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Resumen Introducción: En 2009 la Influenza A H1N1pdm09 provocó en Chile 12.258 casos y 155 muertes. Objetivo: Analizar en adultos egresados de Clínica Dávila con influenza, en 2009, 2010, 2012 y 2014, soporte ventilatorio, costo de hospitalización, Grupos Relacionados por el Diagnóstico (GRD) y letalidad. Material y Método: Estudio descriptivo retrospectivo usando la ficha médica electrónica. Resultados: Egresaron 115.673 adultos, 338 (0,29%) con diagnóstico de Influenza, edad 56,5 ± 22 años, 59% mujeres, letalidad 4%. Hubo 3 grupos, Grupo 1: sin ningún soporte ventilatorio, 295 pacientes, edad 63 ± 20, estadía 6,6 ± 6,9 días, costo promedio de hospitalización $2.885.261, mediana peso GRD 0,41 (p25 = 0,38 y p75 = 0,62), letalidad 1,01% (3 pacientes). Grupo 2: Ventilación mecánica no invasiva (VMNI), 23 casos, edad 77,1 ± 13, letalidad 22% (5 casos), estadía 16,8 ± 12,4, costo $9.245.242, GRD 0,79 (p25 = 0,62 y p75=1,03). Grupo 3: Intubación y ventilación mecánica invasiva (VMI), 20 pacientes, edad 56,4 ± 15, estadía 36,9 ± 41,4, costo $38.681.099, GRD 5,86 (p25 = 5,82 y p75 = 5,86) y letalidad 30% (6 pacientes). Los GRD grupo VMI versus grupo VMNI y ningún soporte fueron diferentes (p < 0,0001 y p < 0,0001 respectivamente). La letalidad por influenza el 2014 fue de 8,5%, mientras que en los años 2012, 2010 y 2009 fue 1,5%, 3% y 2,5% respectivamente. La mediana de edad el año 2009 fue 37,5 años, menor que la de los otros años (p < 0,0001). Conclusiones: En 2009 los pacientes fueron más jóvenes, la necesidad de soporte ventilatorio provocó un peso GRD, estadía, costo y letalidad mayores que aquellos que no lo requirieron. Introduction: In 2009 Influenza A H1N1pdm09 caused in Chile 12,258 cases and 155 deaths. Objective: To analyze ventilatory support, cost of hospitalization, Diagnosis Related Groups (DRG) and lethality in adults patients with influenza discharged from our institution, during 2009, 2010, 2012 and 2014. Patients and Method: Retrospective descriptive study using electronic medical records. Results: 115,673 adults were discharged, 338 (0.29%) with diagnosis of Influenza, age 56.5 ± 22 yr.o., 59% women, lethality 4%. There were 3 groups, Group 1: without any ventilatory support, 295 patients, age 63 ± 20, stay 6.6 ± 6.9 days, average cost of hospitalization 2,885,261 clp, medium weight DRG 0.41 (p25 = 0.38) andp75 = 0.62), lethality 1.01% (3 patients). Group 2: Non-invasive mechanical ventilation (NIMV), 23 cases, age 77.1 ± 13, lethality 22% (5 cases), stay 16.8 ± 12.4, cost 9,245,242 clp, DRG 0.79 (p25 = 0.62 and p75 = 1.03). Group 3: Intubation and invasive mechanical ventilation (IMV), 20 patients, age 56.4 ± 15, stay 36.9 ± 41.4, cost 38.681.099 clp, DRG 5.86 (p25 = 5.82 and p75 = 5,86) and lethality 30% (6 patients). The DRG group VMI versus group VMNI and no support were different (p < 0.0001 and p < 0.0001 respectively). The lethality for influenza in 2014 was 8.5%, while in 2012, 2010 and 2009 it was 1.5%, 3% and 2.5% respectively. The median age in 2009 was 37.5 yr.o significantly minor, than the other years (p < 0.0001). Conclusions: In 2009 the patients were younger, the need for ventilatory support led to a higher DRG weight, stay, cost and lethality than those who did not require it.

