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BackgroundIncorporating cognitive testing into routine clinical practice is a challenge in multiple sclerosis (MS), given the wide spectrum of both cognitive and physical impairments people can have and the time that testing requires. Shortened paper and verbal assessments predominate but still are not used routinely. Computer-based tests are becoming more widespread; however, changes in how a paper test is implemented can impact what exactly is being assessed in an individual. The Symbol Digit Modalities Test (SDMT) is one validated test that forms part of the cognitive batteries used in MS and has some computer-based versions. We developed a tablet-based SDMT variant that has the potential to be ultimately deployed to patients’ own devices. ObjectiveThis paper aims to develop, validate, and deploy a computer-based SDMT variant, the Cognition Reaction (CoRe) test, that can reliably replicate the characteristics of the paper-based SDMT. MethodsWe carried out analysis using Pearson and intraclass correlations, as well as a Bland-Altman comparison, to examine consistency between the SDMT and CoRe tests and for test-retest reliability. The SDMT and CoRe tests were evaluated for sensitivity to disability levels and age. A novel metric in CoRe was found: question answering velocity could be calculated. This was evaluated in relation to disability levels and age for people with MS and compared with a group of healthy control volunteers. ResultsSDMT and CoRe test scores were highly correlated and consistent with 1-month retest values. Lower scores were seen in patients with higher age and some effect was seen with increasing disability. There was no learning effect evident. Question answering velocity demonstrated a small increase in speed over the 90-second duration of the test in people with MS and healthy controls. ConclusionsThis study validates a computer-based alternative to the SDMT that can be used in clinics and beyond. It enables accurate recording of elements of cognition relevant in MS but offers additional metrics that may offer further value to clinicians and people with MS.

Summary: The division of amyloid protein fibrils is required for the propagation of the amyloid state and is an important contributor to their stability, pathogenicity, and normal function. Here, we combine kinetic nanoscale imaging experiments with analysis of a mathematical model to resolve and compare the division stability of amyloid fibrils. Our theoretical results show that the division of any type of filament results in self-similar length distributions distinct to each fibril type and the conditions applied. By applying these theoretical results to profile the dynamical stability toward breakage for four different amyloid types, we reveal particular differences in the division properties of disease-related amyloid formed from α-synuclein when compared with non-disease associated model amyloid, the former showing lowered intrinsic stability toward breakage and increased likelihood of shedding smaller particles. Our results enable the comparison of protein filaments' intrinsic dynamic stabilities, which are key to unraveling their toxic and infectious potentials.

BackgroundViolence is a public health problem. Hospital-based violence intervention programs such as the San Francisco Wraparound Project (WAP) have been shown to reduce future violent injury. The WAP model employs culturally competent case managers who recruit and enroll violently injured patients as clients. Client acceptance of the WAP intervention is variable, and program success depends on streamlined, timely communication and access to resources. High rates of smartphone usage in populations who are at risk for violent reinjury create an opportunity to design a tailored information and communications technology (ICT) tool to support hospital-based violence intervention programs. ObjectiveCurrent evidence shows that ICT tools developed in the health care space may not be successful in engaging vulnerable populations. The goal of this study was to use human-centered design methodology to identify the unique communication needs of the clients and case managers at WAP to design a mobile ICT. MethodsWe conducted 15 semi-structured interviews with users: clients, their friends and families, case managers, and other stakeholders in violence intervention and prevention. We used a human-centered design and general inductive approach to thematic analysis to identify themes in the qualitative data, which were extrapolated to insight statements and then reframed into design opportunities. Wireframes of potential mobile ICT app screens were developed to depict these opportunities. ResultsThematic analysis revealed four main insights that were characterized by the opposing needs of our users. (1) A successful relationship is both professional and personal. Clients need this around the clock, but case managers can only support this while on the clock. (2) Communications need to feel personal, but they do not always need to be personalized. (3) Healing is a journey of skill development and lifestyle changes that must be acknowledged, monitored, and rewarded. (4) Social networks need to provide peer support for healing rather than peer pressure to propagate violence. These insights resulted in the following associated design opportunities: (1) Maximize personal connection while controlling access, (2) allow case managers to personalize automated client interactions, (3) hold clients accountable to progress and reward achievements, and (4) build a connected, yet confidential community. ConclusionsHuman-centered design enabled us to identify unique insights and design opportunities that may inform the design of a novel and tailored mobile ICT tool for the WAP community.

