Diagnostic delay of myositis: an integrated systematic review.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a heterogenous group of rare muscular autoimmune diseases characterised by skeletal muscle inflammation with possible diagnostic delay. Our aim was to review the existing evidence to identify overall diagnostic delay for IIM, factors associated with diagnostic delay, and people's experiences of diagnostic delay. METHODS: Three databases and grey literature sources were searched. Diagnostic delay was defined as the period between the onset of symptoms and the year of first diagnosis of IIM. We pooled the mean delay using random effects inverse variance meta-analysis and performed subgroup analyses. RESULTS: 328 titles were identified from which 27 studies were included. Overall mean diagnostic delay was 27.91 months (95% CI 15.03-40.79, I2 = 99%). Subgroup analyses revealed a difference in diagnostic delay between non-inclusion body myositis (IBM) and IBM types. There was no difference in diagnostic delay between studies in which myositis specific autoantibodies (MSA) were tested or not tested. In countries with gatekeeper health systems, where primary care clinicians authorize access to specialty care, people experienced longer periods of diagnostic delay than people with IIM in countries with non-gatekeeper systems. While studies discussed factors that may influence diagnostic delay, significant associations were not identified. No qualitative studies examining people's experiences of diagnostic delay were identified. CONCLUSION: Diagnostic delay of IIM has extensive impacts on the quality of life of people living with this disease. Understanding the experiences of people with IIM, from symptom onset to diagnosis, and factors that influence diagnostic delay is critical to inform clinical practice and training activities aimed at increasing awareness of this rare disease and expediting diagnosis. TRIAL REGISTRATION: PROSPERO Registration number: CRD42022307236 URL of the PROSPERO registration: https://www.crd.york.ac.uk/PROSPEROFILES/307236_PROTOCOL_20220127.pdf.

Diagnostic delay of myositis: protocol for an integrated systematic review.

INTRODUCTION: Idiopathic inflammatory myopathies (IIM). described as 'inflammatory myositis', are a heterogeneous group of rare muscular autoimmune diseases characterised by skeletal muscle inflammation. Its complex characteristics with lack of accurate diagnostic tests, unified classification system and comprehensive widely used diagnostic criteria could lead to diagnostic delay. This study will review diagnostic delay in myositis and provide an overview and clearer insight of patients' experiences, causes and consequences of diagnostic delay in myositis. METHODS AND ANALYSIS: The literature source will be a systematic search of PubMed/MEDLINE, Scopus, ProQuest and sources of grey literature, conducted from database inception to December 2021 without restrictions on publication date. All study types (qualitative and quantitative) except review articles, examining diagnostic delay, incorrect diagnosis, missed diagnosis or slow diagnosis of all types of myositis in all ages will be included. Evidence of patients' experiences associated with diagnostic delay will also be examined. Studies in languages other than English, German and Indonesian will be excluded. Outcomes will be diagnostic delay time, patients' experiences, and causes and consequences associated with diagnostic delay in myositis. Two review authors will independently screen the titles and abstracts of search results against the inclusion criteria. The Mixed Methods Appraisal Tool (MMAT) will be used to appraise selected studies. Two independent authors will extract data using a prepiloted data extraction tool. If sufficient quantitative data is available, a meta-analysis will be conducted along with subgroup analysis including pooled diagnostic delay in each type of myositis. Qualitative data will be analysed in line with meta-aggregation methods. If data is insufficient, a narrative synthesis will be conducted. ETHICS AND DISSEMINATION: As this work is a systematic review, ethical approval was not required. Findings of the study will be disseminated through publications in peer-reviewed journals, conferences and symposia. PROSPERO REGISTRATION NUMBER: CRD42022289830.

Chronic Pectoralis Major Rupture Reconstruction With Interpositional Acellular Dermal Allograft.

Background: Pectoralis major tendon (PMT) rupture commonly occurs in males 20 to 39 years of age. PMT rupture is most often associated with gym-based exercise, with attempted bench press being the most common causative event, but it is also associated with contact or impact sports. Delayed presentation, misdiagnoses, and chronic PMT rupture can result in a therapeutic dilemma. Case Series: We present 2 cases of chronic PMT rupture that were operatively managed using acellular dermal allograft as an interposition graft. Patients' final follow-ups were at 20 and 30 months, respectively. Strength in their pectoralis major muscle was well preserved on the contralateral side: 88% for patient 1 and 110% for patient 2. Conclusion: Our reported technique using an interpositional acellular dermal allograft is a good option to treat chronic PMT rupture.

The Ecobiomics project: Advancing metagenomics assessment of soil health and freshwater quality in Canada.

