Prevalence and Treatments of Movement Disorders in Prion Diseases: A Longitudinal Cohort Study

BACKGROUND: Prion diseases cause a range of movement disorders involving the cortical, extrapyramidal, and cerebellar systems, and yet there are no large systematic studies of their prevalence, features, associations, and responses to commonly used treatments. OBJECTIVES: We sought to describe the natural history and pharmacological management of movement disorders in prion diseases. METHODS: We studied the serial examination findings, investigation results, and symptomatic treatment recorded for 700 patients with prion diseases and 51 mimics who had been enrolled onto the prospective longitudinal National Prion Monitoring Cohort study between 2008 and 2020. We performed an analysis to identify whether there were patterns of movement disorders associated with disease aetiology, PRNP codon 129 polymorphism, disease severity rating scales, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings. RESULTS: Gait disturbances, myoclonus, and increased tone are the most frequently observed movement disorders in patients with prion diseases. The typical pattern of early motor dysfunction involves gait disturbance, limb ataxia, impaired smooth pursuit, myoclonus, tremor, and increased limb tone. Disturbances of gait, increased tone, and myoclonus become more prevalent and severe as the disease progresses. Chorea, alien limb phenomenon, and nystagmus were the least frequently observed movement disorders, with these symptoms showing spontaneous resolution in approximately half of symptomatic patients. Disease severity and PRNP codon 129 polymorphism were associated with different movement disorder phenotypes. Antiepileptics and benzodiazepines were found to be effective in treating myoclonus. CONCLUSIONS: We describe the prevalence, severity, evolution, treatment, and associated features of movement disorders in prion diseases based on a prospective cohort study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with Schistosomiasis Control Initiative-assisted programmes

The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI)

A systematic review of the burden of, access to services for and perceptions of patients with overweight and obesity, in humanitarian crisis settings

Introduction: Excess body weight causes 4 million deaths annually across the world. The number of people affected by humanitarian crises stands at a record high level with 1 in 95 people being forcibly displaced. These epidemics overlap. Addressing obesity is a post-acute phase activity in non-communicable disease management in humanitarian settings. Information is needed to inform guidelines and timing of interventions. The objective of this review was to explore the prevalence of overweight and obesity in populations directly affected by humanitarian crises; the cascade of care in these populations and perceptions of patients with overweight and obesity. Methods: Literature searches were carried out in five databases. Grey literature was identified. The population of interest was non-pregnant, civilian adults who had experience of humanitarian crises (armed conflict, complex emergencies and natural disasters). All study types published from January 1st, 2011, were included. Screening, data extraction and quality appraisal were carried out in duplicate. A narrative synthesis is presented. Results: Fifty-six reports from forty-five studies were included. Prevalence estimates varied widely across the studies and by subgroups. Estimates of overweight and obesity combined ranged from 6.4% to 82.8%. Studies were heterogenous. Global distribution was skewed. Increasing adiposity was seen over time, in older adults and in women. Only six studies were at low risk of bias. Body mass index was the predominant measure used. There were no studies reporting cascade of care. No qualitative studies were identified. Conclusion: Overweight and obesity varied in crisis affected populations but were rarely absent. Improved reporting of existing data could provide more accurate estimates. Worsening obesity may be prevented by acting earlier in long-term crises and targeting risk groups. The use of waist circumference would provide useful additional information. Gaps remain in understanding the existing cascade of care. Cultural norms around diet and ideal body size vary

AX-PET: A novel PET concept with G-APD readout

Abstract The AX-PET collaboration has developed a novel concept for high resolution PET imaging to overcome some of the performance limitations of classical PET cameras, in particular the compromise between spatial resolution and sensitivity introduced by the parallax error. The detector consists of an arrangement of long LYSO scintillating crystals axially oriented around the field of view together with arrays of wave length shifter strips orthogonal to the crystals. This matrix allows a precise 3D measurement of the photon interaction point. This is valid both for photoelectric absorption at 511 keV and for Compton scattering down to deposited energies of about 100 keV. Crystals and WLS strips are individually read out using Geiger-mode Avalanche Photo Diodes (G-APDs). The sensitivity of such a detector can be adjusted by changing the number of layers and the resolution is defined by the crystal and strip dimensions. Two AX-PET modules were built and fully characterized in dedicated test set-ups at CERN, with point-like 22 Na sources. Their performance in terms of energy ( R energy ≈ 11.8 % (FWMH) at 511 keV) and spatial resolution was assessed ( σ axial ≈ 0.65 mm ), both individually and for the two modules in coincidence. Test campaigns at ETH Zurich and at the company AAA allowed the tomographic reconstructions of more complex phantoms validating the 3D reconstruction algorithms. The concept of the AX-PET modules will be presented together with some characterization results. We describe a count rate model which allows to optimize the planing of the tomographic scans

Transmission of Schistosoma japonicum in Marshland and Hilly Regions of China: Parasite Population Genetic and Sibship Structure