Resumen Introducción: En 2009 la Influenza A H1N1pdm09 provocó en Chile 12.258 casos y 155 muertes. Objetivo: Analizar en adultos egresados de Clínica Dávila con influenza, en 2009, 2010, 2012 y 2014, soporte ventilatorio, costo de hospitalización, Grupos Relacionados por el Diagnóstico (GRD) y letalidad. Material y Método: Estudio descriptivo retrospectivo usando la ficha médica electrónica. Resultados: Egresaron 115.673 adultos, 338 (0,29%) con diagnóstico de Influenza, edad 56,5 ± 22 años, 59% mujeres, letalidad 4%. Hubo 3 grupos, Grupo 1: sin ningún soporte ventilatorio, 295 pacientes, edad 63 ± 20, estadía 6,6 ± 6,9 días, costo promedio de hospitalización $2.885.261, mediana peso GRD 0,41 (p25 = 0,38 y p75 = 0,62), letalidad 1,01% (3 pacientes). Grupo 2: Ventilación mecánica no invasiva (VMNI), 23 casos, edad 77,1 ± 13, letalidad 22% (5 casos), estadía 16,8 ± 12,4, costo $9.245.242, GRD 0,79 (p25 = 0,62 y p75=1,03). Grupo 3: Intubación y ventilación mecánica invasiva (VMI), 20 pacientes, edad 56,4 ± 15, estadía 36,9 ± 41,4, costo $38.681.099, GRD 5,86 (p25 = 5,82 y p75 = 5,86) y letalidad 30% (6 pacientes). Los GRD grupo VMI versus grupo VMNI y ningún soporte fueron diferentes (p < 0,0001 y p < 0,0001 respectivamente). La letalidad por influenza el 2014 fue de 8,5%, mientras que en los años 2012, 2010 y 2009 fue 1,5%, 3% y 2,5% respectivamente. La mediana de edad el año 2009 fue 37,5 años, menor que la de los otros años (p < 0,0001). Conclusiones: En 2009 los pacientes fueron más jóvenes, la necesidad de soporte ventilatorio provocó un peso GRD, estadía, costo y letalidad mayores que aquellos que no lo requirieron.

The type 1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules (SGs) which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region remains unknown. Structural studies indicated that β2- or β4-strands in the mature ectodomain (ME ICA512) form dimers in vitro. Here we show that ME ICA512 prompts proICA512 dimerization in the endoplasmic reticulum. Perturbation of ME ICA512 β2-strand N-glycosylation upon S508A replacement allows for proICA512 dimerization, O-glycosylation, targeting to granules, and conversion, which are instead precluded upon G553D replacement in the ME ICA512 β4-strand. S508A/G553D and N506A/G553D double mutants dimerize but remain in the endoplasmic reticulum. Removal of the N-terminal fragment (ICA512-NTF) preceding ME ICA512 allows an ICA512-ΔNTF G553D mutant to exit the endoplasmic reticulum, and ICA512-ΔNTF is constitutively delivered to the cell surface. The signal for SG sorting is located within the NTF RESP18 homology domain (RESP18-HD), whereas soluble NTF is retained in the endoplasmic reticulum. Hence, we propose that the ME ICA512 β2-strand fosters proICA512 dimerization until NTF prevents N506 glycosylation. Removal of this constraint allows for proICA512 β4-strand-induced dimerization, exit from the endoplasmic reticulum, O-glycosylation, and RESP18-HD-mediated targeting to granules.

he findings of this thesis contribute to the resolution of these clinical challenges, specifically: • Clinical assessment of disability can be improved when (i) UEF and ambu- lation are assessed independently (chapter 3), (ii) tasks of ADL are used in conjunction to other measures (chapter 4), and (iii) a value for MCID of improvement for AMSQ is determined (chapter 5) • Multimodal assessment of UEF and mobility, and subgroup analyses im- prove evaluation of treatment effects (chapter 6) • Reference videos reduce the variability of motor functioning assessment (chapter 7) • Detection of change in UEF and mobility can be improved when video-as- sisted composite measures are used in conjunction with conventional measures (chapter 8) • Autoencoders are a valuable method to preserve data privacy in analyses of patient videos (chapter 9). Final conclusion The clinical assessment of MS patients is an exciting field grounded on illustrious historical foundations and deepened through contemporary technological innovation. Further improvement and integration into multidisciplinary data infrastructures will eventually lead to a better understanding and control of MS, which ultimately improves the quality of the life of our patients.