Technological innovation is transforming traditional clinical practice, enabling people with multiple sclerosis (pwMS) to contribute health care outcome data remotely between clinic visits. In both relapsing and progressive forms of multiple sclerosis (MS), patients may experience variable disability accrual and symptoms throughout their disease course. The potential impact on the quality of life (QoL) in pwMS and their families and carers is profound. The introduction of treatment targets, such as NEDA (no evidence of disease activity) and NEPAD (no evidence of progression or active disease), that guide clinical decision-making, highlight the importance of utilizing sensitive instruments to measure and track disease activity and progression. However, the gold standard neurological disability tool—expanded disability severity scale (EDSS)—has universally recognized limitations. With strides made in our understanding of MS pathophysiology and DMT responsiveness, maintaining the status quo of measuring disability progression is no longer the recommended option. Outside the clinical trial setting, a comprehensive monitoring system has not been robustly established for pwMS. A 21st-century approach is required to integrate clinical, paraclinical, and patient-reported outcome (PRO) data from electronic health records, local databases, and patient registries. Patient and public involvement (PPI) is critical in the design and implementation of this workflow. To take full advantage of the potential of digital technology in the monitoring and care and QoL of pwMS will require iterative feedback between pwMS, health care professionals (HCPs), scientists, and digital experts.

Influenza is a contagious virus affecting both one's health and economic productivity. This study evaluates uses a survey of 2168 individuals across the U.S. Ordered logit regressions are used to model risk perception and generalized ordered logit regressions are used to model risk mitigation travel-related decisions. Models are estimated for three influenza outbreak scenarios, specifically an individual's travel-related: 1) risk perceptions, 2) risk mitigation decisions when infected and the individual wants to prevent spreading it, and may want treatment, and 3) risk mitigation decisions when not infected and the individual wants to reduce exposure. Risk perception results show that a recent personal experience with influenza-like symptoms and being female significantly increased risk perception at mandatory and medical trip locations. Risk mitigation model results show that males are less likely to alter their travel patterns in response to the possible spreading of the virus or increasing exposure. Knowing the difference between influenza and the stomach flu is more influential in reducing travel than a recent influenza experience in one's household. Individuals proactive with their health (i.e., receive the vaccine, have health insurance) are also proactive in seeking medical attention and reducing influenza spread. Lastly, aligned with the Protection Motivation Theory, individuals reduce travel to locations in which they perceived medium or high risk. However, increased risk perceived at one's work location did not significantly reduce travel. The findings provide insight into the risk perception and mitigation behavior of the American public during the COVID-19 pandemic and after restrictions are lifted.

Severe invasive infections such as brain abscess in a child should prompt an immune evaluation. Specific granule deficiency (SGD) is a rare morphologic neutrophil granular defect characterized by reduced granules within neutrophils, absence of granule proteins, and bilobed nuclei. Patients are susceptible to invasive bacterial infections and Candida infections. Mutations in CCAT/enhancer binding protein epsilon (C/EBP-ε) are the most commonly described cause of SGD. The dihydrorhodamine assay is a quantitative and qualitative functional test that determines the oxidative burst and killing potential of neutrophils. Herein, we describe two brothers with specific granule deficiency. The index patient had a history of cellulitis twice in the first year of life and then presented at 13 months age with fever, leukocytosis, and right sided weakness. A large space occupying brain abscess was diagnosed. He underwent surgical drainage and cultures yielded Staphylococcus aureus. This infection prompted his diagnosis. His older brother had also been healthy but too had had several episodes of cellulitis. His brother too was diagnosed with SGD when family genetic screening was performed. Evaluation of the index patient included a peripheral smear that showed absent neutrophil granule presence. Forward and side scatter of whole blood via flow cytometry revealed a loss of granularity of neutrophils. A DHR was performed to rule out functional killing defects. After stimulation with PMA, neutrophils from the index patient displayed three distinct patterns, two with abnormal oxidase production, and two with reduced function. Both patients were ultimately diagnosed with SGD and remain on lifelong anti-bacterial prophylaxis. Diagnosis of SGD relies on establishing reduced or absent granularity within neutrophils. Lifelong anti-bacterial and anti-fungal prophylaxis is indicated. Hematopoietic cell transplantation has also been curative.

