The biochemical features of phenylketonuria have been reproduced in developing rat pups by administering to them a combination of p -chloro-DL-phenylalanine plus L-phenylalanine for the first 21 days after birth. During the treatment period, the experimental animals show delayed eye opening and decreased brain weight compared with controls given saline. Neuropathological examination of developing animals reveals deficient myelination and some inhibition of cerebellar maturation. When tested as adults, after a long recovery period, animals with phenylketonuria are hyperactive in activity wheels. Adult rats are deficient in reversing a position choice and demonstrate impaired performance in a Y-maze. Rats treated with p -chloro-DL-phenylalanine plus L-phenylalanine during the vulnerable period of rapid brain development thus have enduring behavioral changes that persist throughout life.
Patients with hypermobility syndromes often have difficulty using Positive Airway Pressure (PAP) Therapy for treatment of their Sleep Disordered Breathing. To investigate this, the CPAP titrations of patients with hypermobility were studied in detail. The attended PAP titrations of 19 consecutive patients with a Beighton hypermobility score of 5 or greater at a neurology institute were retrospectively reviewed. Of 19 patients, 6 had Sleep Apnea - Unspecified (Upper Airway Resistance Syndrome) (G47.30) and 13 had Obstructive Sleep Apnea (G47.33). All ± values reflect the standard error of the mean. During titrations, after an initial nadir for scorable hypopneas was achieved, 11 of 19 patients experienced an average increase of 10.24 ± 2.5 in their hypopnea index as pressure was increased. At their hypopnea nadir, 15 of 19 patients’ AHI was 0 and an average Respiratory Effort Related Arousal Index of 38.4 ± 6.7 remained. Example titrations and images of typical airways in hypermobile patients will be presented. 1. In typical CPAP titrations hypopneas and RERAs should generally decrease and eventually plateau as PAP is increased. However, the pattern observed in the titration of these patients with hypermobility is somewhat atypical. 2. In hypermobile patients, the high RERA index at the hypopnea nadir, with subsequent increases in both with increasing pressure, could be explained by the following mechanism: In hypermobile patients, the epiglottis is more flexible than usual, and even though the upper portion of the lower airway can be expanded by PAP, increasing pressure in hypermobile patients could lead to epiglottal closure. 3. Auto-titrating CPAPs currently do not measure RERA’s well, because of their inability to assess EEG arousals, despite having formidable algorithms which can measure changes in airway resistance. Thus, the use of auto-titrating PAP devices may not be effective in the relief of sleep complaints in patients with hypermobility and SDB. 4. This lack of effectiveness could lead to poor compliance with PAP therapy in patients with hypermobility. 5. Thus, patients with hypermobility probably need an attended PAP titration to achieve optional airway patency, and resolution of their complaints related to SDB.
To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.
Methods:
Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.
Results:
Alemtuzumab-treated patients were more likely than SC IFN-β-1a–treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a–treated patients.
Conclusions:
In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.
