Publications by authors named "Peter McAllister"

33 Publications

Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial.

JAMA 2021 06;325(23):2348-2356

Lundbeck La Jolla Research Center, San Diego, California.

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion.

Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack.

Design, Setting, And Participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack.

Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine.

Main Outcomes And Measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours.

Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred.

Conclusions And Relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established.

Trial Registration: ClinicalTrials.gov Identifier: NCT04152083.
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http://dx.doi.org/10.1001/jama.2021.7665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207242PMC
June 2021

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

Neurology 2021 Jan 4. Epub 2021 Jan 4.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623).

Methods: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 10, 5.0 × 10, 10 × 10 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15).

Results: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients ( = 0.25).

Conclusions: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.

Classification Of Evidence: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.
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http://dx.doi.org/10.1212/WNL.0000000000011450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055341PMC
January 2021

Functional impairment and disability among patients with migraine: evaluation of galcanezumab in a long-term, open-label study.

Qual Life Res 2021 Feb 17;30(2):455-464. Epub 2020 Sep 17.

Eli Lilly and Company, 893 S. Delaware Street, Indianapolis, IN, 46225, USA.

Purpose: Migraine can negatively impact patient functioning and quality of life. Here, we report the effects of galcanezumab (GMB), a humanized monoclonal antibody that binds to calcitonin gene-related peptide, on patient-reported outcome (PRO) measures in migraine.

Methods: CGAJ was a Phase III, randomized, open-label study (12-month open-label and 4-month post-treatment follow-up) in patients with episodic or chronic migraine. Patients aged 18-65 years with diagnosis of migraine (≥ 4 migraine headache days per month) as defined by International Classification of Headache Disorders (ICHD)-3 beta guidelines were included in the study. Patients were randomized 1:1 with subcutaneous GMB 120 mg (with a loading dose of 240 mg) or GMB 240 mg given once monthly for 12 months. Changes from baseline in PRO measures such as Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ) and Migraine Disability Assessment (MIDAS) were assessed.

Results: A total of 135 patients were randomized to each galcanezumab dose group. Mean (SD) baseline MSQ total scores were 53.85 (20.34) [GMB 120 mg] and 53.69 (18.79) [GMB 240 mg]. For MIDAS, mean (SD) total scores were 45.77 (42.06) [GMB 120 mg] and 53.96 (61.24) [GMB 240 mg]. Within-group mean improvement from baseline on MSQ and MIDAS total scores and all individual item/domain scores were statistically significant for both GMB dose groups, at all-time points during the treatment phase (p < 0.001). For MSQ domain scores, greatest improvement was observed in the Role function-restrictive (RF-R) domain (overall least squares (LS) mean change ± SE: 31.55 ± 1.20 [GMB 120 mg] and 33.40 ± 1.16 [GMB 240 mg]). For MIDAS, the overall LS mean change ± SE from baseline across the entire 12-month treatment phase in total scores were: -33.58 ± 2.11 (GMB 120 mg) and -32.67 ± 2.04 (GMB 240 mg).

Conclusion: Galcanezumab was associated with statistically significant changes from baseline in the PRO measures across the entire 12-month treatment period. These results indicate improved health-related quality of life and decreased disability among patients treated with galcanezumab.
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http://dx.doi.org/10.1007/s11136-020-02632-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886775PMC
February 2021

The Headache Pipeline: Excitement and Uncertainty.

Headache 2020 01 30;60(1):190-199. Epub 2019 Dec 30.

Neurology, New England Institute for Neurology and Headache, Stamford, CT, USA.

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.
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http://dx.doi.org/10.1111/head.13728DOI Listing
January 2020

The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving ≥50%, ≥75%, and 100% response.

Cephalalgia 2020 01 9;40(1):28-38. Epub 2019 Dec 9.

Amgen Inc., Thousand Oaks, CA, USA.

Objective: To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415).

Methods: Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability.

Results: The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population.

Conclusion: For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment.
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http://dx.doi.org/10.1177/0333102419894559DOI Listing
January 2020

Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial.

Lancet Neurol 2019 12;18(12):1081-1090

Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.

Background: Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache.

Methods: We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764.

Findings: Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events.

Interpretation: Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice.

Funding: Autonomic Technologies.
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http://dx.doi.org/10.1016/S1474-4422(19)30322-9DOI Listing
December 2019

Effects on walking of simultaneous upper/lower limb abobotulinumtoxina injections in patients with stroke or brain injury with spastic hemiparesis.

J Rehabil Med 2019 Oct;51(10):813-816

New England Institute for Neurology and Headach, , 06905 Stamford, USA.

Objective: To compare walking speed in patients with spastic hemiparesis who received abobotulinumtoxinA either in the lower limb or simultaneously in both the lower and upper limbs.

Design: Post hoc analysis from a phase 3 study of abobotulinumtoxinA (Dysport®, NCT01251367).

Patients: Adult patients with spastic hemiparesis causing gait dysfunction.

Methods: Comfortable barefoot walking speed over 10 m was evaluated in patients receiving lower limb vs lower and upper limb injections over ≤4 treatment cycles; 1,000 U or 1,500 U in lower limb for cycle 1/2; optional upper limb injections from cycle 3 (500 U: upper limb, 1,000 U: lower limb).

Results: Mean (standard deviation; SD) lower limb cycle 3/4 doses were lower in the lower plus upper limb group vs lower limb only (1,000 U (SD 50), 1,000 U (SD 50) vs 1,380 U (SD 210), 1,360 U (SD 220). Baseline comfortable barefoot walking speed was similar between groups. Changes at cycle 3 week 4, in m/s, were: lower and upper limb: +0.063 (SD 0.131); lower limb only: +0.078 (SD 0.114), and cycle 4 week 4: lower and upper limb: +0.086 (SD 0.166); lower limb only: +0.086 (SD 0.123).

Conclusion: Simultaneous lower and upper limb abobotulinumtoxinA treatment does not hamper improvement in walking speed compared with lower limb treatment alone. Thus, physicians may split the 1,500 U abobotulinumtoxinA dose as needed to best treat patients with spastic paresis.
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http://dx.doi.org/10.2340/16501977-2604DOI Listing
October 2019

Safety and Tolerability of Fremanezumab for the Prevention of Migraine: A Pooled Analysis of Phases 2b and 3 Clinical Trials.