BackgroundSyndromic surveillance through web or phone-based polling has been used to track the course of infectious diseases worldwide. Our study objective was to describe the characteristics, symptoms, and self-reported testing rates of respondents in three different COVID-19 symptom surveys in Canada.MethodsThis was a cross-sectional study using three distinct Canada-wide web-based surveys, and phone polling in Ontario. All three sources contained self-reported information on COVID-19 symptoms and testing. In addition to describing respondent characteristics, we examined symptom frequency and the testing rate among the symptomatic, as well as rates of symptoms and testing across respondent groups.ResultsWe found that over March- April 2020, 1.6% of respondents experienced a symptom on the day of their survey, 15% of Ontario households had a symptom in the previous week, and 44% of Canada-wide respondents had a symptom in the previous month. Across the three surveys, SARS-CoV-2-testing was reported in 2-9% of symptomatic responses. Women, younger and middle-aged adults (versus older adults) and Indigenous/First nations/Inuit/Métis were more likely to report at least one symptom, and visible minorities were more likely to report the combination of fever with cough or shortness of breath.InterpretationThe low rate of testing among those reporting symptoms suggests significant opportunity to expand testing among community-dwelling residents of Canada. Syndromic surveillance data can supplement public health reports and provide much-needed context to gauge the adequacy of SARS-CoV-2 testing rates.

The good intentions of zoos to introduce enrichment practices that stimulate animals mentally and physically are not always achievable. Changes to the policies and procedures in organisations are difficult to fulfil for a range of reasons frequently investigated in change management literature. The implementation of these changes can be the source of ineffective attempts to generate positive interventions in organisations. In this study, we investigate whether interventions to improve animal management in zoos through enrichment are subject to implementation impediments. Qualitative data gathered from interviews with 23 keepers working with big cats across 12 zoos globally provided valuable insights into the barriers and enablers to the implementation of enrichment. Keepers participated voluntarily and worked in accredited zoos across Australia, New Zealand, Europe, south-east Asia, South Africa, and the United States of America. Thematic analysis of the data revealed five key themes that described some of the challenges zoos and keepers experience when implementing enrichment for big cats, in their words: “let’s just be cautious”, “purely surviving”, “struggle to understand the goal”, “can’t always provide what you should”, and “judge the effectiveness”. These themes provide additional insights into potential areas for improvement, including greater attention to the benefits of enrichment for animal mental health and increased transparency around enrichment objectives in zoos.

We define the partition and n-point functions for a vertex operator algebra on a genus two Riemann surface formed by sewing two tori together. We obtain closed formulas for the genus two partition function for the Heisenberg free bosonic string and for any pair of simple Heisenberg modules. We prove that the partition function is holomorphic in the sewing parameters on a given suitable domain and describe its modular properties for the Heisenberg and lattice vertex operator algebras and a continuous orbifolding of the rank two fermion vertex operator super algebra. We compute the genus two Heisenberg vector n-point function and show that the Virasoro vector one point function satisfies a genus two Ward identity for these theories.

