EAN consensus statement for management of patients with neurological diseases during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The recent SARS-CoV-2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast-evolving pandemic, evidence-based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID-19. METHODS: A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co-chairs rated importance on a five-point Likert scale. Results were graded by importance and reported as consensus statements. RESULTS: In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty-nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co-chairs of 29 SPs. Whilst general recommendations related to prevention of COVID-19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy. CONCLUSION: This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID-19 pandemic that provides immediate guidance for neurologists. In this fast-evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges.

The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection.

BACKGROUND AND PURPOSE: Although the main clinical features of COVID-19 infection are pulmonary, several associated neurological signs, symptoms and diseases are emerging. The incidence and characteristics of neurological complications are unclear. For this reason, the European Academy of Neurology (EAN) core COVID-19 Task Force initiated a survey on neurological symptoms observed in patients with COVID-19 infection. METHODS: A 17-question online survey was made available on the EAN website and distributed to EAN members and other worldwide physicians starting on 9 April 2020. RESULTS: By 27 April 2020, proper data were collected from 2343 responders (out of 4199), of whom 82.0% were neurologists, mostly from Europe. Most responders (74.7%) consulted patients with COVID-19 mainly in emergency rooms and in COVID-19 units. The majority (67.0%) had evaluated fewer than 10 patients with neurological manifestations of COVID-19 (neuro COVID-19). The most frequently reported neurological findings were headache (61.9%), myalgia (50.4%), anosmia (49.2%), ageusia (39.8%), impaired consciousness (29.3%) and psychomotor agitation (26.7%). Encephalopathy and acute cerebrovascular disorders were reported at 21.0%. Neurological manifestations were generally interpreted as being possibly related to COVID-19; they were most commonly recognized in patients with multiple general symptoms and occurred at any time during infection. CONCLUSION: Neurologists are currently and actively involved in the management of neurological issues related to the COVID-19 pandemic. This survey justifies setting up a prospective registry to better capture the prevalence of patients with neuro COVID-19, neurological disease characteristics and the contribution of neurological manifestations to outcome.

Factors associated with long-term weight-loss maintenance following bariatric surgery in adolescents with severe obesity.

BACKGROUND/OBJECTIVES: Bariatric surgery produces robust weight loss, however, factors associated with long-term weight-loss maintenance among adolescents undergoing Roux-en-Y gastric bypass surgery are unknown. SUBJECTS/METHODS: Fifty adolescents (mean±s.d. age and body mass index (BMI)=17.1±1.7 years and 59±11 kg m-2) underwent Roux-en-Y gastric bypass surgery, had follow-up visits at 1 year and at a visit between 5 and 12 years following surgery (Follow-up of Adolescent Bariatric Surgery at 5 Plus years (FABS-5+) visit; mean±s.d. 8.1±1.6 years). A non-surgical comparison group (n=30; mean±s.d. age and BMI=15.3±1.7 years and BMI=52±8 kg m-2) was recruited to compare weight trajectories over time. Questionnaires (health-related and eating behaviors, health responsibility, impact of weight on quality of life (QOL), international physical activity questionnaire and dietary habits via surgery guidelines) were administered at the FABS-5+ visit. Post hoc, participants were split into two groups: long-term weight-loss maintainers (n=23; baseline BMI=58.2 kg m-2; 1-year BMI=35.8 kg m-2; FABS-5+ BMI=34.9 kg m-2) and re-gainers (n=27; baseline BMI=59.8 kg m-2; 1-year BMI=36.8 kg m-2; FABS-5+ BMI=48.0 kg m-2) to compare factors which might contribute to differences. Data were analyzed using generalized estimating equations adjusted for age, sex, baseline BMI, baseline diabetes status and length of follow-up. RESULTS: The BMI of the surgical group declined from baseline to 1 year (-38.5±6.9%), which, despite some regain, was largely maintained until FABS-5+ (-29.6±13.9% change). The BMI of the comparison group increased from baseline to the FABS-5+ visit (+10.3±20.6%). When the surgical group was split into maintainers and re-gainers, no differences in weight-related and eating behaviors, health responsibility, physical activity/inactivity, or dietary habits were observed between groups. However, at FABS-5+, maintainers had greater overall QOL scores than re-gainers (87.5±10.5 vs 65.4±20.2, P<0.001) and in each QOL sub-domain (P<0.01 all). CONCLUSIONS: Long-term weight outcomes for those who underwent weight-loss surgery were superior to those who did not undergo surgical treatment. While no behavioral factors were identified as predictors of success in long-term weight-loss maintenance, greater QOL was strongly associated with maintenance of weight loss among adolescents who underwent Roux-en-Y gastric bypass surgery surgery.