Classification of evidence:
This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
BackgroundExcessive sleepiness (ES) is a common symptom of OSA, which often persists despite primary OSA therapy. This phase III randomized withdrawal trial evaluated solriamfetol (JZP-110) for the treatment of ES in adults with OSA.MethodsAfter 2 weeks of clinical titration (n = 174) and 2 weeks of stable dose administration (n = 148), participants who reported improvement on the Patient Global Impression of Change (PGI-C) and had numerical improvements on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were randomly assigned to placebo (n = 62) or solriamfetol (n = 62) for 2 additional weeks. Coprimary end points were change from weeks 4 to 6 in MWT and ESS.ResultsIn the modified intention-to-treat population (n = 122), MWT mean sleep latencies and ESS scores improved from baseline to week 4 (from 12.3-13.1 to 29.0-31.7 minutes and from 15.3-16.0 to 5.9-6.4, respectively). From weeks 4 to 6, participants treated with solriamfetol maintained improvements (least squares [LS] mean [SE] changes of −1.0 [1.4] minutes on MWT and −0.1 [0.7] on ESS), whereas participants treated with placebo worsened (LS mean [SE] change of −12.1 [1.3] minutes on MWT and 4.5 [0.7] on ESS); LS mean differences between treatments were 11.2 minutes (95% CI, 7.8-14.6) and −4.6 (95% CI, −6.4 to −2.8) on MWT and ESS, respectively. Fewer participants treated with solriamfetol reported worsening on the PGI-C from weeks 4 to 6 (20% vs 50%; P = .0005). Common adverse events included headache, dry mouth, nausea, dizziness, and insomnia.ConclusionsThis study demonstrated maintenance of solriamfetol efficacy and safety over 6 weeks.Trial RegistryClinicalTrials.gov; No.: NCT02348619; URL: www.clinicaltrials.gov; EudraCT No.: 2014-005515-16 Excessive sleepiness (ES) is a common symptom of OSA, which often persists despite primary OSA therapy. This phase III randomized withdrawal trial evaluated solriamfetol (JZP-110) for the treatment of ES in adults with OSA. After 2 weeks of clinical titration (n = 174) and 2 weeks of stable dose administration (n = 148), participants who reported improvement on the Patient Global Impression of Change (PGI-C) and had numerical improvements on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were randomly assigned to placebo (n = 62) or solriamfetol (n = 62) for 2 additional weeks. Coprimary end points were change from weeks 4 to 6 in MWT and ESS. In the modified intention-to-treat population (n = 122), MWT mean sleep latencies and ESS scores improved from baseline to week 4 (from 12.3-13.1 to 29.0-31.7 minutes and from 15.3-16.0 to 5.9-6.4, respectively). From weeks 4 to 6, participants treated with solriamfetol maintained improvements (least squares [LS] mean [SE] changes of −1.0 [1.4] minutes on MWT and −0.1 [0.7] on ESS), whereas participants treated with placebo worsened (LS mean [SE] change of −12.1 [1.3] minutes on MWT and 4.5 [0.7] on ESS); LS mean differences between treatments were 11.2 minutes (95% CI, 7.8-14.6) and −4.6 (95% CI, −6.4 to −2.8) on MWT and ESS, respectively. Fewer participants treated with solriamfetol reported worsening on the PGI-C from weeks 4 to 6 (20% vs 50%; P = .0005). Common adverse events included headache, dry mouth, nausea, dizziness, and insomnia. This study demonstrated maintenance of solriamfetol efficacy and safety over 6 weeks.
Objective To assess the safety and efficacy of external trigeminal nerve stimulation for acute pain relief during migraine attacks with or without aura via a sham-controlled trial. Methods This was a double-blind, randomized, sham-controlled study conducted across three headache centers in the United States. Adult patients who were experiencing an acute migraine attack with or without aura were recruited on site and randomly assigned 1:1 to receive either verum or sham external trigeminal nerve stimulation treatment (CEFALY Technology) for 1 hour. Pain intensity was scored using a visual analogue scale (0 = no pain to 10 = maximum pain). The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline. Results A total of 109 participants were screened between February 1, 2016 and March 31, 2017. Of these, 106 patients were randomized and included in the intention-to-treat analysis (verum: n = 52; sham: n = 54). The primary outcome measure was significantly more reduced in the verum group than in the sham group: −3.46 ± 2.32 versus −1.78 ± 1.89 ( p < 0.0001), or −59% versus −30% ( p < 0.0001). With regards to migraine subgroups, there was a significant difference in pain reduction between verum and sham for ‘migraine without aura’ attacks: mean visual analogue scale reduction at 1 hour was −3.3 ± 2.4 for the verum group versus −1.7 ± 1.9 for the sham group ( p = 0.0006). For ‘migraine with aura’ attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean visual analogue scale reduction at 1 hour was −4.3 ± 1.8 for the verum group versus −2.6 ± 1.9 for the sham group ( p = 0.060). No serious adverse events were reported and five minor adverse events occurred in the verum group. Conclusion One-hour treatment with external trigeminal nerve stimulation resulted in significant headache pain relief compared to sham stimulation and was well tolerated, suggesting it may be a safe and effective acute treatment for migraine attacks. Study protocol ClinicalTrials.gov Identifier: NCT02590939.
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