Abstract Objective To examine the feasibility, acceptability, and preliminary effects of Hatha yoga on oxidative stress, motor function, and non-motor symptoms among individuals with Parkinson’s disease (PD). Methods The study has a pilot randomized controlled trial design with two arms: an immediate treatment group and a wait-list control group. The yoga-for-PD program was implemented via twice weekly 60-min group-based classes for 12 weeks. Participants were assessed at baseline, 12 weeks, and 6 months post-intervention. Outcome measures included oxidative stress, motor function, physical activity, cognitive function, sleep quality, and quality of life. Data on program acceptability and yoga adherence were collected during the intervention and at 6 months post-intervention. Results Participants (n = 20) had a mean age of 63 years (SD 8, range 49–75) and disease duration 4.8 years (SD 2.9, range 1–13). All participants had mild-moderate disease severity; 18 (90%) were on dopaminergic medications. Seventeen participants (85%) attended at least 75% of the classes and 4 (20%) attended all classes. Most participants (n = 17) reported they “definitely enjoyed” the intervention program. No adverse events were reported. At 12 weeks, there were no major differences in blood oxidative stress markers between the two groups. Motor function based on the Unified Parkinson’s Disease Rating Scale was better in the treatment group, but their scores on sleep and outlook in Parkinson’s Disease Quality of Life (PDQUALIF) Scale and the physical activity levels based on the Longitudinal Aging Study Amsterdam Physical Activity Questionnaire were worse than those of the control group. In within-group comparisons, motor function, cognitive function, and catalase improved but three PDQUALIF domains (social and role function, sleep, and outlook) and physical activity level worsened by the end of the yoga intervention program compared to baseline. The response rate for the 6-month follow-up survey was 74% (n = 14) with six participants (43%) who signed up for a yoga class and four (29%) who practiced it independently. Health problems were the main barrier to yoga practice. Conclusion Yoga is feasible and acceptable and may serve as a complementary method for improving motor function in PD. Further research using a larger sample size is needed to determine its impact on oxidative stress and non-motor symptoms. Trial registration ClinicalTrials.gov Registration Number: NCT02509610031.

Abstract Background Electroconvulsive therapy (ECT) is one of the most controversial treatments in psychiatry. This controversy and diverse and often strongly held opinions can make decision making processes around ECT more complex. Method This consumer-led project explored the experiences of individuals who had received ECT in terms of the information they received, their experience of ECT and suggestions for ways that decision making processes and experiences of ECT can be improved. Interviews were conducted by consumer researchers who had also received ECT and transcripts were analysed using constant comparative techniques. Results Seventeen individuals participated. Four overarching categories were identified from participant interviews: Information matters; Preparation and decisions before ECT; Experience of ECT; and Suggestions for improvement. Most participants suggested that more information was required and that this information should be made available more regularly to support decision making. Additional suggestions included greater involvement of family and friends (including having a family member or friend present during the ECT procedure), opportunities to gain information from individuals who had received ECT and more support for managing memory and cognitive side effects. Conclusion This study provides valuable consumer-provided insights and recommendations for psychiatrists and mental health clinicians working within ECT clinics and with consumers considering or preparing for ECT.

Mathematical modeling is increasingly accepted as a tool that can inform disease control policy in the face of emerging infectious diseases, such as the 2014–2015 West African Ebola epidemic, but little is known about the relative performance of alternate forecasting approaches. The RAPIDD Ebola Forecasting Challenge (REFC) tested the ability of eight mathematical models to generate useful forecasts in the face of simulated Ebola outbreaks. We used a simple, phenomenological single-equation model (the “IDEA” model), which relies only on case counts, in the REFC. Model fits were performed using a maximum likelihood approach. We found that the model performed reasonably well relative to other more complex approaches, with performance metrics ranked on average 4th or 5th among participating models. IDEA appeared better suited to long- than short-term forecasts, and could be fit using nothing but reported case counts. Several limitations were identified, including difficulty in identifying epidemic peak (even retrospectively), unrealistically precise confidence intervals, and difficulty interpolating daily case counts when using a model scaled to epidemic generation time. More realistic confidence intervals were generated when case counts were assumed to follow a negative binomial, rather than Poisson, distribution. Nonetheless, IDEA represents a simple phenomenological model, easily implemented in widely available software packages that could be used by frontline public health personnel to generate forecasts with accuracy that approximates that which is achieved using more complex methodologies. Keywords: Ebola virus disease, Mathematical modeling, Forecasting