Background: Accurate clinical assessment in multiple sclerosis (MS) is challenging. The Assess MS system is being developed to automatically quantify motor dysfunction in MS, including upper extremity function (UEF) and mobility. Objective: To determine to what extent combinations of standardized movements included in the Assess MS system explain accepted measures of UEF and mobility. Methods: MS patients were recruited at four European MS centres. Eight movements were selected, including tasks of activities of daily living (ADL) and classical neurological tests. Movements were recorded on video and rated by experienced neurologists ( n = 5). Subsequently, multivariate linear regression models were performed to explain the variance of the Nine-Hole Peg Test (9HPT), Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and Timed-25 Foot Walk test (T25WT). Results: In total, 257 patients were included. The movements explained 62.9% to 80.1% of the variance of the 9HPT models, 43.3% and 44.3% of the AMSQ models and 70.8% of the T25WT. In all models, tasks of ADL contributed most to the variance. Conclusion: Combinations of movements are valuable to assess UEF and mobility. Incorporating ADL tasks into daily clinical practice and clinical trials may be more valuable than the classical neurological examination of UEF and mobility.

Objective: To describe a series of patients with relapsing multiple sclerosis (MS) who \ud experienced significant and unexpected disease activity within the first 12 months after \ud switching from fingolimod to alemtuzumab.\ud Methods: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab \ud who experienced significant subsequent disease activity were identified by personal \ud communication with 6 different European neuroscience centres.\ud Results: Nine patients were identified. Median disease duration to alemtuzumab treatment \ud was 94 (39-215) months and follow-up from time of first alemtuzumab cycle 20 (14-21) \ud months. Following first alemtuzumab infusion cycle 8 patients were identified by at least 1 \ud clinical relapse and radiological disease activity and one by significant radiological disease \ud activity alone.\ud Conclusions: We acknowledge the potential for ascertainment bias; however, these cases \ud may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group \ud of MS patients most in need of disease control. We suggest that significant and unexpected \ud subsequent disease activity after alemtuzumab induction results from prolonged \ud sequestration of auto-reactive lymphocytes following fingolimod withdrawal, allowing these \ud cells to be concealed from the usual biological effect of alemtuzumab. Subsequent \ud lymphocyte egress then provokes disease reactivation. Further animal studies and clinical \ud trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in \ud MS when designing personalised treatment regimes.

Background: The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) is the first validated disease specific patient-reported outcome measure (PROM) designed to assess upper extremity function in patients with multiple sclerosis (MS). Objective: To determine correlations between the AMSQ and established physician- and performance based outcome measures. Methods: In a cross-sectional cohort of 533 patients correlations between the AMSQ and the Expanded Disability Status Scale (EDSS), its functional systems, the 9-Hole Peg Test (9-HPT) and the Timed-25 Foot Walk (T25FW) were determined. Subgroup analyses were performed as well. Also, correlations were determined in 110 of 533 patients with available longitudinal data. Results: Strongest correlations were found in the cross-sectional cohort between the AMSQ and the EDSS (β 0.60, p

Personalized treatment is highly desirable in multiple sclerosis (MS). We believe that multidisciplinary measurements including clinical, functional and patient-reported outcome measures in combination with extensive patient profiling can enhance personalized treatment and rehabilitation strategies. We elaborate on four reasons behind this statement: (1) MS disease activity and progression are complex and multidimensional concepts in nature and thereby defy a one-size-fits-all description, (2) functioning, progression, treatment, and rehabilitation effects are interdependent and should be investigated together, (3) personalized healthcare is based on the dynamics of system biology and on technology that confirms a patient’s fundamental biology and (4) inclusion of patient-reported outcome measures can facilitate patient-relevant healthcare. We discuss currently available multidisciplinary MS data initiatives and introduce joint actions to further increase the overall success. With this topical review, we hope to drive the MS community to invest in expanding towards more multidisciplinary and longitudinal data collection.