The transmission dynamics of Schistosoma japonicum remain poorly understood, as over forty species of mammals are suspected of serving as reservoir hosts. However, knowledge of the population genetic structure and of the full-sibship structuring of parasites at two larval stages will be useful in defining and tracking the transmission pattern between intermediate and definitive hosts. S. japonicum larvae were therefore collected in three marshland and three hilly villages in Anhui Province of China across three time points: April and September-October 2006, and April 2007, and then genotyped with six microsatellite markers. Results from the population genetic and sibling relationship analyses of the parasites across two larval stages demonstrated that, within the marshland, parasites from cattle showed higher genetic diversity than from other species; whereas within the hilly region, parasites from dogs and humans displayed higher genetic diversity than those from rodents. Both the extent of gene flow and the estimated proportion of full-sib relationships of parasites between two larval stages indicated that the cercariae identified within intermediate hosts in the marshlands mostly came from cattle, whereas in the hilly areas, they were varied between villages, coming primarily from rodents, dogs or humans. Such results suggest a different transmission process within the hilly region from within the marshlands. Moreover, this is the first time that the sibling relationship analysis was applied to the transmission dynamics for S. japonicum

Mother-offspring recognition via contact calls in cattle, Bos taurus.

Individual recognition in gregarious species is fundamental in order to avoid misdirected parental investment. In ungulates, two very different parental care strategies have been identified: ‘hider’ offspring usually lie concealed in vegetation whereas offspring of ‘follower’ species remain with their mothers while they forage. These two strategies have been suggested to impact on mother-offspring vocal recognition, with unidirectional recognition of the mother by offspring occurring in hiders and bidirectional recognition in followers. In domestic cattle, Bos taurus, a facultative hider species, vocal communication and recognition have not been studied in detail under free-ranging conditions, where cows and calves can graze freely and where hiding behaviour can occur. We hypothesized that, as a hider species, cattle under these circumstances would display unidirectional vocal recognition. To test this hypothesis, we conducted playback experiments using mother-offspring contact calls. We found that cows were more likely to respond, by moving their ears and/or looking, turning or walking towards the loudspeaker, to calls of their own calves than to calls from other calves. Similarly, calves responded more rapidly, and were more likely to move their ears and/or look, turn or walk towards the loudspeaker, and to call back and/or meet their mothers, in response to calls from their own mothers than to calls from other females. Contrary to our predictions, our results suggest that mother-offspring vocal individual recognition is bidirectional in cattle. Additionally, mothers of younger calves tended to respond more strongly to playbacks than mothers of older calves. Therefore, mother responses to calf vocalizations are at least partially influenced by calf age

Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC), and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ("converters"; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (sCJD), iatrogenic (iCJD) and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under two months while two remain asymptomatic after at least three years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies

Human Genome-Wide RNAi Screen for Host Factors That Modulate Intracellular Salmonella Growth

Salmonella enterica is a bacterial pathogen of humans that can proliferate within epithelial cells as well as professional phagocytes of the immune system. While much has been learned about the microbial genes that influence the infectious process through decades of intensive research, relatively little is known about the host factors that affect infection. We performed a genome-wide siRNA screen to identify host genes that Salmonella enterica serovar Typhimurium (S. typhimurium) utilizes to facilitate growth within human epithelial cells. In this screen, with siRNAs targeting every predicted gene in the human genome, we identified 252 new human-host-susceptibility factors (HSFs) for S. typhimurium. We also identified 39 genes whose silencing results in increased intracellular growth of S. typhimurium. The HSFs identified are regulated most centrally by NFκB and associate with each other through an extremely dense network of interactions that center around a group of kinases. Most genes identified were not previously appreciated as playing roles in the intracellular lifecycle of S. enterica. Numerous HSFs identified with interesting characteristics that could play plausible roles in mediating intracellular microbial growth are discussed. Importantly, this study reveals significant overlap between the host network that supports S. typhimurium growth within human epithelial cells and the one that promotes the growth of Mycobacterium tuberculosis within human macrophages. In addition to providing much new information about the molecular mechanisms underlying S. enterica-host cell interplay, all 252 HSFs identified are candidates for new anti-microbial targets for controlling S. enterica infections, and some may provide broad-spectrum anti-microbial activity

Toward an Open-Access Global Database for Mapping, Control, and Surveillance of Neglected Tropical Diseases

There is growing interest in the scientific community, health ministries, and other organizations to control and eventually eliminate neglected tropical diseases (NTDs). Control efforts require reliable maps of NTD distribution estimated from appropriate models and survey data on the number of infected people among those examined at a given location. This kind of data is often available in the literature as part of epidemiological studies. However, an open-access database compiling location-specific survey data does not yet exist. We address this problem through a systematic literature review, along with contacting ministries of health, and research institutions to obtain disease data, including details on diagnostic techniques, demographic characteristics of the surveyed individuals, and geographical coordinates. All data were entered into a database which is freely accessible via the Internet (http://www.gntd.org). In contrast to similar efforts of the Global Atlas of Helminth Infections (GAHI) project, the survey data are not only displayed in form of maps but all information can be browsed, based on different search criteria, and downloaded as Excel files for further analyses. At the beginning of 2011, the database included over 12,000 survey locations for schistosomiasis across Africa, and it is continuously updated to cover other NTDs globally