Analysis of brain and spinal MRI measures in a common domain to investigate directional neurodegeneration in motor neuron disease.

BACKGROUND: Magnetic resonance imaging (MRI) of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology. This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus or retrograde, dying-back. METHODS: In this cross-sectional study, MRI was performed on 75 MND patients and 13 healthy controls. Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy (FA) from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox. To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to z-scores, referenced to healthy control norms. Mixed-effects linear regression models were then fitted to these z-scores, with gradients hypothesised to represent directionality of neurodegeneration. RESULTS: At group-level, z-scores did not differ significantly between precentral gyral and intracranial corticospinal tract tissue damage estimates (regression coefficient - 0.24, [95% CI - 0.62, 0.14], p = 0.222), but step-changes were evident between intracranial corticospinal tract and C1 (1.14, [95% CI 0.74, 1.53], p < 0.001), and between C5 and C6 cord levels (0.98, [95% CI 0.58, 1.38], p < 0.001). DISCUSSION: Analysis of brain and cervical spinal MRI data in a common domain enabled investigation of pathophysiological hypotheses in vivo. A cranio-caudal step-change in MND patients was observed, and requires further investigation in larger cohorts.

Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis.

BACKGROUND: Previous work showed that pericalcarine cortical volume loss is evident early after presentation with acute clinically isolated optic neuritis (ON). The aims of this study were: (1) to determine whether pericalcarine atrophy in patients with ON is associated with conversion to multiple sclerosis (MS); (2) to investigate whether regional atrophy preferentially affects pericalcarine cortex; and (3) to investigate potential causes of early pericalcarine atrophy using MRI. METHODS: 28 patients with acute ON and 10 controls underwent structural MRI (brain and optic nerves) and were followed-up over 12 months. Associations between the development of MS, optic nerve, optic radiation and pericalcarine cortical damage measures were investigated using multiple linear regression models. Regional cortical volumetric differences between patients and controls were calculated using t tests. RESULTS: The development of MS at 12 months was associated with greater whole brain and optic radiation lesion loads, shorter acute optic nerve lesions and smaller pericalcarine cortical volume at baseline. Regional atrophy was not evident in other sampled cortical regions. Pericalcarine atrophy was not directly associated with whole brain lesion load, optic radiation measures or optic nerve lesion length. However, the association between pericalcarine atrophy and MS was not independent of these parameters. CONCLUSIONS: Reduced pericalcarine cortical volumes in patients with early clinically isolated ON were associated with the development of MS but volumes of other cortical regions were not. Hence pericalcarine cortical regions appear particularly susceptible to early damage. These findings could be explained by a combination of pathological effects to visual grey and white matter in patients with ON.

DNA polymerase beta and DNA synthesis in Xenopus oocytes and in a nuclear extract.

The identities of the DNA polymerases required for conversion of single-strand (ss) M13 DNA to double-strand (ds) M13 DNA were examined both in injected Xenopus laevis oocytes and in an oocyte nuclear extract. Inhibitors and antibodies specific to DNA polymerases alpha and beta were used. In nuclear extracts, inhibition by the antibody to polymerase beta could be reversed by purified polymerase beta. The polymerase beta inhibitors, dideoxythymidine triphosphate (ddTTP) and dideoxycytidine triphosphate (ddCTP), also blocked DNA synthesis and indicated that polymerase beta is involved in the conversion of ssDNA to dsDNA. These results also may have particular significance for emerging evidence of an ssDNA replication mode in eukaryotic cells.

Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases.