Headache 2019 06 12;59(6):880-890. Epub 2019 Apr 12.

Teva Pharmaceuticals, Frazer, PA, USA.

Objective: Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo-controlled phase 2b and phase 3 studies.

Background: There is a need for an effective, safe, and well-tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the frequency and severity of migraine attacks in patients with CM or EM who experience 4 or more migraine days per month. Fremanezumab is a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine.

Design/methods: The 4 placebo-controlled phases 2b and 3 studies included in this analysis were 16-week, multicenter, randomized, double-blind, placebo-controlled, and parallel-group studies consisting of a screening visit, a 28-day pretreatment baseline period, and a 12-week treatment period with a final evaluation 4 weeks after the final dose of the study drug. Safety endpoints included adverse events (AEs) and immunogenicity.

Results: A total of 2566 patients were randomized across all studies (fremanezumab, n = 1704; placebo, n = 862), and 2563 patients were treated. Common reasons for study discontinuation were withdrawal by patient (n = 78), patient lost to follow-up (n = 60), and AE (n = 50). The mean (standard deviation) duration of exposure was 83.8 (13.6) days for the patients who received fremanezumab, with a total exposure of 390.4 patient years and maximum exposure of 181 days. AEs were mostly mild to moderate in severity and were reported among 48-69% of patients in all treatment groups, and most were injection site reactions (pain, induration, and erythema). Two deaths occurred (chronic obstructive pulmonary disease and intentional overdose of diphenhydramine), both of which were deemed unrelated to study drug by the investigators and sponsor. Cardiovascular adverse events, abnormal liver function tests, and hypersensitivity were uncommon and occurred at similar rates between the placebo and fremanezumab groups.

Conclusions: Fremanezumab is a generally safe and well-tolerated preventive therapy for migraine in adults.
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http://dx.doi.org/10.1111/head.13534DOI Listing
June 2019

Ancient nuclear genomes enable repatriation of Indigenous human remains.

Sci Adv 2018 12 19;4(12):eaau5064. Epub 2018 Dec 19.

Australian Research Centre for Human Evolution, Environmental Futures Research Institute, Griffith University, Nathan, QLD, Australia.

After European colonization, the ancestral remains of Indigenous people were often collected for scientific research or display in museum collections. For many decades, Indigenous people, including Native Americans and Aboriginal Australians, have fought for their return. However, many of these remains have no recorded provenance, making their repatriation very difficult or impossible. To determine whether DNA-based methods could resolve this important problem, we sequenced 10 nuclear genomes and 27 mitogenomes from ancient pre-European Aboriginal Australians (up to 1540 years before the present) of known provenance and compared them to 100 high-coverage contemporary Aboriginal Australian genomes, also of known provenance. We report substantial ancient population structure showing strong genetic affinities between ancient and contemporary Aboriginal Australian individuals from the same geographic location. Our findings demonstrate the feasibility of successfully identifying the origins of unprovenanced ancestral remains using genomic methods.
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http://dx.doi.org/10.1126/sciadv.aau5064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300400PMC
December 2018

Early onset of efficacy with erenumab in patients with episodic and chronic migraine.

J Headache Pain 2018 Oct 1;19(1):92. Epub 2018 Oct 1.

Amgen Inc., Thousand Oaks, CA, USA.

Background: Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a ≥ 50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo.

Methods: There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥ 50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data.

Results: In both studies (EM: N = 955; CM: N = 667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean [LSM] [95% CI]): placebo, - 0.1 (- 0.3, 0.0); erenumab 70 mg, - 0.3 (- 0.5, - 0.2) p = 0.130; erenumab 140 mg, - 0.6 (- 0.7, - 0.4) p < 0.001. For CM the changes were: placebo, - 0.5 (- 0.8, - 0.3); erenumab 70 mg, - 0.9 (- 1.2, - 0.7) p = 0.047; erenumab 140 mg, - 0.8 (- 1.1, - 0.5) p = 0.18. Achievement of ≥ 50% reduction in WMD was observed as early as Week 1 (adjusted OR [95% CI] erenumab vs placebo) in EM: erenumab 70 mg, 1.3 (1.0, 1.9) p = 0.097; erenumab 140 mg, 2.0 (1.4, 2.7) p < 0.001. A similar outcome was observed for CM: erenumab 70 mg, 1.8 (1.1, 2.8) p = 0.011; erenumab 140 mg, 1.9 (1.2, 2.9) p = 0.009. Seven-day moving averages of observed data showed each treatment arm differed from placebo by Week 1 (OR [95% CI]): in EM Day 3 for erenumab 140 mg, 0.7 (0.5, 1.0) p = 0.031 and at Day 7 for 70 mg, 0.6 (0.4, 0.8) p = 0.002; in CM: Day 6 for erenumab 70 mg, 0.6 (0.4, 0.9) p = 0.022 and at Day 7 for 140 mg, 0.7 (0.4, 1.0); p = 0.038.

Conclusion: Erenumab showed early onset of efficacy with separation from placebo within the first week of treatment in both chronic and episodic migraine patients.
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http://dx.doi.org/10.1186/s10194-018-0923-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755616PMC
October 2018

Periorbital necrotising soft tissue infection in a 12-year-old patient.

Scott Med J 2018 Aug 27;63(3):87-90. Epub 2018 May 27.

4 Consultant, Oral and Maxillofacial Surgery, Queen Elizabeth University Hospital, UK.

Head and neck necrotising soft-tissue infection is exceptionally uncommon in the paediatric population. necrotising soft-tissue infection is severe and often life-threatening. Rapid spread of infection and systemic illness make necrotising soft-tissue infection a challenge for the medical and surgical teams. Early identification and surgical intervention are essential for a favourable patient outcome. This report details the case of periorbital necrotising soft-tissue infection in a 12-year-old male patient following an uncomplicated facial laceration. Prompt surgical debridement with planned return visits to theatre and guided empirical antibiotic therapy ensured that a satisfactory patient outcome was achieved. The failure of current necrotising soft-tissue infection diagnostic scoring tools to be positive in this case may suggest that these tools require refinement and validation.
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http://dx.doi.org/10.1177/0036933018776830DOI Listing
August 2018

Metastasising Pleomorphic Salivary Adenoma: A Rare Case Report of a Massive Untreated Minor Salivary Gland Pleomorphic Adenoma with Concurrent Ipsilateral Cervical Node Metastases.