Mathematical models are often regarded as recent innovations in the description and analysis of infectious disease outbreaks and epidemics, but simple mathematical expressions have been in use for projection of epidemic trajectories for more than a century. We recently introduced a single equation model (the incidence decay with exponential adjustment, or IDEA model) that can be used for short-term epidemiological forecasting. In the mid-19th century, Dr. William Farr made the observation that epidemic events rise and fall in a roughly symmetrical pattern that can be approximated by a bell-shaped curve. He noticed that this time-evolution behavior could be captured by a single mathematical formula (“Farr's law”) that could be used for epidemic forecasting. We show here that the IDEA model follows Farr's law, and show that for intuitive assumptions, Farr's Law can be derived from the IDEA model. Moreover, we show that both mathematical approaches, Farr's Law and the IDEA model, resemble solutions of a susceptible-infectious-removed (SIR) compartmental differential-equation model in an asymptotic limit, where the changes of disease transmission respond to control measures, and not only to the depletion of susceptible individuals. This suggests that the concept of the reproduction number (R0) was implicitly captured in Farr's (pre-microbial era) work, and also suggests that control of epidemics, whether via behavior change or intervention, is as integral to the natural history of epidemics as is the dynamics of disease transmission.

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.

Abstract Background In Canada, active tuberculosis (TB) disease rates remain disproportionately higher among the Indigenous population, especially among the Inuit in the north. We used mathematical modeling to evaluate how interventions might enhance existing TB control efforts in a region of Nunavut. Methods We developed a stochastic, agent-based model of TB transmission that captured the unique household and community structure. Evaluated interventions included: (i) rapid treatment of active cases; (ii) rapid contact tracing; (iii) expanded screening programs for latent TB infection (LTBI); and (iv) reduced household density. The outcomes of interest were incident TB infections and total diagnosed active TB disease over a 10- year time period. Results Model-projected incidence in the absence of additional interventions was highly variable (range: 33–369 cases) over 10 years. Compared to the ‘no additional intervention’ scenario, reducing the time between onset of active TB disease and initiation of treatment reduced both the number of new TB infections (47% reduction, relative risk of TB = 0.53) and diagnoses of active TB disease (19% reduction, relative risk of TB = 0.81). Expanding general population screening was also projected to reduce the burden of TB, although these findings were sensitive to assumptions around the relative amount of transmission occurring outside of households. Other potential interventions examined in the model (school-based screening, rapid contact tracing, and reduced household density) were found to have limited effectiveness. Conclusions In a region of northern Canada experiencing a significant TB burden, more rapid treatment initiation in active TB cases was the most impactful intervention evaluated. Mathematical modeling can provide guidance for allocation of limited resources in a way that minimizes disease transmission and protects population health.

Prions are protein-based infectious entities associated with fatal brain diseases in animals, but also modify a range of host-cell phenotypes in the budding yeast, Saccharomyces cerevisiae. Many questions remain about the evolution and biology of prions. Although several functionally distinct prion-forming proteins exist in S. cerevisiae, [HET-s] of Podospora anserina is the only other known fungal prion. Here we investigated prion-like, protein-based epigenetic transmission in the fission yeast Schizosaccharomyces pombe. We show that S. pombe cells can support the formation and maintenance of the prion form of the S. cerevisiae Sup35 translation factor [PSI+], and that the formation and propagation of these Sup35 aggregates is inhibited by guanidine hydrochloride, indicating commonalities in prion propagation machineries in these evolutionary diverged yeasts. A proteome-wide screen identified the Ctr4 copper transporter subunit as a putative prion with a predicted prion-like domain. Overexpression of the ctr4 gene resulted in large Ctr4 protein aggregates that were both detergent and proteinase-K resistant. Cells carrying such [CTR+] aggregates showed increased sensitivity to oxidative stress, and this phenotype could be transmitted to aggregate-free [ctr–] cells by transformation with [CTR+] cell extracts. Moreover, this [CTR+] phenotype was inherited in a non-Mendelian manner following mating with naïve [ctr–] cells, but intriguingly the [CTR+] phenotype was not eliminated by guanidine-hydrochloride treatment. Thus, Ctr4 exhibits multiple features diagnostic of other fungal prions and is the first example of a prion in fission yeast. These findings suggest that transmissible protein-based determinants of traits may be more widespread among fungi.

