bluuebunny/crossref_metadata_2025_split huggingface dataset:
053 Pregnancy outcomes with delayed-release dimethyl fumarate: interim results from an international registry
Authors: Everage Nicholas J , Liu Shifang , Yun Jang , Prada Claudia , Hanna Jerome 
Published: May 2018

IntroductionClinical trials and post marketing reports show no safety signals with delayed-release dimethyl fumarate (DMF) exposure during pregnancy; however, these data are limited and the product label recommends use during pregnancy only if the potential benefit justifies the potential risk to the foetus. We assessed pregnancy outcomes in an ongoing international registry (NCT01911767) of women with MS exposed to DMF since the first day of their last menstrual period prior to conception or at any time during pregnancy.MethodsDMF-exposed women were prospectively evaluated for live births and pregnancy loss. Ectopic and molar pregnancies, birth defects, congenital anomalies or infant death occurring at ≤52 weeks of age, and maternal death at ≤12 weeks post-delivery, were reported. Data were collected at baseline (enrolment), 6–7 months of gestation, 4 weeks after the estimated delivery date, and 4, 12, and 52 weeks after birth. Potential birth defects were adjudicated by an external expert.ResultsAs of 30, Sept 2016 104 patients were enrolled in the registry; mean (SD) age was 315 years. DMF exposure occurred in the first (95%), second (1%), and third (0%) trimester in the 94 patients with a known exposure date. To date, 58 pregnancy outcomes have been reported, including 52 patients with 54 live births and 4 (7%) spontaneous abortions (<22 weeks). Of the 54 (93%) live births, 47 (87%) were full term (delivered ≥37 weeks) and four (7%) premature. Two (4%) infants had adjudicator-confirmed birth defects; one with pyloric stenosis, and one with transposition of the great vessels/patent ductus arteriosus. No maternal, neonatal, perinatal, or infant deaths were reported.ConclusionThe results from this ongoing registry did not identify a safety signal for DMF exposure on pregnancy outcomes, are consistent with previous reports, and provide essential information concerning exposure to DMF during pregnancy.
071 Natalizumab extended interval dosing (EID) is associated with a significant reduction in progressive multifocal leukoencephalopathy (PML) risk compared with standard interval dosing (SID) in the touch® prescribing program
Authors: Ryerson Lana Zhovtis , Foley John , Chang Ih , Kister Ilya , Cutter Gary , Metzger Ryan , Goldberg Judith D , Li Xiaochun , Riddle Evan , Smirnakis Karen , Yu Bei , Ren Zheng , Hotermans Christophe , Ho Pei-Ran , Campbell Nolan 
Published: May 2018

IntroductionNatalizumab, approved for 300 mg intravenous every-4-weeks dosing, is associated with PML risk. Prior studies have been inconclusive regarding EID’s impact on PML risk. The US REMS program (TOUCH) offers the largest data source that can inform on PML risk in patients on EID. This analysis aimed to determine whether natalizumab EID is associated with reduced PML risk compared with SID.MethodsInvestigators developed SID and EID definitions and finalised the statistical analysis plan while blinded to PML events. Average dosing intervals (ADIs) were ≥3 to<5 weeks for SID and >5 to≤12 weeks for EID. The primary analysis assessed ADI in the last 18 months of infusion history. The secondary analysis identified any prolonged period of EID at any time in the infusion history. The tertiary analysis assessed ADI over the full infusion history. Only anti-JC virus antibody positive (JCV Ab+) patients with dosing intervals≥3 to≤12 weeks were included. PML hazard ratios (HRs) were compared using adjusted Cox regression models and Kaplan-Meier estimates.ResultsAnalyses included 13,132 SID and 1988 EID patients (primary), 15,424 SID and 3331 EID patients (secondary), and 23,168 SID and 815 EID patients (tertiary). In primary analyses, ADI (days) was 30 for SID and 37 for EID; median exposure (months) was 44 for SID and 59 for EID. Most EID patients received >2 years SID prior to EID. The PML HR (95% CI) was 0.06 (0.01–0.22; p<0.001) for primary analysis and 0.12 (0.05–0.29; p<0.001) for secondary analysis (both in favour of EID); no EID PML cases were observed in tertiary analyses (Kaplan-Meier log-rank test p=0.02).ConclusionIn JCV Ab +patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID. As TOUCH does not collect effectiveness data, further studies are needed.Study supportBiogen
081 Description of a stroke unit mimic admissions
Authors: Cashion Catelyn , Gawarikar Yash , Patel Ronak 
Published: May 2018