Head Neck Pathol 2019 Sep 3;13(3):500-506. Epub 2018 May 3.

OMFS Consultant, St John's Hospital, Livingston, Scotland, UK.

Salivary gland tumours constitute approximately 1-5% of all human neoplasms. Pleomorphic adenoma (PA) is the commonest benign neoplasm affecting the parotid gland most often (> 75%), followed by the submandibular gland (13%), then the palate (9%). Metastasising pleomorphic adenoma (MPA) is extremely rare. The effects can be severe and a reported 40% of MPA patients die with disease. This case represents the first known case in English literature of an untreated minor salivary gland PSA of the palate metastasising to an ipsilateral cervical node. We report a 61 year old female who presented with a large tumour occupying the palatal vault, and cervical neck mass. The oral tumour was believed to have been growing over four decades. The patient died eight months following surgical resection. Of known cases, male: female ratio is 35:51 and the mean age at diagnosis is 49.2. Most commonly, MPA is detected in bone 33.3% (n = 29), lung 31% (n = 27) and cervical lymph nodes 20.7% (n = 18). Thorough reporting is deemed essential to further understand the biological differences of non metastasising and metastasising PAs, treatment outcomes, prognosis and survival rates.
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http://dx.doi.org/10.1007/s12105-018-0920-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684680PMC
September 2019

A Cost-Effective, In-House, Positioning and Cutting Guide System for Orthognathic Surgery.

J Maxillofac Oral Surg 2018 Mar 12;17(1):112-114. Epub 2017 Dec 12.

Department of Oral and Maxillofacial Surgery, St John's Hospital, Howden Road West, Livingston, EH54 6PP UK.

Introduction: Technological advances in 3D printing can dramatically improve orthognathic surgical planning workflow. Custom positioning and cutting guides enable intraoperative reproduction of pre-planned osteotomy cuts and can result in greater surgical accuracy and patient safety.

Objectives: This short paper describes the use of freeware (some with open-source) combined with in-house 3D printing facilities to produce reliable, affordable osteotomy cutting guides.

Methods: Open-source software (3D Slicer) is used to visualise and segment three-dimensional planning models from imported conventional computed tomography (CT) scans. Freeware (Autodesk Meshmixer ©) allows digital manipulation of maxillary and mandibular components to plan precise osteotomy cuts. Bespoke cutting guides allow exact intraoperative positioning. These are printed in polylactic acid (PLA) using a fused-filament fabrication 3D printer. Fixation of the osteotomised segments is achieved using plating templates and four pre-adapted plates with planned screw holes over the thickest bone. We print maxilla/ mandible models with desired movements incorporated to use as a plating template.

Results: A 3D printer capable of reproducing a complete skull can be procured for £1000, with material costs in the region of £10 per case. Our production of models and guides typically takes less than 24 hours of total print time. The entire production process is frequently less than three days. Externally sourced models and guides cost significantly more, frequently encountering costs totalling £1500-£2000 for models and guides for a bimaxillary osteotomy.

Conclusion: Three-dimensional guided surgical planning utilising custom cutting guides enables the surgeon to determine optimal orientation of osteotomy cuts and better predict the skeletal maxilla/mandible relationship following surgery. The learning curve to develop proficiency using planning software and printer settings is offset by increased surgical predictability and reduced theatre time, making this form of planning a worthy investment.
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http://dx.doi.org/10.1007/s12663-017-1067-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772032PMC
March 2018

Efficacy and safety of abobotulinumtoxinA in spastic lower limb: Randomized trial and extension.

Neurology 2017 Nov 1;89(22):2245-2253. Epub 2017 Nov 1.

Author affiliations are provided at the end of the article.

Objective: To demonstrate single abobotulinumtoxinA injection efficacy in lower limb vs placebo for adults with chronic hemiparesis and assess long-term safety and efficacy of repeated injections.

Methods: In a multicenter, double-blind, randomized, placebo-controlled, single-cycle study followed by a 1-year open-label, multiple-cycle extension, adults ≥6 months after stroke/brain injury received one lower limb injection (abobotulinumtoxinA 1,000 U, abobotulinumtoxinA 1,500 U, placebo) followed by ≤4 open-label cycles (1,000, 1,500 U) at ≥12-week intervals. Efficacy measures included Modified Ashworth Scale (MAS) in gastrocnemius-soleus complex (GSC; double-blind primary endpoint), physician global assessment (PGA), and comfortable barefoot walking speed. Safety was the open-label primary endpoint.

Results: After a single injection, mean (95% confidence interval) MAS GSC changes from baseline at week 4 (double-blind, n = 381) were as follows: -0.5 (-0.7 to -0.4) (placebo, n = 128), -0.6 (-0.8 to -0.5) (abobotulinumtoxinA 1,000 U, n = 125; = 0.28 vs placebo), and -0.8 (-0.9 to -0.7) (abobotulinumtoxinA 1,500 U, n = 128; = 0.009 vs placebo). Mean week 4 PGA scores were as follows: 0.7 (0.5, 0.9) (placebo), 0.9 (0.7, 1.1) (1,000 U; = 0.067 vs placebo), and 0.9 (0.7, 1.1) (1,500 U; = 0.067); walking speed was not significantly improved vs placebo. At cycle 4, week 4 (open-label), mean MAS GSC change reached -1.0. Incremental improvements in PGA and walking speed occurred across open-label cycles; by cycle 4, week 4, mean PGA was 1.9, and walking speed increased +25.3% (17.5, 33.2), with 16% of participants walking >0.8 m/s (associated with community mobility; 0% at baseline). Tolerability was good and consistent with the known abobotulinumtoxinA safety profile.

Conclusions: In chronic hemiparesis, single abobotulinumtoxinA (Dysport Ipsen) administration reduced muscle tone. Repeated administration over a year was well-tolerated and improved walking speed and likelihood of achieving community ambulation.

Clinicaltrialgov Identifiers: NCT01249404, NCT01251367.