HIV integrase is the enzyme responsible for inserting the viral DNA into the host chromosome; it is essential for HIV replication. The crystal structure of the catalytically active core domain (residues 50 to 212) of HIV-1 integrase was determined at 2.5 A resolution. The central feature of the structure is a five-stranded beta sheet flanked by helical regions. The overall topology reveals that this domain of integrase belongs to a superfamily of polynucleotidyl transferases that includes ribonuclease H and the Holliday junction resolvase RuvC. The active site region is identified by the position of two of the conserved carboxylate residues essential for catalysis, which are located at similar positions in ribonuclease H. In the crystal, two molecules form a dimer with a extensive solvent-inaccessible interface of 1300 A2 per monomer.

Diagnosis and management of primary progressive multiple sclerosis.

Primary progressive multiple sclerosis (MS) is a chronic demyelinating degenerative disorder of the central nervous system. The most common presentation is with a spastic paraparesis, which may be asymmetrical. In contrast to relapsing remitting MS, discrete attacks are not a characteristic feature and the temporal course is of gradual symptomatic deterioration. The current diagnostic criteria are based on this clinical phenotype, with supportive evidence from magnetic resonance imaging, and examination of cerebrospinal fluid and visual evoked potentials in some cases. At present, there is no effective disease modifying therapy, but a wide range of symptomatic treatments are available. These may be of great benefit to individual patients and include pharmacological measures, multidisciplinary therapist input and neurorehabilitation. New treatments which target neurodegeneration and promote brain repair are required, and research in these areas offers hope for the future.

Recurrent rhabdomyolysis caused by carnitine palmitoyltransferase II deficiency, common but under-recognised: Lessons to be learnt.

We discuss two adult siblings who presented with symptoms of myalgia and rhabdomyolysis following exercise with myoglobinuria; genetic testing confirmed carnitine palmitoyltransferase II deficiency and resulted in institution of appropriate crisis management and dietary advice. We explore the phenotypic variability of this commonest fatty oxidation defect that remains under-diagnosed in the adult population and provide clues for early recognition and diagnosis.

Structural cortical network reorganization associated with early conversion to multiple sclerosis.

Brain structural covariance networks (SCNs) based on pairwise statistical associations of cortical thickness data across brain areas reflect underlying physical and functional connections between them. SCNs capture the complexity of human brain cortex structure and are disrupted in neurodegenerative conditions. However, the longitudinal assessment of SCN dynamics has not yet been explored, despite its potential to unveil mechanisms underlying neurodegeneration. Here, we evaluated the changes of SCNs over 12 months in patients with a first inflammatory-demyelinating attack of the Central Nervous System and assessed their clinical relevance by comparing SCN dynamics of patients with and without conversion to multiple sclerosis (MS) over one year. All subjects underwent clinical and brain MRI assessments over one year. Brain cortical thicknesses for each subject and time point were used to obtain group-level between-area correlation matrices from which nodal connectivity metrics were obtained. Robust bootstrap-based statistical approaches (allowing sampling with replacement) assessed the significance of longitudinal changes. Patients who converted to MS exhibited significantly greater network connectivity at baseline than non-converters (p = 0.02) and a subsequent connectivity loss over time (p = 0.001-0.02), not observed in non-converters' network. These findings suggest SCN analysis is sensitive to brain tissue changes in early MS, reflecting clinically relevant aspects of the condition. However, this is preliminary work, indicated by the low sample sizes, and its results and conclusions should be treated with caution and confirmed with larger cohorts.

Cytoplasmic incompatibility and mating preference in Colombian Drosophila pseudoobscura.

MACRAE and ANDERSON observed a large frequency change of mitochondrial DNA (mtDNA) haplotypes in a population initiated with two allopatric strains of Drosophila pseudoobscura, BogER from Colombia and AH162 from California. They concluded that mtDNA haplotypes in D. pseudoobscura are not always selectively neutral. NIGRO and PROUT suggested, however, that a maternally transmitted incompatibility system, similar to the one they observed in two strains of D. simulans from Italy, could account for the observed mtDNA frequency changes. SINGH and HALE postulated that a mating preference between the strains BogER and AH162 in MACRAF and ANDERSON's experiment, in the form of negative assortative mating, could also account for the mtDNA frequency changes. We report two experiments designed to test the hypotheses: that a maternally transmitted cytoplasmic incompatibility system exists between D. pseudoobscura strains BogER and AH162; and, that BogER females mate preferentially with AH162 males. Our results do not support either hypothesis.

