intercostal muscles. They are generally benign and self-limited, however, in some cases they are chronic and debilitating. There are approximately 4000 admissions for hiccups each year in the United States. The hiccup reflex arc is composed of three components: (1) an afferent limb including the phrenic, vagus, and sympathetic nerves, (2) the central processing unit in the midbrain, and (3) the efferent limb carrying motor fibers to the diaphragm and intercostal muscles. Hiccups may be idiopathic, organic, psychogenic, or medication-induced. Data obtained largely from case studies of hiccups either induced by or treated with medications have led to hypotheses on the neurotransmitters involved. The central neurotransmitters implicated in hiccups include GABA, dopamine, and serotonin, while the peripheral neurotransmitters are epinephrine, norepinephrine, acetylcholine, and histamine. Further studies are needed to characterize the nature of neurotransmitters at each anatomical level of the reflex arc to better target hiccups pharmacologically.

The Effectiveness of Aromatherapy in Reducing Pain: A Systematic Review and Meta-Analysis.

Background. Aromatherapy refers to the medicinal or therapeutic use of essential oils absorbed through the skin or olfactory system. Recent literature has examined the effectiveness of aromatherapy in treating pain. Methods. 12 studies examining the use of aromatherapy for pain management were identified through an electronic database search. A meta-analysis was performed to determine the effects of aromatherapy on pain. Results. There is a significant positive effect of aromatherapy (compared to placebo or treatments as usual controls) in reducing pain reported on a visual analog scale (SMD = -1.18, 95% CI: -1.33, -1.03; p < 0.0001). Secondary analyses found that aromatherapy is more consistent for treating nociceptive (SMD = -1.57, 95% CI: -1.76, -1.39, p < 0.0001) and acute pain (SMD = -1.58, 95% CI: -1.75, -1.40, p < 0.0001) than inflammatory (SMD = -0.53, 95% CI: -0.77, -0.29, p < 0.0001) and chronic pain (SMD = -0.22, 95% CI: -0.49, 0.05, p = 0.001), respectively. Based on the available research, aromatherapy is most effective in treating postoperative pain (SMD = -1.79, 95% CI: -2.08, -1.51, p < 0.0001) and obstetrical and gynecological pain (SMD = -1.14, 95% CI: -2.10, -0.19, p < 0.0001). Conclusion. The findings of this study indicate that aromatherapy can successfully treat pain when combined with conventional treatments.

Zingiberaceae extracts for pain: a systematic review and meta-analysis.

BACKGROUND: Members of the family Zingiberaceae including turmeric, ginger, Javanese ginger, and galangal have been used for centuries in traditional medicine. Preclinical studies of Zingiberaceae extracts have shown analgesic properties. This study aims to systematically review and meta-analyze whether extracts from Zingiberaceae are clinically effective hypoalgesic agents. METHODS: Literature was screened from electronic databases using the key words Zingiberaceae AND pain OR visual analogue score (VAS) to identify randomized trials. From this search, 18 studies were identified, and of these, 8 randomized, double-blinded, placebo-controlled trials were found that measured pain by VAS for inclusion in the meta-analysis. RESULTS: Findings indicated significant efficacy of Zingiberaceae extracts in reducing subjective chronic pain (SMD - 0.67; 95 % CI - 1.13 to - 0.21; P = 0.004). A linear dose-effect relationship was apparent between studies (R(2) = 0.71). All studies included in the systematic review reported a good safety profile for extracts, without the renal risks associated with non-steroidal anti-inflammatory drugs, and with similar effectiveness. CONCLUSION: Our findings indicated that Zingiberaceae extracts are clinically effective hypoalgesic agents and the available data show a better safety profile than non-steroidal anti-inflammatory drugs. However, both non-steroidal anti-inflammatory drugs and Zingiberaceae have been associated with a heightened bleeding risk, and there have been no comparator trials of this risk. Further clinical studies are recommended to identify the most effective type of Zingiberaceae extract and rigorously compare safety, including bleeding risk.

Botulinum Toxin-A for Painful Diabetic Neuropathy: A Meta-Analysis.