IntroductionThere is evidence to support both clinically and economically that stroke units improve stroke outcomes, but this is offset by high stroke mimics rates, which account for up to quarter of stroke unit admissions. There is no Australian data looking at stroke mimic rates and the time of day when they are admitted.MethodsWe conducted a retrospective cross-sectional study at Calvary Public Hospital, Bruce from May 2014 to May 2017 looking at stroke unit admission rates and mimic types. We collected data on the times of stroke unit admission, business hours Monday to Friday 0800–1630 hours and after-hours Monday to Friday 1630–0800 hours, weekends 0800–0800 hours. Stroke mimics length of stay (LOS) was compared with TIA mild strokes (NIHSS <5) LOS.ResultsOut of 1017 stoke unit admissions, 257 (25.3%) were stroke mimics. The most common mimic diagnoses were migraine and headaches (18.3%), peripheral vestibulopathy (14.0%), and functional neurology (13.2%). Data on admission times were available for 240 of 257 (93.4%) mimics of which more than 2/3 s of mimics were admitted after-hours; Bayes factor 0.912 demonstrating this is unlikely to be a significant difference. 3.5% of stroke mimics were thrombolysed with 2/3 s occurring after-hours. The average LOS was 2.3 days for mimics, compared to 4.0 days for TIA and minor strokes (p=0.00017).ConclusionOur study shows similar stroke mimic rates as previously described in literature with a higher proportion of these patients were admitted after-hours. However, there is little evidence that this difference is significant. The LOS for stroke mimics was less than TIAs and minor strokes. Our study highlights the need for better recognition of stroke mimics in order to prevent unnecessary utilisation of a valuable resource such as the stroke unit.
085 Clinical outcomes were better for relapsing-remitting multiple sclerosis (RRMS) patients who remained on natalizumab compared to those who switched to oral or injectable therapies after 2 years in the tysabri® observational program (TOP)
Authors: Butzkueven Helmut , Kappos Ludwig , Spelman Tim , Trojano Maria , Wiendl Heinz , Dong Qunming , Licata Stephanie , Ho Pei-Ran , Campbell Nolan 
Published: May 2018

IntroductionNatalizumab is a high-efficacy RRMS therapy. Data on post-natalizumab disease activity may be important for physician consideration. We compared outcomes in patients who switched to an oral or injectable therapy or remained on natalizumab and analysed post-natalizumab relapse predictors using data from TOP, an ongoing 10 year observational study of natalizumab-treated RRMS patients.MethodsData from November 2016 were analysed for patients who stayed on natalizumab (≥3 years natalizumab and only natalizumab during follow-up; n=2466; mean time on natalizumab: 5.5 years) or switched to oral (n=660) or injectable (n=95) therapies for ≥1 year after ≥2 years on natalizumab (mean post-natalizumab follow-up 2.5 vs 2.4 years). Annualised relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) worsening risks were evaluated. Disease activity predictors were compared using adjusted Cox models.ResultsRelapse risk was higher for oral switchers (hazard ratio [HR]=2.18; p<0.001) or injectable switchers (HR=3.02; p<0.001) than for patients who stayed on natalizumab >2 years. EDSS worsening risk was similar for oral (HR=1.19; p=0.266) and higher for injectable (HR=2.52; p<0.001) switchers compared with stayed-on-natalizumab patients. ARRs decreased after 2 years by 20.2% for stayed-on-natalizumab patients but increased from on-natalizumab rates by 17.8% in oral switchers (p<0.001) and 108.1% in injectable switchers (p<0.001). In oral switchers, lower relapse risk was predicted by shorter washout time (>12 weeks vs ≤4 weeks; HR=2.03; p<0.001), fewer pre-natalizumab relapses (HR=1.24/relapse in the prior year; p<0.001), lower baseline EDSS (>3.5 vs≤3.5; HR=1.44; p=0.007), and longer natalizumab duration (>3 years vs ≤3 years; HR=0.76; p=0.040).ConclusionStaying on natalizumab >2 years yields better clinical outcomes than switching to oral or injectable therapies. For those discontinuing natalizumab, switching to an oral versus an injectable yields better outcomes. Disease activity risk in oral switchers is predicted by washout time, pre-natalizumab relapses and EDSS, and time on natalizumab.Study supportBiogen.
088 Cryoglobulinemic neuropathy associated with lymphoplasmacytic lymphoma
Authors: Dang Yew Li , Foster Emma , Finlay Moira , Evans Andrew 
Published: May 2018