Classification Of Evidence: The double-blind phase of this study provides Class I evidence that for adults with chronic spastic hemiparesis, a single abobotulinumtoxinA injection reduces lower extremity muscle tone.
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http://dx.doi.org/10.1212/WNL.0000000000004687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705248PMC
November 2017

Efficacy and Safety of AbobotulinumtoxinA (Dysport) for the Treatment of Hemiparesis in Adults With Upper Limb Spasticity Previously Treated With Botulinum Toxin: Subanalysis From a Phase 3 Randomized Controlled Trial.

PM R 2017 12 16;9(12):1181-1190. Epub 2017 Jun 16.

EA 7377 BIOTN, Université Paris-Est Créteil, Service de Rééducation Neurolocomotrice, Hôpitaux Universitaires Henri Mondor, Créteil, France(¶¶).

Objective: To assess the efficacy and safety of abobotulinumtoxinA in adults with upper limb spasticity previously treated with botulinum toxin A (BoNT-A).

Design: A post hoc analysis from a Phase 3, prospective, double-blind, randomized, placebo-controlled study (NCT01313299).

Setting: A total of 34 neurology or rehabilitation clinics in 9 countries.

Participants: Adults aged 18-80 years with hemiparesis, ≥6 months after stroke or traumatic brain injury. This analysis focused on a subgroup of subjects with previous onabotulinumtoxinA or incobotulinumtoxinA treatment (n = 105 of 243 in the total trial population) in the affected limb. The mean age was 52 years, and 62% were male.

Intervention: Study subjects were randomized 1:1:1 to receive a single injection session with abobotulinumtoxinA 500 or 1000 U or with placebo in the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and ≥2 additional muscle groups from the upper limb.

Main Outcome Measurements: Efficacy and safety measures were assessed, including muscle tone (Modified Ashworth Scale [MAS] in the PTMG), Physician Global Assessment (PGA), perceived function, spasticity, active movement, and treatment-emergent adverse events.

Results: At week 4, more subjects had ≥1 grade improvement in MAS for the PTMG with abobotulinumtoxinA versus placebo (abobotulinumtoxinA 500 U, 81.1%; abobotulinumtoxinA 1000 U, 75.0%; placebo, 25.0%). PGA scores ≥1 were achieved by 75.7% and 87.5% of abobotulinumtoxinA 500 and 1000 U subjects versus 41.7% with placebo. Perceived function (Disability Assessment Scale), spasticity angle (Tardieu Scale), and active movement were also improved with abobotulinumtoxinA. There were no treatment-related deaths or serious adverse events.

Conclusions: The efficacy and safety of abobotulinumtoxinA in subjects previously treated with BoNT-A were consistent with those in the total trial population. Hence, abobotulinumtoxinA is a treatment option in these patients, and no difference in initial dosing appears to be required compared to that in individuals not treated previously.

Level Of Evidence: III.
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http://dx.doi.org/10.1016/j.pmrj.2017.06.007DOI Listing
December 2017

Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan.

Headache 2017 Jun 11;57(6):862-876. Epub 2017 May 11.

Avanir Pharmaceuticals, Inc, Aliso Viejo, CA, USA.

Objective: To further characterize the clinical utility of AVP-825 based on additional prespecified outcomes and post hoc analyses of COMPASS, a Phase 3 comparative efficacy trial of AVP-825 vs 100 mg oral sumatriptan (NCT01667679). AVP-825 was approved in January 2016 by the US Food and Drug Administration under the name ONZETRA Xsail (sumatriptan nasal powder) for the acute treatment of migraine with or without aura in adults.

Background: AVP-825 is a delivery system that uses a patient's own breath to deliver low-dose sumatriptan powder to the upper posterior regions of the nasal cavity beyond the narrow nasal valve, areas lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. The recommended dose of AVP-825 is 22 mg sumatriptan powder administered as one 11 mg nosepiece in each nostril, which delivers approximately 15-16 mg of sumatriptan intranasally. The COMPASS trial compared AVP-825 22-100 mg oral sumatriptan across multiple migraine attacks for efficacy, safety, and tolerability endpoints.

Design/methods: COMPASS was a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study with two 12-week double-blind periods. Patients with 2-8 migraine attacks/month were randomized 1:1 to AVP-825 (22 mg) plus oral placebo or an identical placebo delivery system plus 100 mg oral sumatriptan for the first period, and then patients switched treatments for the second period. Patients treated up to 5 qualifying migraines per period within 1 h of onset, even if the intensity of the attack was mild. Results from the primary endpoint (SPID-30, defined as the sum of pain intensity differences from dosing to 30 minutes), key secondary efficacy endpoints and safety assessments have been reported in the primary publication (Tepper et al., 2015). This article reports additional prespecified outcomes, including the SPID-30 for attacks treated when baseline severity was mild vs moderate/severe, measures of sustained response and consistency of effect in patients who experienced multiple migraine attacks, and the results of post hoc analyses performed to assess total migraine freedom (defined as no pain and no migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia), time to pain freedom, time to meaningful pain relief, and local (occurring at the site of administration in the nose) vs systemic treatment-emergent adverse events (TEAEs).

Results: A total of 185 patients completed both treatment periods, yielding 1,531 migraine attacks which were treated and assessed (765 AVP-825, 766 oral sumatriptan). Treatment with AVP-825 provided greater reduction in migraine pain intensity which was statistically significant vs oral sumatriptan in the first 30 minutes postdose regardless of whether attacks were treated when pain was mild (least squares mean SPID-30 = 3.90 vs 0.24, P = .0013) or moderate/severe (least squares mean SPID-30 = 13.83 vs 10.07, P = .0002). At every time point from 15 to 90 minutes postdose, the proportion of attacks achieving total migraine freedom was greater and statistically significant after treatment with AVP-825 vs 100 mg oral sumatriptan. AVP-825 treatment resulted in greater odds of achieving pain freedom (odds ratio, OR = 1.29, P < .01) and meaningful pain relief (OR = 1.32, P < .0001), which were also statistically significant compared with oral sumatriptan. In addition, a greater proportion of attacks treated with AVP-825 vs oral sumatriptan was associated with sustained pain freedom, achieving statistical significance when assessed from 1 h postdose through 24 hours postdose (33.3% vs 27.9%; P < .05) and through 48 hours postdose (32.7% vs 27.4%; P < .05). For patients who treated multiple migraine attacks in both treatment periods, a greater proportion had consistent pain relief and pain freedom following treatment with AVP-825 compared to oral sumatriptan across multiple attacks, a difference that achieved statistical significance at 30 minutes postdose. Local TEAEs of abnormal taste and nasal discomfort were more common following AVP-825 treatment. Of the patients experiencing either of these TEAEs, about 90% described the intensity as mild, and only one discontinued treatment because of either of these two TEAEs.