Transformative advances in metagenomics are providing an unprecedented ability to characterize the enormous diversity of microorganisms and invertebrates sustaining soil health and water quality. These advances are enabling a better recognition of the ecological linkages between soil and water, and the biodiversity exchanges between these two reservoirs. They are also providing new perspectives for understanding microorganisms and invertebrates as part of interacting communities (i.e. microbiomes and zoobiomes), and considering plants, animals, and humans as holobionts comprised of their own cells as well as diverse microorganisms and invertebrates often acquired from soil and water. The Government of Canada's Genomics Research and Development Initiative (GRDI) launched the Ecobiomics Project to coordinate metagenomics capacity building across federal departments, and to apply metagenomics to better characterize microbial and invertebrate biodiversity for advancing environmental assessment, monitoring, and remediation activities. The Project has adopted standard methods for soil, water, and invertebrate sampling, collection and provenance of metadata, and nucleic acid extraction. High-throughput sequencing is located at a centralized sequencing facility. A centralized Bioinformatics Platform was established to enable a novel government-wide approach to harmonize metagenomics data collection, storage and bioinformatics analyses. Sixteen research projects were initiated under Soil Microbiome, Aquatic Microbiome, and Invertebrate Zoobiome Themes. Genomic observatories were established at long-term environmental monitoring sites for providing more comprehensive biodiversity reference points to assess environmental change.

Assessing Performance of Spore Samplers in Monitoring Aeromycobiota and Fungal Plant Pathogen Diversity in Canada.

Spore samplers are widely used in pathogen surveillance but not so much for monitoring the composition of aeromycobiota. In Canada, a nationwide spore-sampling network (AeroNet) was established as a pilot project to assess fungal community composition in air and rain samples collected using three different spore samplers in the summers of 2010 and 2011. Metabarcodes of the internal transcribed spacer (ITS) were exhaustively characterized for three of the network sites, in British Columbia (BC), Québec (QC), and Prince Edward Island (PEI), to compare performance of the samplers. Sampler type accounted for ca. 20% of the total explainable variance in aeromycobiota compositional heterogeneity, with air samplers recovering more Ascomycota and rain samplers recovering more Basidiomycota. Spore samplers showed different abilities to collect 27 fungal genera that are plant pathogens. For instance, Cladosporium spp., Drechslera spp., and Entyloma spp. were collected mainly by air samplers, while Fusarium spp., Microdochium spp., and Ustilago spp. were recovered more frequently with rain samplers. The diversity and abundance of some fungi were significantly affected by sampling location and time (e.g., Alternaria and Bipolaris) and weather conditions (e.g., Mycocentrospora and Leptosphaeria), and depended on using ITS1 or ITS2 as the barcoding region (e.g., Epicoccum and Botrytis). The observation that Canada's aeromycobiota diversity correlates with cooler, wetter conditions and northward wind requires support from more long-term data sets. Our vision of the AeroNet network, combined with high-throughput sequencing (HTS) and well-designed sampling strategies, may contribute significantly to a national biovigilance network for protecting plants of agricultural and economic importance in Canada.IMPORTANCE The current study compared the performance of spore samplers for collecting broad-spectrum air- and rain-borne fungal pathogens using a metabarcoding approach. The results provided a thorough characterization of the aeromycobiota in the coastal regions of Canada in relation to the influence of climatic factors. This study lays the methodological basis to eventually develop knowledge-based guidance on pest surveillance by assisting in the selection of appropriate spore samplers.

Discoidin domain receptor 1 contributes to tumorigenesis through modulation of TGFBI expression.

Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family. The receptor is activated upon binding to its ligand, collagen, and plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Although DDR1 is expressed in many normal tissues, upregulated expression of DDR1 in a variety of human cancers such as lung, colon and brain cancers is known to be associated with poor prognosis. Using shRNA silencing, we assessed the oncogenic potential of DDR1. DDR1 knockdown impaired tumor cell proliferation and migration in vitro and tumor growth in vivo. Microarray analysis of tumor cells demonstrated upregulation of TGFBI expression upon DDR1 knockdown, which was subsequently confirmed at the protein level. TGFBI is a TGFß-induced extracellular matrix protein secreted by the tumor cells and is known to act either as a tumor promoter or tumor suppressor, depending on the tumor environment. Here, we show that exogenous addition of recombinant TGFBI to BXPC3 tumor cells inhibited clonogenic growth and migration, thus recapitulating the phenotypic effect observed from DDR1 silencing. BXPC3 tumor xenografts demonstrated reduced growth with DDR1 knockdown, and the same xenograft tumors exhibited an increase in TGFBI expression level. Together, these data suggest that DDR1 expression level influences tumor growth in part via modulation of TGFBI expression. The reciprocal expression of DDR1 and TGFBI may help to elucidate the contribution of DDR1 in tumorigenesis and TGFBI may also be used as a biomarker for the therapeutic development of DDR1 specific inhibitors.

In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates.