IntroductionA 64 year old woman presented with livedo reticularis and peripheral neuropathy secondary to Type 1 (IgM paraproteinemia) cryoglobulinemia, associated with lymphoplasmacytic lymphoma. Type 1 cryoglobulinemia is rare and remains poorly studied. However, given the common association of Type 1 cryoglobulinemia with lymphoproliferative diseases, it is important to consider Type 1 cryoglobulinemia as a differential diagnosis in presentations of a rash and peripheral neuropathy, and search for underlying malignancy.CaseOur patient presented with a leukocytoclastic vasculitic rash over bilateral lower limbs, which improved with topical betamethasone and oral prednisolone. Two months later, she had rapidly progressive right upper limb and bilateral lower limb weakness, absent reflexes in these limbs, and right arm reduced sensation. Nerve conduction studies revealed generalised axonal sensorimotor peripheral neuropathy in all four limbs, most prominent in the right upper limb. She then developed a livedo reticularis rash over her right forearm and punch biopsy revealed luminal pseudo-thrombi in small vessels consistent with Type 1 cryoglobulinemia. Her cryoglobulin (1558 mg/L, N 0–50 mg/L) and IgM paraprotein levels (4 g/L, N 0.4–2.3) were elevated. Vasculitic and other infective screens were unremarkable. Computer tomography imaging of chest, abdomen and pelvis found widespread lymphadenopathy. Subsequent lymph node core biopsy and bone marrow aspirate revealed lymphoplasmacytic lymphoma—the likely underlying cause of the Type 1 (IgM paraproteinemia) cryoglobulinemia.ConclusionPeripheral neuropathy is commonly associated with Type 2 and 3 cryoglobulinemia, especially in the presence of hepatitis C infection. However, reports of vasculitic peripheral neuropathy due to Type 1 cryoglobulinemia are limited. Early recognition is essential to allow the identification and treatment of the underlying haematological malignancy, commonly associated with Type 1 cryoglobulinemia. Treatment of the underlying cause indirectly treats the cryoglobulinemia, and avoids or reduces the associated; sometimes severe; cutaneous, neurological, and renal manifestations of this condition.
089 Prognostic significance of magnetic resonance imaging in patients with severe non-penetrating traumatic brain injury requiring decompressive craniectomy
Authors: Ho Kwok-Ming , Honeybul Stephen , Ambati Ravi 
Published: May 2018

IntroductionDiffuse axonal injury (DAI) detected on magnetic resonance imaging (MRI) may be useful to predict outcome after traumatic brain injury (TBI).MethodsThis study compared the ability of the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic model with DAI on MRI, to predict 18 months neurological outcome in 56 patients who had required a decompressive craniectomy after TBI.Of the 56 patients included in the study (19 scans occurred within 14 days; median time for all patients 24 days, interquartile range 14–42), 18 (32%) had evidence of DAI on the MRI scans. The presence of DAI on the MRI diffusion-weighted (DW), T2*-weighted-gradient echo and susceptibility-weighted (SWI) sequences was associated with an increased risk of unfavourable outcome at 18 months compared to those without DAI (44% vs. 17%, difference=27%, 95% confidence interval 2.4%–46.7%; p=0.032), particularly when brainstem was involved. However, neither the grading (I to IV) nor the number of brain regions with DAI was as good as the IMPACT model in discriminating between patients with unfavourable and favourable outcome (area under the receiver-operating-characteristic curve: 0.625 and 0.621 vs 0.918, respectively; p<0.001 for both comparisons). After adjusting for the IMPACT prognostic risks, DAI in different brain regions and the grading of DAI were also not independently associated with unfavourable outcome.ConclusionThe prognostic significance of DAI on MRI may, in part, be captured by the IMPACT prognostic model. More research is needed before MRI should be routinely used to prognosticate outcomes of patients with TBI requiring decompressive craniectomy.
090 The expanding clinical phenotype of late onset pompe disease: a multi-system disorder
Authors: Reardon Katrina , McKelvie Penny 
Published: May 2018