Conclusions: These results from the COMPASS study further demonstrate that treatment with AVP-825 provides earlier onset and more consistent across-episode improvement of pain and migraine-associated symptoms compared with oral sumatriptan, highlighting the clinical advantages of this newly approved intranasal delivery system for low-dose sumatriptan powder.
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http://dx.doi.org/10.1111/head.13105DOI Listing
June 2017

Aboriginal Australian mitochondrial genome variation - an increased understanding of population antiquity and diversity.

Sci Rep 2017 03 13;7:43041. Epub 2017 Mar 13.

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Victoria, Australia.

Aboriginal Australians represent one of the oldest continuous cultures outside Africa, with evidence indicating that their ancestors arrived in the ancient landmass of Sahul (present-day New Guinea and Australia) ~55 thousand years ago. Genetic studies, though limited, have demonstrated both the uniqueness and antiquity of Aboriginal Australian genomes. We have further resolved known Aboriginal Australian mitochondrial haplogroups and discovered novel indigenous lineages by sequencing the mitogenomes of 127 contemporary Aboriginal Australians. In particular, the more common haplogroups observed in our dataset included M42a, M42c, S, P5 and P12, followed by rarer haplogroups M15, M16, N13, O, P3, P6 and P8. We propose some major phylogenetic rearrangements, such as in haplogroup P where we delinked P4a and P4b and redefined them as P4 (New Guinean) and P11 (Australian), respectively. Haplogroup P2b was identified as a novel clade potentially restricted to Torres Strait Islanders. Nearly all Aboriginal Australian mitochondrial haplogroups detected appear to be ancient, with no evidence of later introgression during the Holocene. Our findings greatly increase knowledge about the geographic distribution and phylogenetic structure of mitochondrial lineages that have survived in contemporary descendants of Australia's first settlers.
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http://dx.doi.org/10.1038/srep43041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347126PMC
March 2017

Mitochondrial DNA diversity of present-day Aboriginal Australians and implications for human evolution in Oceania.

J Hum Genet 2017 Mar 1;62(3):343-353. Epub 2016 Dec 1.

Department of Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia.

Aboriginal Australians are one of the more poorly studied populations from the standpoint of human evolution and genetic diversity. Thus, to investigate their genetic diversity, the possible date of their ancestors' arrival and their relationships with neighboring populations, we analyzed mitochondrial DNA (mtDNA) diversity in a large sample of Aboriginal Australians. Selected mtDNA single-nucleotide polymorphisms and the hypervariable segment haplotypes were analyzed in 594 Aboriginal Australians drawn from locations across the continent, chiefly from regions not previously sampled. Most (~78%) samples could be assigned to mtDNA haplogroups indigenous to Australia. The indigenous haplogroups were all ancient (with estimated ages >40 000 years) and geographically widespread across the continent. The most common haplogroup was P (44%) followed by S (23%) and M42a (9%). There was some geographic structure at the haplotype level. The estimated ages of the indigenous haplogroups range from 39 000 to 55 000 years, dates that fit well with the estimated date of colonization of Australia based on archeological evidence (~47 000 years ago). The distribution of mtDNA haplogroups in Australia and New Guinea supports the hypothesis that the ancestors of Aboriginal Australians entered Sahul through at least two entry points. The mtDNA data give no support to the hypothesis of secondary gene flow into Australia during the Holocene, but instead suggest long-term isolation of the continent.
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http://dx.doi.org/10.1038/jhg.2016.147DOI Listing
March 2017

A genomic history of Aboriginal Australia.

Nature 2016 Oct 21;538(7624):207-214. Epub 2016 Sep 21.

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.
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http://dx.doi.org/10.1038/nature18299DOI Listing
October 2016

Bilateral Breast Reconstruction with Abdominal Free Flaps: A Single Centre, Single Surgeon Retrospective Review of 55 Consecutive Patients.

Plast Surg Int 2016 18;2016:6085624. Epub 2016 Jul 18.

Department of Plastic and Reconstructive Surgery, Ninewells Hospital and Medical School, Dundee DD1 9SE, UK.

Breast reconstruction using free tissue transfer is an increasingly utilised oncoplastic procedure. The aim was to review all bilateral breast reconstructions using abdominal free flaps by a single surgeon over an 11-year period (2003-2014). A retrospective review was performed on all patients who underwent bilateral breast reconstruction using abdominal free flaps between 2003 and 2014 by the senior author (DAM). Data analysed included patient demographics, indication for reconstruction, surgical details, and complications. Fifty-five female patients (mean 48.6 years [24-71 years]) had bilateral breast reconstruction. The majority (41, 74.5%) underwent immediate reconstruction and DIEP flaps were utilised on 41 (74.5%) occasions. Major surgical complications occurred in 6 (10.9%) patients, all of which were postoperative vascular compromise of the flap. Failure to salvage the reconstruction occurred on 3 (5.5%) occasions resulting in a total flap failure rate of 2.7%. Obesity (>30 kg/m(2)) and age > 60 years were shown to have a statistically increased risk of developing postoperative complications (P < 0.05). Our experience demonstrates that abdominal free flaps for bilateral breast reconstruction fares well, with a flap failure rate of 2.7%. Increased body mass index and patient age (>60 years) were associated with higher complication rates.
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http://dx.doi.org/10.1155/2016/6085624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967676PMC
August 2016

Deep Roots for Aboriginal Australian Y Chromosomes.

Curr Biol 2016 Mar 25;26(6):809-13. Epub 2016 Feb 25.