Background In chronic neurological diseases, especially in multiple sclerosis (MS), clinical assessment of motor dysfunction is crucial to monitor the disease in patients. Traditional scales are not sensitive enough to detect slight changes. Video recordings of patient performance are more accurate and increase the reliability of severity ratings. When these recordings are automated, quantitative disability assessments by machine learning algorithms can be created. Creation of these algorithms involves non–health care professionals, which is a challenge for maintaining data privacy. However, autoencoders can address this issue. Objective The aim of this proof-of-concept study was to test whether coded frame vectors of autoencoders contain relevant information for analyzing videos of the motor performance of patients with MS. Methods In this study, 20 pre-rated videos of patients performing the finger-to-nose test were recorded. An autoencoder created encoded frame vectors from the original videos and decoded the videos again. The original and decoded videos were shown to 10 neurologists at an academic MS center in Basel, Switzerland. The neurologists tested whether the 200 videos were human-readable after decoding and rated the severity grade of each original and decoded video according to the Neurostatus-Expanded Disability Status Scale definitions of limb ataxia. Furthermore, the neurologists tested whether ratings were equivalent between the original and decoded videos. Results In total, 172 of 200 (86.0%) videos were of sufficient quality to be ratable. The intrarater agreement between the original and decoded videos was 0.317 (Cohen weighted kappa). The average difference in the ratings between the original and decoded videos was 0.26, in which the original videos were rated as more severe. The interrater agreement between the original videos was 0.459 and that between the decoded videos was 0.302. The agreement was higher when no deficits or very severe deficits were present. Conclusions The vast majority of videos (172/200, 86.0%) decoded by the autoencoder contained clinically relevant information and had fair intrarater agreement with the original videos. Autoencoders are a potential method for enabling the use of patient videos while preserving data privacy, especially when non–health-care professionals are involved.

Background: The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) has been developed to assess upper extremity function of patients with multiple sclerosis (MS). A minimal clinically important difference (MCID) value has not been determined yet. Objective: The objective of this study is to determine an MCID for AMSQ. Methods: We used the sensitivity- and specificity-based approach with dichotomized global perceived effect as an anchor. Results: The receiver operating characteristic (ROC) curve yielded an optimal threshold value of 14.5 (sensitivity 0.68 and specificity 0.79). The area under the ROC curve value was 0.77. Conclusion: We identified an MCID of 15 points for the AMSQ (range 31–186).

Background: Fampridine is an effective treatment to improve ambulation for some multiple sclerosis (MS) patients. Remarkable discrepancies exist between responder rates in clinical trials and the proportion of patients continuing treatment in clinical practice. This may be related to clinical phenotypes of MS patients, and the influence of patient reported outcome (PRO) on treatment decision making. Objective: To analyse responder rates to fampridine on ambulation and upper extremity function (UEF) and the influence on treatment decision making in different clinical subgroups in a real-world setting. Methods: MS patients with ambulatory impairment treated with fampridine were included. Patients were subdivided based on disease duration, clinical phenotype, Expanded Disability Status Scale (EDSS), baseline walking speed, and presence of UEF impairment. Ambulatory response was assessed with the Timed 25-Foot Walk (T25FW, responder defined as ≥20% improvement) and with the MS Walking Scale (MSWS, responder defined as ≥8 points improvement) as a PRO. For patients also reporting impaired UEF, the Arm Function in MS Questionnaire (AMSQ, responder defined as ≥15 improvement) was the PRO of choice. Decision on treatment continuation was based on improvement of T25FW, MSWS and the clinicians’ overall impression for improvement. Results: In total 344 patients were included of which 75.3% continued treatment. More patients with a relapsing clinical phenotype continued treatment vs patients with a progressive phenotype (83.6 vs 68.6%, p < 0.01). A positive linear trend was found between severity of walking disability, as determined by baseline walking speed, and T25FW response (p < 0.01), while there was an inverse linear association between walking disability and MSWS response (p = 0.03). However, the proportion of patients continuing treatment was similar between subgroups of baseline walking speed. Impaired UEF was reported by 183 (66.5%) patients, of which 64 (39.3%) were AMSQ responders. Patients responding on AMSQ compared to non-responders, were also more frequently MSWS responders (82.8 vs 65.3%, p = 0.02), while response on T25FW was similar, and continued treatment more often (85.9 vs 70.7%, p = 0.04). This suggests an influence of PRO on treatment decision making. Conclusion: Responder rates and treatment continuation of fampridine differed between clinical subgroups of MS. PROs influenced treatment decision making of fampridine in clinical practice, particularly in patients with mild ambulatory impairment or those reporting UEF impairment. To some extent, these findings explain discrepancies found between clinical trials and clinical practice, and support the importance of subgroup analyses and incorporation of PROs in clinical trials. For clinical practice, using PROs to assess patients experience in conjunction with performance measures helps in treatment decision making.