IntroductionThe diagnosis of late onset Pompe disease (LOPD) can be difficult and delayed due to heterogeneous presentation. LOPD was typically a triad of weakness affecting the limb girdle, respiratory and axial muscles. Recent reports highlight more widespread, less well recognised, multi system manifestations of LOPD.CasesThree clinical cases of LOPD are described with atypical presenting manifestations for many years, who after diagnosis and investigation all qualified for enzyme replacement therapy. A review of the literature on the manifestations of LOPD is presented. These three clinical cases highlight important clues and pitfalls in making a diagnosis of LOPD when there are subtle presenting symptoms for many years on history, examination or investigations. The literature review has broadened our clinical perspective with reports of multi-system manifestations of LOPD. The manifestations of LOPD may be seen by clinicians in a wide variety of fields including neurology, stroke, rheumatology, gastroenterology, cardiovascular, respiratory, genitourinary and metabolic bone medicine. LOPD will present to a wide variety of specialists with symptoms, who may not be aware of this potential diagnosis. These reports will change our concept of what is LOPD and encourage investigation for this disorder. The dried blood spot testing for diagnosis of LOPD is beneficial, cost effective and non-invasive.ConclusionLOPD is an under diagnosed and often misdiagnosed neuromuscular disorder which is now recognised as having other associated multi-system features which can be identified on history, examination or laboratory findings. These patients may present to a wide variety of health professionals with symptoms and greater awareness in needed. Early diagnosis of patients with LOPD disease will allow better management, prevent complications and may improve outcomes now that enzyme replacement therapy is available for certain individuals.
Diagnosis of Vertigo and Dizziness Syndromes in a Neurological Outpatient Clinic
Authors: Pan Qi , Zhang Yixin , Long Ting , He Wei , Zhang Shanshan , Fan Yulan , Zhou Jiying 
Published: May 2018

<b><i>Background:</i></b> Dizziness and vertigo are frequent complaints of outpatients in the neurological department. Our objective was to explore the epidemiological category and clinical features of patients with dizziness or vertigo in the neurological outpatient department of a tertiary hospital. <b><i>Methods:</i></b> We consecutively recruited all patients with dizziness and/or vertigo visiting the neurological outpatient clinic of the First Affiliated Hospital of Chongqing Medical University from January 2016 to June 2017. All patients were interviewed by 4 neurologists and they completed self-administered questionnaires. General physical and standardized neuro-otology bedside examinations were performed in all participants. Instrumental examinations and other related examinations were prescribed as needed. <b><i>Results:</i></b> A total of 392 patients, 272 female and 120 male, were enrolled and the ratio of males to females was 1: 2.27. The mean age was 52.39 ± 13.87 years (range 11–90). Elderly patients (≥60 years) accounted for about one-third of the patients. Peripheral vestibular disorders accounted for 54.6% of patients, central vestibular disorders (including vestibular migraine [VM]) accounted for 22.4% of patients, psychogenic vertigo in 64 (16.3%), other reasons in 9 (2.3%) and unknown in 17 (4.3%). Benign paroxysmal positional vertigo (BPPV; 30.8%), psychiatric dizziness (20.5%), and VM (14.4%) were the 3 major vestibular diseases in patients under 60 years of age; however, BPPV (27.9%), central vertigo (21.7%), and Meniere’s disease (11.7%) were more common in patients over 60 years of age. <b><i>Conclusions:</i></b> This study provided a classification and clinical features of vestibular disorders in a neurological outpatient department of a tertiary hospital in China. The spectrum of vertigo or dizziness is different between different age groups and clinicians should pay attention to this difference in clinical reasoning.
Intraoperative Cryoanalgesia for Reducing Post-Tonsillectomy Pain: A Systemic Review
Authors: Raggio Blake S. , Barton Blair M. , Grant Maria C. , McCoul Edward D. 
Published: May 2018