The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. Electronic address:

Australia was one of the earliest regions outside Africa to be colonized by fully modern humans, with archaeological evidence for human presence by 47,000 years ago (47 kya) widely accepted [1, 2]. However, the extent of subsequent human entry before the European colonial age is less clear. The dingo reached Australia about 4 kya, indirectly implying human contact, which some have linked to changes in language and stone tool technology to suggest substantial cultural changes at the same time [3]. Genetic data of two kinds have been proposed to support gene flow from the Indian subcontinent to Australia at this time, as well: first, signs of South Asian admixture in Aboriginal Australian genomes have been reported on the basis of genome-wide SNP data [4]; and second, a Y chromosome lineage designated haplogroup C(∗), present in both India and Australia, was estimated to have a most recent common ancestor around 5 kya and to have entered Australia from India [5]. Here, we sequence 13 Aboriginal Australian Y chromosomes to re-investigate their divergence times from Y chromosomes in other continents, including a comparison of Aboriginal Australian and South Asian haplogroup C chromosomes. We find divergence times dating back to ∼50 kya, thus excluding the Y chromosome as providing evidence for recent gene flow from India into Australia.
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http://dx.doi.org/10.1016/j.cub.2016.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819516PMC
March 2016

Antiquity and diversity of aboriginal Australian Y-chromosomes.

Am J Phys Anthropol 2016 Mar 30;159(3):367-81. Epub 2015 Oct 30.

Department of Biochemistry and Genetics, La Trobe Institute of Molecular Sciences, La Trobe University, Melbourne, VIC, Australia.

Objective: Understanding the origins of Aboriginal Australians is crucial in reconstructing the evolution and spread of Homo sapiens as evidence suggests they represent the descendants of the earliest group to leave Africa. This study analyzed a large sample of Y-chromosomes to answer questions relating to the migration routes of their ancestors, the age of Y-haplogroups, date of colonization, as well as the extent of male-specific variation.

Methods: Knowledge of Y-chromosome variation among Aboriginal Australians is extremely limited. This study examined Y-SNP and Y-STR variation among 657 self-declared Aboriginal males from locations across the continent. 17 Y-STR loci and 47 Y-SNPs spanning the Y-chromosome phylogeny were typed in total.

Results: The proportion of non-indigenous Y-chromosomes of assumed Eurasian origin was high, at 56%. Y lineages of indigenous Sahul origin belonged to haplogroups C-M130*(xM8,M38,M217,M347) (1%), C-M347 (19%), K-M526*(xM147,P308,P79,P261,P256,M231,M175,M45,P202) (12%), S-P308 (12%), and M-M186 (0.9%). Haplogroups C-M347, K-M526*, and S-P308 are Aboriginal Australian-specific. Dating of C-M347, K-M526*, and S-P308 indicates that all are at least 40,000 years old, confirming their long-term presence in Australia. Haplogroup C-M347 comprised at least three sub-haplogroups: C-DYS390.1del, C-M210, and the unresolved paragroup C-M347*(xDYS390.1del,M210).

Conclusions: There was some geographic structure to the Y-haplogroup variation, but most haplogroups were present throughout Australia. The age of the Australian-specific Y-haplogroups suggests New Guineans and Aboriginal Australians have been isolated for over 30,000 years, supporting findings based on mitochondrial DNA data. Our data support the hypothesis of more than one route (via New Guinea) for males entering Sahul some 50,000 years ago and give no support for colonization events during the Holocene, from either India or elsewhere.
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http://dx.doi.org/10.1002/ajpa.22886DOI Listing
March 2016

Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial.

Lancet Neurol 2015 Oct 26;14(10):992-1001. Epub 2015 Aug 26.

Ipsen Innovation, Les Ulis, France.

Background: Resistance from antagonistic muscle groups might be a crucial factor reducing function in chronic hemiparesis. The resistance due to spastic co-contraction might be reduced by botulinum toxin injections. We assessed the effects of abobotulinumtoxinA injection in the upper limb muscles on muscle tone, spasticity, active movement, and function.

Methods: In this randomised, placebo-controlled, double-blind study, we enrolled adults (aged 18-80 years) at least 6 months after stroke or brain trauma from 34 neurology or rehabilitation clinics in Europe and the USA. Eligible participants were randomly allocated in a 1:1:1 ratio with a computer-generated list to receive a single injection session of abobotulinumtoxinA 500 U or 1000 U or placebo into the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and into at least two additional muscle groups from the elbow, wrist, or finger flexors or shoulder extensors. Patients and investigators were masked to treatment allocation. The primary endpoint was the change in muscle tone (Modified Ashworth Scale [MAS]) in the PTMG from baseline to 4 weeks. Secondary endpoints were Physician Global Assessment (PGA) at week 4 and change from baseline to 4 weeks in the perceived function (Disability Assessment Scale [DAS]) in the principal target of treatment, selected by the patient together with physician from four functional domains (dressing, hygiene, limb position, and pain). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01313299.

Findings: 243 patients were randomly allocated to placebo (n=81), abobotulinumtoxinA 500 U (n=81), or abobotulinumtoxinA 1000 U (n=81). Mean change in MAS score from baseline at week 4 in the PTMG was -0·3 (SD 0·6) in the placebo group (n=79), -1·2 (1·0) in the abobotulinumtoxinA 500 U group (n=80; difference -0·9, 95% CI -1·2 to -0·6; p<0·0001 vs placebo), and -1·4 (1·1) in the abobotulinumtoxinA 1000 U group (n=79; -1·1, -1·4 to -0·8; p<0·0001 vs placebo). Mean PGA score at week 4 was 0·6 (SD 1·0) in the placebo group (n=78), 1·4 (1·1) in the abobotulinumtoxinA 500 U group (n=80; p=0·0003 vs placebo), and 1·8 (1·1) in the abobotulinumtoxinA 1000 U group (n=78; p<0·0001 vs placebo). Mean change from baseline at week 4 in DAS score for the principal target of treatment was -0·5 (0·7) in the placebo group (n=79), -0·7 (0·8) in the abobotulinumtoxinA 500 U group (n=80; p=0·2560 vs placebo), and -0·7 (0·7) in the abobotulinumtoxinA 1000 U group (n=78; p=0·0772 vs placebo). Three serious adverse events occurred in each group and none were treatment related; two resulted in death (from pulmonary oedema in the placebo group and a pre-existing unspecified cardiovascular disorder in the abobotulinumtoxinA 500 U group). Adverse events that were thought to be treatment related occurred in two (2%), six (7%), and seven (9%) patients in the placebo, abobotulinumtoxinA 500 U, and abobotulinumtoxinA 1000 U groups, respectively. The most common treatment-related adverse event was mild muscle weakness. All adverse events were mild or moderate.