Background: Proprioceptive impairment is a common feature of Parkinson's disease (PD). Proprioceptive function is only partially restored with anti-parkinsonian medication or deep brain stimulation. Behavioral exercises focusing on somatosensation have been promoted to overcome this therapeutic gap. However, conclusive evidence on the effectiveness of such somatosensory-focused behavioral training for improving somatosensory function is lacking. Moreover, it is unclear, if such training has any effect on motor performance in PD.Objective: To investigate, whether proprioception improves with a somatosensory focused, robot-aided training in people with PD (PWPs), and whether enhanced proprioception translates to improved motor performance.Method: Thirteen PWPs of mild-moderate clinical severity were assessed and trained ON medication using a robotic wrist exoskeleton. Thirteen healthy elderly participants served as controls. Training involved making increasingly accurate, continuous, precise small amplitude wrist flexion/extension movements. Wrist position sense acuity, as a marker of proprioception function, and spatial error during wrist pointing, as a marker of untrained motor performance, were recorded twice before and once after training. Functional hand writing kinematics exhibited during training were evaluated in the PD group for determining training-induced changes.Results: Training improved position sense acuity in all PWPs (mean change: 28%; p < 0.001) and healthy controls (mean change: 23%; p < 0.01). Second, 10/13 PD participants and 10/13 healthy control participants had reduced spatial movement error in the untrained wrist pointing task after training. Third, spatial error for the functional handwriting tasks (line tracing and tracking) did not improve with training in the PD group.Conclusion: Proprioceptive function in mild to moderate PD is trainable and improves with a somatosensory-focused motor training. Learning showed a local transfer within the trained joint degree-of-freedom as improved spatial accuracy in an unpracticed motor task. No learning gains were observed for the untrained functional handwriting task, indicating that training may be specific to the trained joint degree-of-freedom.

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.

Thomas S MacKinnon,1 Norbert F Banhidy,1 Daniel R Tuite21School of Medicine, Imperial College London, London, 2Faculty of Medicine, Brighton and Sussex Medical School, Brighton, UKWe read with great interest the article by Patel et al1 discussing the changing perspectives towards complementary and alternative medicine (CAM), and an impetus for additional physician knowledge of the strengths and drawbacks of CAM. These findings are indeed relevant in the UK, with an estimated 41.1% one-year prevalence of CAM use, responsible for an annual out-of-pocket expenditure of £1.6 billion.2 We agree that improved training and education in medical school and residencies – which can be thought of as a “bottom-up” approach – are fundamental in preparing the health care system for improved integration of CAM. However, we also suggest that “top-down” changes are required to optimize patient care.Authors' reply Sejal J Patel,1 Kathi J Kemper,2 Joseph P Kitzmiller31College of Public Health, The Ohio State University, 2Center for Integrative Health and Wellness, The Ohio State Wexner University Medical Center, 3Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USAWe agree the letter is worthy of publication but have a little to add: a top-down approach (as suggested and described by the authors of the letter) certainly complements the bottom-up approach (described in our article).1View the original paper by Patel et al.