Distinct physiological roles of animal succinate thiokinases. Association of guanine nucleotide-linked succinate thiokinase with ketone body utilization.

Two distinct succinate thiokinases have recently been shown to exist in animal tissues, one specific for guanine nucleotide and the other for adenine nucleotide. Their physiological roles have here been investigated by comparing the levels of the two enzymes in liver and brain of normal and diabetic rats. A marked rise in the level of brain guanine nucleotide-linked succinate thiokinase in the diabetic condition is consistent with an enhanced utilization of ketone bodies and hence with the associated elevated demand for succinyl-CoA for the activation of acetoacetate. Taken together with the reported mitochondrial values of the ATP/ADP and GTP/GDP ratios, the results are interpreted to indicate that the adenine nucleotide-linked enzyme functions as a component of the citric acid cycle whereas the guanine nucleotide-linked enzyme functions in the opposite metabolic direction to produce succinyl-CoA from succinate.

Physiological roles of animal succinate thiokinases. Specific association of the guanine nucleotide-linked enzyme with haem biosynthesis.

The discovery of two distinct succinate thiokinases in mammalian tissues, one (G-STK) specific for GDP/GTP and the other (A-STK) for ADP/ATP, poses the question of their differential metabolic roles. Evidence has suggested that the A-STK functions in the citric acid cycle in the direction of succinyl-CoA breakdown (and ATP formation) whereas one role of the G-STK appears to be the re-cycling of succinate to succinyl-CoA (at the expense of GTP) for the purpose of ketone body activation. A third metabolic participation of succinyl-CoA is in haem biosynthesis. This communication shows that in chemically induced hepatic porphyria, when the demand for succinyl-CoA is increased, it is the level of G-STK only which is elevated, that of A-STK being unaffected. The results implicate G-STK in the provision of succinyl-CoA for haem biosynthesis, a conclusion which is further supported by the observation of a high G-STK/A-STK ratio in bone marrow.

Transcervical Foley catheter for preinduction cervical ripening in an outpatient versus inpatient setting.

OBJECTIVE: To compare use of the Foley catheter for preinduction cervical ripening in an inpatient versus outpatient setting. METHODS: A randomized trial was conducted from May 1998 to December 1999. Women with a term gestation in the vertex presentation, a reactive nonstress test, an amniotic fluid index above the fifth percentile, and a Bishop score of no more than 5 were included. The primary outcome variable was a change in Bishop score. A Foley catheter with a 30-mL balloon was placed through the cervix on gentle traction in each group. The outpatient group was then discharged home with written instructions and returned in the morning for induction. The inpatient group was admitted to labor and delivery, with induction started upon extrusion of the Foley. RESULTS: Sixty-one women were randomized into the outpatient group, and 50 women into the inpatient group. Maternal age, gravidity, previous cesarean delivery, and gestational age did not differ between the groups. The median Bishop score at entry was 3.0 for each group (P =.97). The mean change in Bishop scores after catheter placement was not different between the inpatient and outpatient groups (3.0 versus 3.0; P =.74). The maximum dose of oxytocin, time of oxytocin, epidural rate, induction time, 1-minute and 5-minute Apgar scores, and cord pH were not significantly different. The outpatient group on average avoided 9.6 hours of hospitalization. There were no adverse events or maternal morbidity in either group. CONCLUSIONS: The Foley bulb is as effective in the outpatient as the inpatient setting for preinduction cervical ripening.

Photon and electron response of silicon-diode neutron detectors.

The photon response of silicon-diode neutron detectors is analyzed theoretically and measured in the 15-25-MeV region. The main mechanism for producing a response in the diode is shown to be the displacement of silicon atoms by scattering of electrons. If the photon source is an electron accelerator target, the response is mostly due to electrons originating in the target with a smaller contribution from electrons produced in the diode by photons generated at small angles to the beam.

First trimester prenatal diagnosis: chorionic villus sampling.