Interpretation: AbobotulinumtoxinA at doses of 500 U or 1000 U injected into upper limb muscles provided tone reduction and clinical benefit in hemiparesis. Future research into the treatment of spastic paresis with botulinum toxin should use active movement and function as primary outcome measures.

Funding: Ipsen.
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http://dx.doi.org/10.1016/S1474-4422(15)00216-1DOI Listing
October 2015

Alcohol consumption and interpersonal injury in a pediatric oral and maxillofacial trauma population: a retrospective review of 1,192 trauma patients.

Craniomaxillofac Trauma Reconstr 2015 Jun 27;8(2):83-7. Epub 2014 Oct 27.

Department of Oral and Maxillofacial Surgery, University Hospital, Liverpool, United Kingdom.

The social, financial, and health implications of adult alcohol-related oral and maxillofacial trauma have been recognized for several years. Affordability and widespread accessibility of alcohol and issues of misuse in the pediatric trauma population have fostered concerns alcohol may be similarly implicated in young patients with orofacial trauma. The aim of this study was to review data of pediatric facial injuries at a regional maxillofacial unit, assess the prevalence of alcohol use, and review data of patients sustaining injury secondary to interpersonal violence. This study is a retrospective, 3-year review of a Regional Maxillofacial Unit (RMU) trauma database. Inclusion criterion was consecutive facial trauma patients under 16 years of age, referred to RMU for further assessment and/or management. Alcohol use and injuries sustained were reviewed. Of 1,192 pediatric facial trauma patients, 35 (2.9%) were associated with alcohol intake. A total of 145 (12.2%) alleged assault as the mechanism of injury, with older (12-15 years) (n = 129; 88.9%), male (n = 124; 85.5%) (p < 0.001) patients commonly involved and alcohol use implicated in 26 (17.9%) presentations. A proportion of vulnerable adolescents misuse alcohol to the risk of traumatic facial injury, and prospective research to accurately determine any role of alcohol in the pediatric trauma population is essential.
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http://dx.doi.org/10.1055/s-0034-1393730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428731PMC
June 2015

Prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depression: An open-label, multicenter, pilot study of efficacy, safety and effect on headache-related disability, depression, and anxiety.

Int J Gen Med 2015 18;8:79-86. Epub 2015 Feb 18.

Montefiore Headache Center and the Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Chronic migraine is associated with significant headache-related disability and psychiatric comorbidity. OnabotulinumtoxinA (BOTOX(®)) is effective and well tolerated in the prophylactic treatment of chronic migraine. This study aimed to provide preliminary data on the efficacy and safety of prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depressive symptoms.

Methods: This was a prospective, open-label, multicenter pilot study. Eligible patients met International Classification of Headache Disorders 2nd edition Revision criteria for chronic migraine and had associated depressive symptoms, including Patient Health Questionnaire depression module scores of 5-19. Eligible participants received 155 units of onabotulinumtoxinA, according to the PREEMPT protocol, at baseline and week 12. Assessments included headache frequency, the Headache Impact Test™, the Migraine Disability Assessment, the Beck Depression Inventory(®)-II, the nine-item Patient Health Questionnaire depression module, and the seven-item Generalized Anxiety Disorder questionnaire. Adverse events were also monitored.

Results: Overall, 32 participants received treatment. At week 24, there were statistically significant mean (standard deviation [SD]) improvements relative to baseline in the number of headache/migraine-free days (+8.2 [5.8]) (P<0.0001) and in the number of headache/migraine days (-8.2 [5.8]) (P<0.0001) per 30-day period. In addition, there were significant improvements in Headache Impact Test scores (-6.3 [6.9]) (P=0.0001) and Migraine Disability Assessment scores (-44.2 [67.5]) (P=0.0058). From baseline to week 24, statistically significant improvements were also seen in Beck Depression Inventory-II (-7.9 [6.0]) (P<0.0001), Patient Health Questionnaire depression module (-4.3 [4.7]) (P<0.0001), and Generalized Anxiety Disorder questionnaire (-3.5 [5.0]) (P=0.0002) scores. No serious adverse events were reported. Adverse events considered related to treatment occurred in 30% of patients and were mild or moderate.

Conclusion: Prophylactic onabotulinumtoxinA was well tolerated in patients with chronic migraine and comorbid depression, and was effective in reducing headache frequency, impact, and related disability, which led to statistically significant improvements in depression and anxiety symptoms.
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http://dx.doi.org/10.2147/IJGM.S70456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340374PMC
March 2015

A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study).

Headache 2015 Jan 30;55(1):88-100. Epub 2014 Oct 30.

Headache Care Center, Springfield, MO, USA.

Objective: To evaluate the efficacy and safety of AVP-825, a drug-device combination of low-dose sumatriptan powder (22 mg loaded dose) delivered intranasally through a targeted Breath Powered device vs an identical device containing lactose powder (placebo device) in the treatment of migraine headache.

Background: Early treatment of migraine headaches is associated with improved outcome, but medication absorption after oral delivery may be delayed in migraineurs because of reduced gastric motility. Sumatriptan powder administered with an innovative, closed-palate, Bi-Directional, Breath Powered intranasal delivery mechanism is efficiently absorbed across the nasal mucosa and produces fast absorption into the circulation. Results from a previously conducted placebo-controlled study of AVP-825 showed a high degree of headache relief with an early onset of action (eg, 74% AVP-825 vs 38% placebo device at 1 hour, P<.01).

Methods: In this double-blind, placebo-controlled, parallel-group study in adults with a history of migraine with or without aura, participants were randomized via computer-generated lists to AVP-825 or placebo device to treat a single migraine headache of moderate or severe intensity. The primary endpoint was headache relief (defined as reduction of headache pain intensity from severe or moderate migraine headache to mild or none) at 2 hours post-dose.