Immunisation against rotavirus infection was introduced into Ireland in December 2016. We report on the viruses causing gastroenteritis before (2015–2016) and after (2017–2019) implementation of the Rotarix vaccine, as well as changes in the diversity of circulating rotavirus genotypes. Samples from patients aged ≤ 5 years (n = 11,800) were received at the National Virus Reference Laboratory, Dublin, and tested by real-time RT-PCR for rotavirus, Rotarix, norovirus, sapovirus, astrovirus, and enteric adenovirus. Rotavirus genotyping was performed either by multiplex or hemi-nested RT-PCR, and a subset was characterised by sequence analysis. Rotavirus detection decreased by 91% in children aged 0–12 months between 2015/16 and 2018/19. Rotarix was detected in 10% of those eligible for the vaccine and was not found in those aged >7 months. Rotavirus typically peaks in March–May, but following vaccination, the seasonality became less defined. In 2015–16, G1P[8] was the most common genotype circulating; however, in 2019 G2P[4] was detected more often. Following the introduction of Rotarix, a reduction in numbers of rotavirus infections occurred, coinciding with an increase in genotype diversity, along with the first recorded detection of an equine-like G3 strain in Ireland.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a condition that often evolves into Parkinson's disease (PD). Therefore, by monitoring iRBD it is possible to track the neurodegeneration of individuals who may progress to PD. Here we aimed at piloting the characterization of brain tissue properties in mid-brain subcortical regions of 10 healthy subjects, 8 iRBD, and 9 early-diagnosed PD. We used a battery of magnetic resonance imaging (MRI) contrasts at 3 T, including adiabatic and non-adiabatic rotating frame techniques developed by our group, along with diffusion tensor imaging (DTI) and resting-state fMRI. Adiabatic T1ρ and T2ρ, and non-adiabatic RAFF4 (Relaxation Along a Fictitious Field in the rotating frame of rank 4) were found to have lower coefficient of variations and higher sensitivity to detect group differences as compared to DTI parameters such as fractional anisotropy and mean diffusivity. Significantly longer T1ρ were observed in the amygdala of PD subjects vs. controls, along with a trend of lower functional connectivity as measured by regional homogeneity, thereby supporting the notion that amygdalar dysfunction occurs in PD. Significant abnormalities in reward networks occurred in iRBD subjects, who manifested lower network strength of the accumbens. In agreement with previous studies, significantly longer T1ρ occurred in the substantia nigra compacta of PD vs. controls, indicative of neuronal degeneration, while regional homogeneity was lower in the substantia nigra reticulata. Finally, other trend-level findings were observed, i.e., lower RAFF4 and T2ρ in the midbrain of iRBD subjects vs. controls, possibly indicating changes in non-motor features as opposed to motor function in the iRBD group. We conclude that rotating frame relaxation methods along with functional connectivity measures are valuable to characterize iRBD and PD subjects, and with proper validation in larger cohorts may provide pathological signatures of iRBD and PD.

Transmissible amyloid particles called prions are associated with infectious prion diseases in mammals and inherited phenotypes in yeast. All amyloid aggregates can give rise to potentially infectious seeds that accelerate their growth. Why some amyloid seeds are highly infectious prion particles while others are less infectious or even inert, is currently not understood. To address this question, we analyzed the suprastructure and dimensions of synthetic amyloid fibrils assembled from the yeast (Saccharomyces cerevisiae) prion protein Sup35NM. We then quantified the ability of these particles to induce the [PSI+] prion phenotype in cells. Our results show a striking relationship between the length distribution of the amyloid fibrils and their ability to induce the heritable [PSI+] prion phenotype. Using a simple particle size threshold model to describe transfection activity, we explain how dimensions of amyloid fibrils are able to modulate their infectious potential as prions.

The Metropolitan Museum of Art, New York Curated by Helen Molesworth, Dieter Roelstraete, and Ian Alteveer Reviewed by Diana Tuite

Mammalian and fungal prions arise de novo; however, the mechanism is poorly understood in molecular terms. One strong possibility is that oxidative damage to the non-prion form of a protein may be an important trigger influencing the formation of its heritable prion conformation. We have examined the oxidative stress-induced formation of the yeast [PSI+] prion, which is the altered conformation of the Sup35 translation termination factor. We used tandem affinity purification (TAP) and mass spectrometry to identify the proteins which associate with Sup35 in a tsa1 tsa2 antioxidant mutant to address the mechanism by which Sup35 forms the [PSI+] prion during oxidative stress conditions. This analysis identified several components of the cortical actin cytoskeleton including the Abp1 actin nucleation promoting factor, and we show that deletion of the ABP1 gene abrogates oxidant-induced [PSI+] prion formation. The frequency of spontaneous [PSI+] prion formation can be increased by overexpression of Sup35 since the excess Sup35 increases the probability of forming prion seeds. In contrast to oxidant-induced [PSI+] prion formation, overexpression-induced [PSI+] prion formation was only modestly affected in an abp1 mutant. Furthermore, treating yeast cells with latrunculin A to disrupt the formation of actin cables and patches abrogated oxidant-induced, but not overexpression-induced [PSI+] prion formation, suggesting a mechanistic difference in prion formation. [PIN+], the prion form of Rnq1, localizes to the IPOD (insoluble protein deposit) and is thought to influence the aggregation of other proteins. We show Sup35 becomes oxidized and aggregates during oxidative stress conditions, but does not co-localize with Rnq1 in an abp1 mutant which may account for the reduced frequency of [PSI+] prion formation.