Chorionic villus sampling has been used successfully for first trimester diagnosis of genetic disorders for over 14 years. When performed between 10 and 14 weeks' gestation, it is both safe and effective in the diagnosis of fetal chromosomal, biochemical, and molecular disorders, with risks comparable to those of second trimester amniocentesis. Cytogenetic results have been confirmed to be reliable and accurate. Although confined placental mosaicism occurs in approximately 1% of cases requiring interpretation, and occasionally additional invasive testing, its finding adds additional information about perinatal outcome and can alert the practitioner to fetal genetic disorders. Earlier concerns about procedure-induced limb defects have been reduced with the accumulation of additional data, showing minimal to no risk when chorionic villus sampling is performed after 70 days of gestation. In experienced hands, it may be the procedure of choice for sampling multiple gestations. Secondary to the advantage of safe, early diagnosis, chorionic villus sampling appears to be the optimal choice for first trimester testing.

The new genetic era in reproductive medicine: possibilities, probabilities and problems.

The "New Genetic Era" will be a period of enormous exponential growth in our knowledge of the structure and function of the basic information blocks of life. The Human Genome Project will soon provide a complete and accurate sequence of the human genome. This will give us an abundance of basic genetic knowledge and provide a molecular understanding of disease, allowing for improved diagnosis and more sensitive and specific screening for disease. This will, we hope, lead to better treatments, prevention and cures through gene therapy, patient-specific drug design, and earlier and more specific behavioral interventions to prevent disease. With this information comes a complexity of legal, ethical and social concerns about potential use and abuse. The public has expressed its concerns about the potential for genetic discrimination. However, genetic information is enhancing our knowledge as to the causes of infertility, allowing diagnosis of more diseases in the prenatal period, and may aid our identification of patients at increased risk for breast and ovarian cancer. Doctors involved in reproductive medicine must become knowledgeable about the new genetic era so as to offer our patients the most appropriate and informed care.

Measurements of accelerator-produced leakage neutron and photon transmission through concrete.

Optimum shielding of the radiation from particle accelerators requires knowledge of the attenuation characteristics of the shielding material. The most common material for shielding this radiation is concrete, which can be made using various materials of different densities as aggregates. These different concrete mixes can have very different attenuation characteristics. Information about the attenuation of leakage photons and neutrons in ordinary and heavy concrete is, however, very limited. To increase our knowledge and understanding of the radiation attenuation in concrete of various compositions, we have performed measurements of the transmission of leakage radiation, photons and neutrons, from a Varian Clinac 2100C medical linear accelerator operating at maximum electron energies of 6 and 18 MeV. We have also calculated, using Monte Carlo techniques, the leakage neutron spectra and its transmission through concrete. The results of these measurements and calculations extend the information currently available for designing shielding for medical electron accelerators. Photon transmission characteristics depend more on the manufacturer of the concrete than on the atomic composition. A possible cause for this effect is a non-uniform distribution of the high-density aggregate, typically iron, in the concrete matrix. Errors in estimated transmission of photons can exceed a factor of three, depending on barrier thickness, if attenuation in high-density concrete is simply scaled from that of normal density concrete. We found that neutron transmission through the high-density concretes can be estimated most reasonably and conservatively by using the linear tenth-value layer of normal concrete if specific values of the tenth-value layer of the high-density concrete are not known. The reason for this is that the neutron transmission depends primarily on the hydrogen content of the concrete, which does not significantly depend on concrete density. Errors of factors of two to more than ten, depending on barrier thickness, in the estimated transmission of neutrons through high-density concrete can be made if the attenuation is scaled by density from normal concrete.

Radiation protection systems for the final focus test beam at SLAC.

The Final Focus Test Beam (FFTB) is a new beam line at the Stanford Linear Accelerator Center designed to test new beam optics concepts, hardware, and techniques necessary to achieve and measure the small spot sizes required for future generations of high-energy e+e- linear colliders. The FFTB takes a 47 GeVc-1, 1 kW electron beam at the end of the Stanford Linear Accelerator Center linear accelerator and transports it to the FFTB beam dump. A radiation protection system was designed and installed for the FFTB with the primary goal that the integrated dose equivalent outside the shielding resulting from beam loss would not exceed 10 mSv y-1. This system is comprised of shielding, a beam containment system and a personnel protection system. This paper presents various aspects of radiation safety at Stanford Linear Accelerator Center that were considered in the design of the FFTB radiation protection system. Beam tests were conducted in which the performance of various beam containment devices and the shielding effectiveness were evaluated. Preliminary results from these tests are presented.