Results: Two hundred and thirty patients (116 AVP-825 and 114 placebo device) were randomized, of whom 223 (112 and 111, respectively) experienced a qualifying migraine headache (their next migraine headache that reached moderate or severe intensity). A significantly greater proportion of AVP-825 patients reported headache relief at 2 hours post-dose compared with those using the placebo device (68% vs 45%, P=.002, odds ratio 2.53, 95% confidence interval [1.45, 4.42]). Between-group differences in headache relief were evident as early as 15 minutes, reached statistical significance at 30 minutes post-dose (42% vs 27%, P=.03), and were sustained at 24 hours (44% vs 24%, P=.002) and 48 hours (34% vs 20%, P=.01). Thirty-four percent of patients treated with AVP-825 were pain-free at 2 hours compared with 17% using the placebo device (P=.008). More AVP-825 patients reported meaningful pain relief (patient interpretation) of migraine within 2 hours of treatment vs placebo device (70% vs 45%, P<.001), and fewer required rescue medication (37% vs 52%, P=.02). Total migraine freedom (patients with no headache, nausea, phonophobia, photophobia, or vomiting) reached significance following treatment with AVP-825 at 1 hour (19% vs 9%; P=.04). There were no serious adverse events (AEs), and no systemic AEs occurred in more than one patient. Chest pain or pressure was not reported, and only one patient taking AVP-825 reported mild paresthesia. No other triptan sensations were reported.

Conclusions: Targeted delivery of a low-dose of sumatriptan powder via a novel, closed-palate, Breath Powered, intranasal device (AVP-825) provided fast relief of moderate or severe migraine headache in adults that reached statistical significance over placebo by 30 minutes. The treatment was well tolerated with a low incidence of systemic AEs.
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http://dx.doi.org/10.1111/head.12472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320758PMC
January 2015

Efficacy of treatment of insomnia in migraineurs with eszopiclone (Lunesta®) and its effect on total sleep time, headache frequency, and daytime functioning: A randomized, double-blind, placebo-controlled, parallel-group, pilot study.

Cranio 2015 Apr 16;33(2):115-21. Epub 2014 Oct 16.

Aims: A review on headache and insomnia revealed that insomnia is a risk factor for increased headache frequency and headache intensity in migraineurs. The authors designed a randomized, double blind, placebo-controlled, parallel-group, pilot study in which migraineurs who also had insomnia were enrolled, to test this observation.

Methodology: In the study, the authors treated 79 subjects with IHS-II migraine with and/or without aura and with DSM-IV primary insomnia for 6 weeks with 3 mg eszopiclone (Lunesta(®)) or placebo at bedtime. The treatment was preceded by a 2-week baseline period and followed by a 2-week run-out period.

Results: Of the 79 subjects treated, 75 were evaluable, 35 in the eszopiclone group, and 40 in the placebo group. At baseline, the groups were comparable except for sleep latency. Of the three remaining sleep variables, total sleep time, nighttime awakenings, and sleep quality, the number of nighttime awakenings during the 6-week treatment period was significantly lower in the eszopiclone group than in the placebo group (P = 0.03). Of the three daytime variables, alertness, fatigue, and functioning, this was also the case for fatigue (P = 005). The headache variables, frequency, duration, and intensity, did not show a difference from placebo during the 6-week treatment period.

Conclusions: The study did not meet primary endpoint, that is, the difference in total sleep time during the 6-week treatment period between eszopiclone and placebo was less than 40 minutes. Therefore, it failed to answer the question as to whether insomnia is, indeed, a risk factor for increased headache frequency and headache intensity in migraineurs.
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http://dx.doi.org/10.1179/0886963414Z.00000000084DOI Listing
April 2015

Brief communication: the Australian Barrineans and their relationship to Southeast Asian negritos: an investigation using mitochondrial genomics.

Hum Biol 2013 Feb-Jun;85(1-3):485-94

PERAHU, School of Humanities, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.

The existence of a short-statured Aboriginal population in the Far North Queensland (FNQ) rainforest zone of Australia's northeast coast and Tasmania has long been an enigma in Australian anthropology. Based on their reduced stature and associated morphological traits such as tightly curled hair, Birdsell and Tindale proposed that these "Barrinean" peoples were closely related to "negrito" peoples of Southeast Asia and that their ancestors had been the original Pleistocene settlers of Sahul, eventually displaced by taller invaders. Subsequent craniometric and blood protein studies, however, have suggested an overall homogeneity of indigenous Australians, including Barrineans. To confirm this finding and determine the degree of relatedness between Barrinean people and Southeast Asian negritos, we compared indigenous Australian mitochondrial DNA (mtDNA) sequences in populations from the FNQ rainforest ecozone and Tasmania with sequences from other Australian Aboriginal populations and from Southeast Asian negrito populations (Philippines Batek and Mamanwa, and mainland Southeast Asian Jahai, Mendriq, and Batak). The results confirm that FNQ and Tasmanian mtDNA haplogroups cluster with those of other Australian Aboriginal populations and are only very distantly related to Southeast Asian negrito haplogroups.
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http://dx.doi.org/10.3378/027.085.0322DOI Listing
April 2015

Toxicology screening in oral and maxillofacial trauma patients.

Br J Oral Maxillofac Surg 2013 Dec 9;51(8):773-8. Epub 2013 Sep 9.

Oral and Maxillofacial Surgery Department, Ninewells Hospital and School, Ninewells Avenue, Dundee DD1 9SE, United Kingdom. Electronic address:

The role of alcohol in facial trauma is recognised but we know of no research on the possible contribution made by the use of illicit drugs in patients with facial injuries, or the interactions that may occur during anaesthesia. We aimed to find out whether illegal drugs were identified in the urine of patients with maxillofacial injuries, what substances were present, and whether patients were willing to disclose use of drugs at the time of injury. Over a 12-month period we prospectively studied consecutive patients with facial injuries who were referred by accident and emergency (A&E) to the department of oral and maxillofacial surgery (OMFS) for inpatient assessment and treatment within 24 h of injury. Anonymised data on patients were obtained from questionnaires that were linked to a urine sample provided on admission. Results were obtained using immunoassay and gas chromatography with mass spectrometry. A total of 105 patients with facial injuries were eligible and 95 (90%) provided a urine sample and completed the questionnaire; 2 samples were of insufficient volume and were discarded before analysis. Twelve patients (13%) admitted using drugs at the time of injury but 44 (47%) samples tested positive for illegal drugs; fewer showed the presence of alcohol (n=37; 40%). Use of drugs, although often denied, is widespread among patients with facial injuries. It is important to consider the role that drugs have in patients who present with traumatic injuries, the interactions misused drugs may have with anaesthesia, and any possible benefits that targeted prevention strategies would have in this group.
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http://dx.doi.org/10.1016/j.bjoms.2013.03.017DOI Listing
December 2013
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