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Background The majority of persons with Huntington disease (HD) experience mental health symptoms. Patient-reported outcome (PRO) measures are capable of capturing unobservable behaviors and feelings relating to mental health. The current study aimed to test the reliability and responsiveness to self-reported and clinician-rated change over time of Neuro-QoL and PROMIS mental health PROs over the course of a 24-month period. Methods At baseline, 12-months, and 24-months, 362 participants with premanifest or manifest HD completed the Neuro-QoL Depression computer adaptive test (CAT), PROMIS Depression short form (SF), Neuro-QoL Anxiety CAT, PROMIS Anxiety SF, PROMIS Anger CAT and SF, Neuro-QoL Emotional/Behavioral Dyscontrol CAT and SF, Neuro-QoL Positive Affect and Well-Being CAT and SF, and Neuro-QoL Stigma CAT and SF. Participants completed several clinician-administered measures at each time point, as well as several global ratings of change at 12- and 24-months. Reliability (test-retest reliability and measurement error) and responsiveness (using standardized response means and general linear models) were assessed. Results Test-retest reliability and measurement error were excellent for all PROs (all ICC ≥ .90 for test-retest reliability and all SEM percentages ≤ 6.82%). In addition, 12- and 24-month responsiveness were generally supported for the Neuro-QoL and PROMIS mental health PROs; findings relative to clinician-rated anchors of change (e.g., SRMs for the group with declines ranged from .38 to .91 for 24-month change and .09 to .45, with the majority above .25 for 12-month change) were generally more robust than those relative to self-reported anchors of change (e.g., SRMs for the group with declines ranged from .02 to .75, with the majority above .39 for 24-month change and .09 to .45, with the majority above .16 for 12-month change). Conclusions The Neuro-QoL and PROMIS mental health PROs demonstrated strong psychometric reliability, as well as responsiveness to self-reported and clinician-rated change over time in people with HD.

Low spatial frequency (SF) processing has been shown to be impaired in people with schizophrenia, but it is not clear how this varies with clinical state or illness chronicity. We compared schizophrenia patients (SCZ, n = 34), first episode psychosis patients (FEP, n = 22), and healthy controls (CON, n = 35) on a gender/facial discrimination task. Images were either unaltered (broadband spatial frequency, BSF), or had high or low SF information removed (LSF and HSF conditions, respectively). The task was performed at hospital admission and discharge for patients, and at corresponding time points for controls. Groups were matched on visual acuity. At admission, compared to their BSF performance, each group was significantly worse with low SF stimuli, and most impaired with high SF stimuli. The level of impairment at each SF did not depend on group. At discharge, the SCZ group performed more poorly in the LSF condition than the other groups, and showed the greatest degree of performance decline collapsed over HSF and LSF conditions, although the latter finding was not significant when controlling for visual acuity. Performance did not change significantly over time for any group. HSF processing was strongly related to visual acuity at both time points for all groups. We conclude the following: 1) SF processing abilities in schizophrenia are relatively stable across clinical state; 2) face processing abnormalities in SCZ are not secondary to problems processing specific SFs, but are due to other known difficulties constructing visual representations from degraded information; and 3) the relationship between HSF processing and visual acuity, along with known SCZ- and medication-related acuity reductions, and the elimination of a SCZ-related impairment after controlling for visual acuity in this study, all raise the possibility that some prior findings of impaired perception in SCZ may be secondary to acuity reductions.

Objective In an era where digital devices become increasingly available, passive and active capturing of patient data during their everyday life becomes possible. However, it is still unclear to what extent people with chronic diseases are willing to use digital health technology (DHT) to assess study-relevant endpoints. The aim of the present study was therefore to determine such acceptance rates for clinical studies and which type of DHT patients prefer. Methods A survey with 492 people with Parkinson's disease (64 ± 11 years, 41% female) and 75 people with an immune-mediated inflammatory disease (58 ± 15 years, 99% female) was conducted. Results The vast majority of people (93%) were willing to use at least two devices simultaneously during a clinical study. Two-thirds indicated that they would use DHT for ≥6 days following a visit in the context of a study. The appearance of the device turned out to be important as the most popular devices were smartwatches, whereas more complex DHT, clearly recognisable as medical-grade were least popular. The effects of gender, age and disease could be detected, such as, for example, a tendency for men to be willing to use more devices simultaneously than women. Conclusion Overall, our findings suggest a willingness among individuals with Parkinson's disease and immune-mediated inflammatory disease to engage in clinical studies involving DHT. It is also evident that elderly patients can be integrated into these studies provided that the participation demands are aligned with clinical imperatives and the devices are user friendly.

Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.

Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB ( www.innatedb.ca ) has been developed to facilitate systems‐level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity‐relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user‐supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems‐oriented manner. Synopsis The importance of the innate immune response has long been recognized in the front line of defense against invading pathogens. If not tightly regulated, however, an overwhelming immune response can lead to what is sometimes called a cytokine storm. One such out‐of‐control response, sepsis, results in more than 200 000 deaths a year in the United States alone (Angus et al , 2001 ). Over the course of the last decade, significant progress has been made in understanding the innate immune response, including the detailed dissection of some of the critical signaling pathways involved (Lang and Mansell, 2007 ; Matsukawa, 2007 ). Despite these efforts, many questions remain unanswered including how the innate immune system initiates distinct responses toward particular pathogens. It is becoming increasingly clear that the innate immune response does not involve simple linear pathways but rather complex networks of pathways and interactions, positive and negative feedback loops and multifaceted transcriptional responses (Tegner et al , 2006 ; Lee and Kim, 2007 ). To better understand the complexities of the innate immune response and the cross‐talk between its components, complementary systems‐level analyses and more focused follow‐up experimental approaches are now needed. Recently, researchers have started to apply systems biology approaches to the study of the immune system (Gilchrist et al , 2006 ; Tegner et al , 2006 ; Andersen et al , 2008 ) and bioinformatics resources are now emerging to aid these types of analyses. Despite the enormous efforts of the major publicly available interaction and pathway databases to provide as wide‐ranging cover as possible (Salwinski et al , 2004 ; Alfarano et al , 2005 ; Joshi‐Tope et al , 2005 ; Breitkreutz et al , 2007 ; Chatr‐aryamontri et al , 2007 ; Kanehisa et al , 2007 ; Kerrien et al , 2007 ), it was quickly apparent to us that currently available bioinformatics resources provided poor coverage and detail of the molecular interactions and pathways relevant to innate immunity, information that is essential for the systems‐orientated interpretation of large‐scale genomics data. To overcome these problems and to provide a resource that will enable biologists without a computational background to explore their data in a more systems‐oriented manner, we have developed InnateDB. InnateDB ( www.innatedb.ca ) is a publicly available database and analysis platform for the genes, proteins, experimentally verified interactions and pathways involved in the human and murine innate immune responses. One of the primary goals of InnateDB is to provide a manually curated centralized resource for experimentally verified human and mouse protein, gene and RNA molecular interactions involved in the innate immune system. To do this, a dedicated full‐time team of curators has been assembled to review the relevant biomedical literature and to submit detailed annotation on these interactions and pathways to InnateDB through customized submission system software. To date, more than 3500 innate immunity‐relevant interactions, involving around 1000 genes, have been manually curated through the review of approximately 1000 publications. Only interactions with published direct experimental evidence of a physical or biochemical interaction are submitted to InnateDB. The importance of manual curation is clear, as we are often able to double the number of interactions for a given gene or protein compared to the number currently present in the other interaction databases combined. Furthermore, this detailed manual curation permitted us to richly annotate these interactions and to place them in their relevant context. Interaction data in InnateDB are also curated, stored and downloadable in the Proteomics Standards Initiative Molecular Interaction (PSI‐MI) 2.5‐compliant XML format (Hermjakob et al , 2004 ). In addition to the detailed manual curation of the genes, proteins and their interactions and pathways that are specifically known to have a role in the innate immune response, InnateDB also incorporates data on the entire human and mouse interactomes. To do this, annotation on more than 100 000 human and mouse interactions was integrated from several of the major publicly available interaction databases into InnateDB (Figure 1 ). To enable the investigation of genes, proteins and their molecular interactions that are relevant to particular pathways, InnateDB also includes cross‐references of genes not only to innate immunity‐relevant pathways but also to more than 2500 pathways from several of the major publicly available pathway databases (Figure 1 ). Detailed gene and protein annotation has also been extracted from a variety of other data sources. Specific interactions, pathways and genes or proteins of interest can be interactively searched for in InnateDB through the flexible web‐based search interface of the database, providing a knowledge base for the community, whereas the bioinformatics and network visualization tools incorporated into InnateDB elevate the system from database to robust analysis platform. InnateDB allows one to integrate quantitative data (such as differential gene expression) into a molecular interaction network and pathway context, enabling the interrogation of such data in novel and insightful ways. Investigating differentially expressed molecular interaction networks may identify subnetworks or as‐yet unidentified pathways as being significantly involved in the response to a particular stimulus. By incorporating Cytoscape into InnateDB, investigators are able to take a closer look at the interactions involved in these pathways or subnetworks, potentially identifying cross‐talk between key pathways, and highlighting the molecules that are the hubs of these networks. Our Cerebral plugin allows one to further extend this experience, visually interrogating quantitative data across multiple conditions in more biologically intuitive pathway‐like layouts of networks, which are generated using subcellular localization information. Integrated pathway over‐representation analysis can identify those pathways that are significantly associated with differentially regulated genes, highlighting those pathways that are significantly altered in their gene expression. Through such pathway analysis, it is possible to identify common pathways that are involved in the innate immune response to particular infections, and to identify the common central regulators of these pathways as attractive targets for immune modulation. (Figure 4 ). InnateDB, along with other emerging resources for bioinformatics and systems‐level analysis of immunology (Kelley et al , 2005 ; Ortutay and Vihinen, 2006 ; Hijikata et al , 2007 ; Korb et al , 2008 ), will undoubtedly lead to novel and much deeper insights into the innate immune response to particular pathogens. InnateDB is a molecular interaction and pathway database and analysis platform that has been developed to facilitate systems level analyses of the complex networks of pathways and interactions that govern the innate immune response, the wider immune system and the entire mammalian interactome. To date, more than 3,500 innate immunity relevant interactions have been contextually annotated through the review of 1,000 plus publications. Integrated into InnateDB are novel bioinformatics resources including, network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user‐supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, that will enable biologists without a computational background to explore their data in a more systems‐oriented, yet user‐friendly, manner.