Motor dysfunction, particularly ataxia, is one of the predominant clinical manifestations in patients with multiple sclerosis (MS). Assessment of motor dysfunction suffers from a high variability. We investigated whether the clinical rating of ataxia can be improved through the use of reference videos, covering the spectrum of severity degrees as defined in the Neurostatus-Expanded Disability Status Scale. Twenty-five neurologists participated. The variability of their assessments was significantly lower when reference videos were used (SD = 0.12; range = 0.40 vs SD = 0.26; range = 0.88 without reference videos; p = 0.013). Reference videos reduced the variability of clinical assessments and may be useful tools to improve the precision and consistency in the clinical assessment of motor functions in MS.

Objective:To investigate disease activity and disability progression following pregnancy-related discontinuation of natalizumab (NTZ) in patients with relapsing-remitting MS.Methods:A retrospective cohort study of clinical and radiologic data in patients who discontinued NTZ for pregnancy-related reasons.Results:Twenty-two pregnancy-related NTZ discontinuations in 17 patients were evaluated. The median time to conception was 3.4 months. Relapses were more frequent in patients in whom conception did not occur within 6 months (p = 0.022). Confirmed disability progression occurred in 27.3% and was associated with time to conception (p < 0.001).Conclusions:Early conception after NTZ discontinuation is associated with a reduced risk of disease activity and disability progression. Continuation of NTZ treatment until confirmed pregnancy should be considered in patients with previously active MS. However, the advantages of continuing the drug until pregnancy should be balanced against the uncertainties in postnatal outcomes.

Carotid sinus massage is a widely used method for diagnosis and treatment of supraventricular tachycardia and carotid sinus hypersensitivity. Complications, mostly neurological, can occur but are rare. Carotid stenosis is a risk factor for complications. Hearing a carotid bruit on auscultation indicates stenosis, and is a contraindication for performing carotid sinus massage. However, the sensitivity of auscultation is insufficient. Case description: A 71-year-old man with a history of hypertension and hypercholesterolemia presented to the cardiology accident and emergency department with palpitations. A supraventricular tachycardia was found on examination, for which carotid sinus massage was performed. The patient developed severe aphasia and right-sided hemiparesis caused by an extensive stroke, and died a few days later. Conclusion: The chance of complications following carotid sinus massage is slight; however, this type of complication can have severe consequences. Safer alternative methods may be used for patients with supraventricular tachycardia. In older patients with vascular risk factors, more extensive diagnostic investigations for carotid stenosis should be considered in the diagnostic workup for carotid sinus hypersensitivity.

The aim of this work was to determine the value of stroking the lateral dorsal border of the foot, in addition to stroking the sole in patients with a suspected pyramidal tract lesion. In addition, we studied the differences in interpretation between neurologists, residents, and medical students. We included subjects who had weakness of at least one leg and in whom a pyramidal tract lesion was suspected. After testing muscle power, tone, reflexes, and foot tapping, a decision on the presence of a pyramidal syndrome had to be made by each observer. After stimulating the sole as well as the lateral border of the foot, observers made a decision about the presence of a pyramidal syndrome again. Twenty-two legs of 18 patients were examined. Testing the plantar reflex (according to both methods) led to a change of opinion on the presence of a pyramidal syndrome in 45 of 69 (65 %) observations. On analysis according to level of experience, a change of opinion occurred in 19 (86 %) observations by medical students, 15 (65 %) by residents, and 11 (46 %) by neurologists. On eight occasions, the change was prompted by stimulation of the lateral border; in five of these cases the examiner (three medical students and two residents) found a new pathological response. Consecutively stroking the sole and the lateral border may be of added value, especially for less-experienced physicians. It seems that more-experienced physicians need fewer tests in the physical examination in order to identify a pyramidal syndrome of the leg.

