Switching Multiple Sclerosis Patients with Breakthrough Disease to Second-Line Therapy

BACKGROUND: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown. METHODS: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch. RESULTS: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p =  0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004). CONCLUSIONS: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies

Demographic uncertainty and disease risk influence climate-informed management of an alpine species

Climate change is expected to disproportionately affect species occupying ecosystems with relatively hard boundaries, such as alpine ecosystems. Wildlife managers must identify actions to conserve and manage alpine species into the future, while considering other issues and uncertainties. Climate change and respiratory pathogens associated with widespread pneumonia epidemics in bighorn sheep (Ovis canadensis) may negatively affect mountain goat (Oreamnos americanus) populations. Mountain goat demographic and population data are challenging to collect and sparsely available, making population management decisions difficult. We developed predictive models incorporating these uncertainties and analyzed results within a structured decision making framework to make management recommendations and identify priority information needs in Montana, USA. We built resource selection models to forecast occupied mountain goat habitat and account for uncertainty in effects of climate change, and a Leslie matrix projection model to predict population trends while accounting for uncertainty in population demographics and dynamics. We predicted disease risks while accounting for uncertainty about presence of pneumonia pathogens and risk tolerance for mixing populations during translocations. Our analysis predicted that new introductions would produce more area occupied by mountain goats at mid-century, regardless of the effects of climate change. Population augmentations, carnivore management, and harvest management may improve population trends, although this was associated with considerable uncertainty. Tolerance for risk of disease transmission affected optimal management choices because translocations are expected to increase disease risks for mountain goats and sympatric bighorn sheep. Expected value of information analyses revealed that reducing uncertainty related to population dynamics would affect the optimal choice among management strategies to improve mountain goat trends. Reducing uncertainty related to the presence of pneumonia-associated pathogens and consequences of mixing microbial communities should reduce disease risks if translocations are included in future management strategies. We recommend managers determine tolerance for disease risks associated with translocations that they and constituents are willing to accept. From this, an adaptive management program can be constructed wherein a portfolio of management actions are chosen based on risk tolerance in each population range, combined with the amount that uncertainty is reduced when paired with monitoring, to ultimately improve achievement of fundamental objectives

Energy extraction from the biologic battery in the inner ear

Endocochlear potential (EP) is a battery-like electrochemical gradient found in and actively maintained by the inner ear [superscript 1, 2]. Here we demonstrate that the mammalian EP can be used as a power source for electronic devices. We achieved this by designing an anatomically sized, ultra-low quiescent-power energy harvester chip integrated with a wireless sensor capable of monitoring the EP itself. Although other forms of in vivo energy harvesting have been described in lower organisms [superscript 3, 4, 5], and thermoelectric [superscript 6], piezoelectric [superscript 7] and biofuel [superscript 8, 9] devices are promising for mammalian applications, there have been few, if any, in vivo demonstrations in the vicinity of the ear, eye and brain. In this work, the chip extracted a minimum of 1.12 nW from the EP of a guinea pig for up to 5 h, enabling a 2.4 GHz radio to transmit measurement of the EP every 40–360 s. With future optimization of electrode design, we envision using the biologic battery in the inner ear to power chemical and molecular sensors, or drug-delivery actuators for diagnosis and therapy of hearing loss and other disorders.Focus Center Research Program. Focus Center for Circuit & System Solutions. Semiconductor Research Corporation. Interconnect Focus CenterNational Institutes of Health (U.S.) (Grant K08 DC010419)National Institutes of Health (U.S.) (Grant T32 DC00038)Bertarelli Foundatio

Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment

Obesity-Related Oxidative Stress: the Impact of Physical Activity and Diet Manipulation

Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Importance: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. Objectives To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting, and Participants: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Main Outcomes and Measures: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Results: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. Conclusions and Relevance: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score