OBJECTIVES: Painful diabetic neuropathy (PDN) is a debilitating complication of diabetes that greatly affects the quality of life of those afflicted. There are many treatment options for neuropathic pain. Recent studies show a promising analgesic effect using botulinum toxin-A (BTX-A) for neuropathic pain. METHODS: This article is a meta-analysis of two studies using BTX-A in the treatment of neuropathic pain. Electronic searches of MEDLINE/PubMed, EMBASE, and Cochrane Libraries using the terms "botulinum neurotoxin" and "neuropathic pain" were conducted. Only class I and class II therapeutic trials, as classified by the American Academy of Neurology were included. The primary outcome measured was the difference in visual analogue scale (VAS) from pre-intervention and post-intervention after 1 month. Data were analyzed for biases and heterogeneity following Cochrane and PRISMA guidelines. RESULTS: Two studies on PDN were analyzed in the meta-analysis showing improvement of 1.96 VAS points (95% CI, -3.09 to -0.84; Z score = 3.43, P < 0.001) following treatment with BTX-A. This corresponds to clinically significant improvement of "minimum change in pain." The adverse effects of infection at injection site was not statistically significant (P = 0.49). BTX-A may be effective for PDN. CONCLUSION: Tests for significance, low overall risk of bias, and almost no statistical heterogeneity suggests that there is a correlation between BTX-A and improvement of pain scores in PDN. Further large-scale controlled trials are needed.

Efficacy and tolerability of quetiapine versus haloperidol in first-episode schizophrenia: a randomized clinical trial.

BACKGROUND: Schizophrenia is a chronic disease of global importance. The second-generation antipsychotic quetiapine has a favorable side-effect profile, however, its clinical effectiveness has been called into question when compared with first-generation antipsychotics such as haloperidol. This study evaluates the efficacy and tolerability of quetiapine versus haloperidol for first-episode schizophrenia in the outpatient setting. METHODS: 156 adult patients with first-episode schizophrenia participated in an outpatient clinical trial and were randomized to quetiapine (200 mg/d; n = 78) or haloperidol (5 mg/d; n = 78). The study medications were titrated to a mean daily dose of 705 mg for quetiapeine and 14 mg for haloperidol. The patients were assessed at baseline, six weeks, and twelve weeks. The primary outcome measures were positive and negative scores of the Positive and Negative Syndrome Scale (PANSS). Secondary measures were Global Assessment of Functioning (GAF) scale for overall psychosocial functioning, and Simpson-Angus Scale (SAS) for extra-pyramidal symptoms. RESULTS: At twelve weeks, the quetiapine group had a greater decrease in PANSS positive (18.9 vs. 15.3, p = 0.013) and negative scores (15.5 vs. 11.6, p = 0.012), however, haloperidol showed a greater decrease in general psychopathology score (23.8 vs. 27.7, p = 0.012). No significant difference between groups were found for total PANSS (58.3 vs. 54.8, p = 0.24) and GAF (45.7 vs. 46.2, p = 0.79).ANOVA identified significant group interactions on PANSS positive (F = 18.72, df = 1.6,52.4, p < 0.0001), negative (F = 5.20, df = 1.1,35.7, p < 0.0001), depression/anxiety (F = 106.49, df = 1.14,37.8, p < 0.0001), and total scores (F = 7.51, df = 1.4,45.6, p = 0.001).SAS (8.62 vs. 0.26, p < 0.0001) and adverse events of akathisia (78% vs. 0%, p = 0.000), parkinsonism (66.6% vs. 0%, p < 0.0001), and fatigue (84.6% vs. 66.6%, p = 0.009) were greater in haloperidol compared to quetiapine, whereas headache was more common in quetiapine treated patients (11.5% vs. 35.9%, p < 0.0001). CONCLUSIONS: Quetiapine has greater efficacy for positive and negative symptoms with less extra-pyramidal symptoms than haloperidol when used for first-episode schizophrenia in the outpatient setting.

The history of reimbursements in neurology.

The Patient Protection and Affordable Care Act (PPACA) addresses consumer protection, employer-provided insurance coverage, as well as the government's role in providing health care access to the most vulnerable populations. Within the practice of neurology, the PPACA has the challenging goal of reconciling the needs of the growing elderly population with the financial barriers to costly yet available health care services. To bridge that gap, all health care professionals working in the field of neurology must reflect on the effect previous Medicare reimbursement policies have had on the current practice of neurology, and utilize lessons learned in recent years. The test of time will tell whether the PPACA will achieve the goal of decreasing in health care spending while ensuring quality universal healthcare services.