Blood brain barrier-crossing molecules targeting transferrin receptor (TfR) and CD98 heavy chain (CD98hc) are widely reported to promote enhanced brain delivery of therapeutics. Here, we provide a comprehensive and unbiased biodistribution characterization of TfR and CD98hc antibody transport vehicles (ATV TfR and ATV CD98hc ) compared to control IgG. Mouse whole-body tissue clearing reveals distinct organ localization for each molecule. In the brain, ATV TfR and ATV CD98hc achieve enhanced exposure and parenchymal distribution even when brain exposures are matched between ATV and control IgG in bulk tissue. Using a combination of cell sorting and single-cell RNAseq, we reveal that control IgG is nearly absent from parenchymal cells and is distributed primarily to brain perivascular and leptomeningeal cells. In contrast, ATV TfR and ATV CD98hc exhibit broad and unique parenchymal cell-type distribution. Finally, we profile in detail brain region-specific biodistribution of ATV TfR in cynomolgus monkey brain and spinal cord. Taken together, this in-depth multiscale characterization will guide platform selection for therapeutic targets of interest. Transferrin receptor (TfR) and CD98hc are increasingly used to enable more effective drug delivery to the central nervous system. Here, the authors reveal comprehensive and distinct brain cellular and whole body biodistribution patterns of TfR- and CD98hc-binding molecules.

Given the recent trend towards establishing very large marine protected areas (MPAs) and the high potential of these to contribute to global conservation targets, we review outcomes of the last decade of marine conservation research in the British Indian Ocean Territory (BIOT), one of the largest MPAs in the world. The BIOT MPA consists of the atolls of the Chagos Archipelago, interspersed with and surrounded by deep oceanic waters. Islands around the atoll rims serve as nesting grounds for sea birds. Extensive and diverse shallow and mesophotic reef habitats provide essential habitat and feeding grounds for all marine life, and the absence of local human impacts may improve recovery after coral bleaching events. Census data have shown recent increases in the abundance of sea turtles, high numbers of nesting seabirds and high fish abundance, at least some of which is linked to the lack of recent harvesting. For example, across the archipelago the annual number of green turtle clutches (Chelonia mydas) is ~ 20,500 and increasing and the number of seabirds is ~ 1 million. Animal tracking studies have shown that some taxa breed and/or forage consistently within the MPA (e.g. some reef fishes, elasmobranchs and seabirds), suggesting the MPA has the potential to provide long-term protection. In contrast, post-nesting green turtles travel up to 4000 km to distant foraging sites, so the protected beaches in the Chagos Archipelago provide a nesting sanctuary for individuals that forage across an ocean basin and several geopolitical borders. Surveys using divers and underwater video systems show high habitat diversity and abundant marine life on all trophic levels. For example, coral cover can be as high as 40–50%. Ecological studies are shedding light on how remote ecosystems function, connect to each other and respond to climate-driven stressors compared to other locations that are more locally impacted. However, important threats to this MPA have been identified, particularly global heating events, and Illegal, Unreported and Unregulated (IUU) fishing activity, which considerably impact both reef and pelagic fishes.

Purpose Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. Methods Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. Results We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. Conclusion The findings indicate that variants in DLG2 /PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.

Background Anticholinergic medications are drugs that block cholinergic transmission, either as their primary therapeutic action or as a secondary effect. Patients with dementia may be particularly sensitive to the central effects of anticholinergic drugs. Anticholinergics also antagonise the effects of the main dementia treatment, cholinesterase inhibitors. Our study aimed to investigate anticholinergic prescribing for dementia patients in UK acute hospitals before and after admission. Methods We included 352 patients with dementia from 17 UK hospital sites in 2019. They were all inpatients on surgical, medical or Care of the Elderly wards. Information about each patient’s medications were collected using a standardised form, and the anticholinergic drug burden of each patient was calculated with an evidence-based online calculator. Wilcoxon’s rank test was used to look at the correlation between two subgroups upon admission and discharge. Results On admission to hospital, 37.8% of patients had an anticholinergic burden score ≥ 1 and 5.68% ≥3. On discharge, 43.2% of patients with an anticholinergic burden score ≥ 1 and 9.1% ≥3. The increase in scores was statistically significant ( p  = 0.001). Psychotropics were the most common group of anticholinergic medications prescribed at discharge. Of those patients taking cholinesterase inhibitors, 44.9% were also prescribed anticholinergic medications. Conclusions Our cross-sectional, multicentre study found that people with dementia are commonly prescribed anticholinergic medications, even if concurrently taking cholinesterase inhibitors, and are significantly more likely to be discharged from hospital with a higher anticholinergic burden than on admission.