Joshua Oppenheimer (b. 1974) is the director of several award-winning documentary films and Reader in Documentary Film and Artistic Director of the Centre for Documentary and Experimental Film at the University of Westminster. From 2007 to 2011, he was senior researcher on the UK Arts and Humanities Research Council (AHRC)’s Genocide and Genre project. For over a decade, he has worked with militias, death squads and their victims to explore the relationship between political violence and the public imagination. We sat down with him to talk about his Oscar-nominated film, The Act of Killing (2012), in which former Indonesian death-squad leaders reenact their real-life mass killings in their favorite cinematic genres, including film noir, westerns and musicals.

Traditionally, multiple sclerosis (MS) is considered to be a disease primarily affecting the white matter (WM). However, the development of some clinical symptoms such as cognitive impairment cannot be fully explained by the severity of WM pathology alone. During the past decades it became clear that gray matter (GM) damage of the brain is also of major importance in patients with MS. Thanks to improved magnetic resonance imaging techniques, the in vivo detection of GM pathology became possible, enabling a better understanding of the manifestation of various clinical symptoms, such as cognitive impairment. Using higher field strengths and specific sequences, detection of cortical lesions was increased. However, despite these improvements, visualization of cortical MS lesions remains difficult (only about 30-50% of histopathologically confirmed lesions can be detected at 7 Tesla magnetic resonance imaging (MRI)). Furthermore, more research is needed to understand the exact interplay of cortical lesions, GM atrophy and WM pathology in the development of clinical symptoms. In this review, we summarize the historical background that preceded current research and provide an overview of the current knowledge on clinical consequences of GM pathology in MS in terms of disability, cognitive impairment and other clinically important signs such as epileptic seizures.

Janus Metz (b. 1974) is director of several documentary films, including Armadillo (2010), for which he received the Grand Prix de la Semaine de la Critique at the Cannes Film Festival.1 Sine Plambech (b. 1975) is an anthropologist at the Danish Institute for International Studies specializing in human trafficking, international migration and gender. Together, Metz and Plambech made the films Love on Delivery (2008) and Ticket to Paradise (2008), both official selections at the 2008 International Documentary Film Festival in Amsterdam (IDFA). The outcome of a meeting between academic research and the art and craft of documentary filmmaking, the films explore migration and transnational ties and identities under conditions of globalization by focusing on marital arrangements among Thai women and men in provincial Denmark. Love on Delivery and Ticket to Paradise challenge conventional narratives of victimhood by focusing on the self-perceptions of Thai women as they make the life-determining choice to settle in an unknown country on the other side of the planet, leaving behind family and communities. We sat down with Metz and Plambech to talk about their collaboration and the opportunities and challenges of bringing together (anthropological) research and documentary filmmaking.

The atomic bomb is a fetish of modernity. As Gabrielle Hecht has elegantly put it: ‘The atom bomb has become the ultimate fetish of our times. Salvation and apocalypse, sacred and profane, sex and death: the bomb contains it all’ (Hecht 2007: 100; see also Harrington de Santana 2009). A crucial part of the concept of the fetish concerns how an object is presented as something else or more than what it also or really is. Fetishism is therefore intimately bound up with representation and reproduction. But as Hecht’s observation about the ‘ultimate’ nature of the nuclear fetish suggests, the imagery and vocabulary we deploy to represent nuclear weapons harbor radical dualisms that constantly deny full closure. Perhaps the theme of life and death is the most plentiful and historically significant in our representation of nuclear weapons – a trait related to the sheer power of these weapons, as well as to their association with both triumph and ruin since the dawn of the nuclear age – but many forms of dissonance surrounding these weapons have been subjected to scrutiny in cultural history and related disciplines.1 Ambiguity even extends to modern notions of the technological sublime, where awe, pleasure and pride in nature and technology are undermined by the central role of human creation.2