Objective: Summarize the effectiveness of intraoperative cryoanalgesia in the management of postoperative pain among patients undergoing palatine tonsillectomy. Methods: A systematic review of PubMED, MEDLINE, EMBASE, Google Scholar, and Cochrane trial registries was performed through January 2017 using the PRISMA standards. We included English-language randomized controlled trials evaluating patients of all age groups with benign pathology who underwent tonsillectomy with cryoanalgesia versus without. Results: Three limited quality randomized controlled trials involving 153 participants (age range, 1-60 years) were included. Cryoanalgesia was performed with a cryotherapy probe (−56°C) in 1 trial and ice-water cooling (4°C to 10°C) in 2. In the 3 trials reviewed, patients who received cryoanalgesia reported 21.38%, 28.33%, and 31.53% less average relative postoperative pain than controls on the visual analog scale. Review of secondary outcomes suggested no significant difference in time to resume normal diet (2 studies) or postoperative bleeding (2 studies) between the 2 groups. Cryoanalgesia allowed patients to return to work 4 days earlier than controls in 1 study. Two studies reported a trend toward less postoperative analgesia use among the treatment group; however, no statistical conclusions could be drawn. Conclusion: The available evidence suggests that patients undergoing tonsillectomy with cryoanalgesia experience less average postoperative pain without additional complications.
Titanium dioxide nanoparticles induce in vitro autophagy
Authors: Dai X , Liu R , Li N , Yi J 
Published: May 2018

Aim: Concerns about the possible toxicity to environment and human health of titanium dioxide nanoparticles (TiO2 NPs) are increasing. The aim of this study was to investigate the relationship between toxicology and autophage in vitro. Methods: RAW 264.7 cells were exposed to five concentrations (50, 100, 200, 300, and 400 μg/mL) and two particle size of TiO2 NPs (30 and 100 nm) for 24 h. Results: The results showed that TiO2 NPs decreased cell viability, phagocytic rate, and phagocytic index in a concentration-dependent manner, thereby inducing autophagy. TiO2 NPs-induced autophagy was indicated by monodansyl cadaverine staining and transmission electron microscopy. TiO2 NPs-induced messenger RNA expression of autophagy-related proteins LC3 and Beclin-1 was also significantly increased compared with those of the unexposed control cells. LC3 and Beclin-1 protein expression levels were markedly increased with the increase of TiO2 NPs concentrations. Conclusion: These results suggest the possibility that TiO2 NPs-induced toxicology probably plays a key role in autophagy in RAW 264.7 cells, and further exhaustive research on the harmful effects of these NPs in relevant organisms is needed for their safe application.
Modeling adverse event counts in phase I clinical trials of a cytotoxic agent
Authors: Muenz Daniel G , Braun Thomas M , Taylor Jeremy MG 
Published: May 2018

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient’s richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.
In reply to: “Intra-aortic balloon pump protects against hydrostatic pulmonary oedema during peripheral venoarterial-extracorporeal membrane oxygenation”
Authors: Privratsky Jamie R , Diaz Sebastian , Nicoara Alina , Daneshmand Mani A 
Published: May 2018

Abstract
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an increasingly utilized life-saving measure. However, left-ventricular distention from inadequate left-ventricular off-loading can lead to unwanted pulmonary and cardiac complications. We are writing to indicate our agreement with a recent article by Brechot et al. published in the June 2017 issue where the authors demonstrated that intra-aortic balloon pump provides mechanical support to off-load the left ventricle during VA-ECMO, which prevents pulmonary edema.