Patients commonly present to the emergency department with acute respiratory distress; however, the differentials are broad and at times difficult to distinguish. We describe a case of severe community-acquired pneumonia (CAP) secondary to invasive Streptococcus pneumoniae. The patient was intubated within 3 h of presentation and suffered multiorgan failure within 72 h of intensive care unit (ICU) admission. This case is a stark illustration of how the most common bacteria associated with CAP can be fatal and highlights the associated markers of severity. It also outlines other potential complications including a very rare phenomenon of cardiomyopathy with myocarditis associated with S. pneumoniae bacteraemia.

Life requires the maintenance of molecular function in the face of stochastic processes that tend to adversely affect macromolecular integrity. This is particularly relevant during ageing, as many cellular functions decline with age, including growth, mitochondrial function and energy metabolism. Protein synthesis must deliver functional proteins at all times, implying that the effects of protein synthesis errors like amino acid misincorporation and stop-codon read-through must be minimized during ageing. Here we show that loss of translational accuracy accelerates the loss of viability in stationary phase yeast. Since reduced translational accuracy also reduces the folding competence of at least some proteins, we hypothesize that negative interactions between translational errors and age-related protein damage together overwhelm the cellular chaperone network. We further show that multiple cellular signalling networks control basal error rates in yeast cells, including a ROS signal controlled by mitochondrial activity, and the Ras pathway. Together, our findings indicate that signalling pathways regulating growth, protein homeostasis and energy metabolism may jointly safeguard accurate protein synthesis during healthy ageing.

We report on results of a microcosm experiment to study the interactive effects of elevated CO2, high organic and inorganic nutrient loading, and high irradiance on phytoplankton and bacterioplankton from the Mediterranean coastal ecosystem of the Alboran Sea. This experiment was part of the Group for Aquatic Productivity 9th international workshop and was conducted by Working Group 1 (WG1: Phytoplankton of coastal waters, www.gap9.uma.es). Over a 7 d period, we measured the variation in physical and chemical variables and the characteristics of phytoplankton and bacterioplankton in microcosms incubated under 8 treatments, representing full factorial combinations of 2 levels each of CO2 supply, nutrient concentrations and solar radiation exposure. For each treatment combination, we incubated triplicate microcosms consisting of 20 l polyethylene bags which were transparent to ultraviolet radiation. Sustained growth of phytoplankton biomass (chl a) occurred in all treatments. The absence of mesozooplankton in the microcosms resulted in a trophic cascade. Picophytoplankton were initially stimulated but then decreased, apparently due to microzooplankton grazing, and were largely replaced by diatoms. Bacteria were also initially stimulated and then decreased, but eventually recovered. Responses were modified markedly by nutrient enrichment and light availability, with moderate effects of elevated CO2. Relative to ambient CO2, elevated CO2 resulted in higher chl a under low irradiance, but lower chl a under high irradiance.

Probe vehicles with smart phones or other advanced technologies are attractive options for collecting real-time traffic data. In this paper, a method is proposed to estimate the minimum number of equipped vehicles needed to completely cover the network within a specified updating period considering time dependent link travel times. The method uses a traverse indicator, which is a function of a travel time factor, coverage factor, number of times a link has been traversed, and link travel time. The approach is applied to two network structures (radial and grid) to test the sensitivity of the results to network structure, number of origins, travel time and coverage factors, and the updating period. Assuming travel time and coverage factors equal to 0.1 and 0.9, respectively, in the grid network and both equal to 0.5 in the radial network produce minimum fleet sizes. Increasing numbers of origins and updating periods generally yield lower fleet sizes.