Antibody drug conjugates (ADCs) are monoclonal antibodies designed to deliver a cytotoxic drug selectively to antigen expressing cells. Several components of an ADC including the selection of the antibody, the linker, the cytotoxic drug payload and the site of attachment used to attach the drug to the antibody are critical to the activity and development of the ADC. The cytotoxic drugs or payloads used to make ADCs are typically conjugated to the antibody through cysteine or lysine residues. This results in ADCs that have a heterogeneous number of drugs per antibody. The number of drugs per antibody commonly referred to as the drug to antibody ratio (DAR), can vary between 0 and 8 drugs for a IgG1 antibody. Antibodies with 0 drugs are ineffective and compete with the ADC for binding to the antigen expressing cells. Antibodies with 8 drugs per antibody have reduced in vivo stability, which may contribute to non target related toxicities. In these studies we incorporated a non-natural amino acid, para acetyl phenylalanine, at two unique sites within an antibody against Her2/neu. We covalently attached a cytotoxic drug to these sites to form an ADC which contains two drugs per antibody. We report the results from the first direct preclinical comparison of a site specific non-natural amino acid anti-Her2 ADC and a cysteine conjugated anti-Her2 ADC. We report that the site specific non-natural amino acid anti-Her2 ADCs have superior in vitro serum stability and preclinical toxicology profile in rats as compared to the cysteine conjugated anti-Her2 ADCs. We also demonstrate that the site specific non-natural amino acid anti-Her2 ADCs maintain their in vitro potency and in vivo efficacy against Her2 expressing human tumor cell lines. Our data suggests that site specific non-natural amino acid ADCs may have a superior therapeutic window than cysteine conjugated ADCs.

Acyl-lipid thioesterase1-4 from Arabidopsis thaliana form a novel family of fatty acyl-acyl carrier protein thioesterases with divergent expression patterns and substrate specificities.

Hydrolysis of fatty acyl thioester bonds by thioesterases to produce free fatty acids is important for dictating the diversity of lipid metabolites produced in plants. We have characterized a four-member family of fatty acyl thioesterases from Arabidopsis thaliana, which we have called acyl-lipid thioesterase1 (ALT1), ALT2, ALT3, and ALT4. The ALTs belong to the Hotdog fold superfamily of thioesterases. ALT-like genes are present in diverse plant taxa, including dicots, monocots, lycophytes, and microalgae. The four Arabidopsis ALT genes were found to have distinct gene expression profiles with respect to each other. ALT1 was expressed specifically in stem epidermal cells and flower petals. ALT2 was expressed specifically in root endodermal and peridermal cells as well as in stem lateral organ boundary cells. ALT3 was ubiquitously expressed in aerial and root tissues and at much higher levels than the other ALTs. ALT4 expression was restricted to anthers. All four proteins were localized in plastids via an N-terminal targeting sequence of about 48 amino acids. When expressed in Escherichia coli, the ALT proteins used endogenous fatty acyl-acyl carrier protein substrates to generate fatty acids that varied in chain length (C6-C18), degree of saturation (saturated and monounsaturated), and oxidation state (fully reduced and ß-ketofatty acids). Despite their high amino acid sequence identities, each enzyme produced a different profile of lipids in E. coli. The biological roles of these proteins are unknown, but they potentially generate volatile lipid metabolites that have previously not been reported in Arabidopsis.

Three Arabidopsis fatty acyl-coenzyme A reductases, FAR1, FAR4, and FAR5, generate primary fatty alcohols associated with suberin deposition.

Suberin is a protective hydrophobic barrier consisting of phenolics, glycerol, and a variety of fatty acid derivatives, including C18:0-C22:0 primary fatty alcohols. An eight-member gene family encoding alcohol-forming fatty acyl-coenzyme A reductases (FARs) has been identified in Arabidopsis (Arabidopsis thaliana). Promoter-driven expression of the beta-glucuronidase reporter gene indicated that three of these genes, FAR1(At5g22500), FAR4(At3g44540), and FAR5(At3g44550), are expressed in root endodermal cells. The three genes were transcriptionally induced by wounding and salt stress. These patterns of gene expression coincide with known sites of suberin deposition. We then characterized a set of mutants with T-DNA insertions in FAR1, FAR4, or FAR5 and found that the suberin compositions of roots and seed coats were modified in each far mutant. Specifically, C18:0-OH was reduced in far5-1, C20:0-OH was reduced in far4-1, and C22:0-OH was reduced in far1-1. We also analyzed the composition of polymer-bound lipids of leaves before and after wounding and found that the basal levels of C18:0-C22:0 primary alcohols in wild-type leaves were increased by wounding. In contrast, C18:0-OH and C22:0-OH were not increased by wounding in far5-1 and far1-1 mutants, respectively. Heterologous expression of FAR1, FAR4, and FAR5 in yeast confirmed that they are indeed active alcohol-forming FARs with distinct, but overlapping, chain length specificities ranging from C18:0 to C24:0. Altogether, these results indicate that Arabidopsis FAR1, FAR4, and FAR5 generate the fatty alcohols found in root, seed coat, and wound-induced leaf tissue.

Do current beliefs predict hypomanic symptoms beyond personality style? Factor analysis of the hypomanic attitudes and positive predictions inventory (HAPPI) and its association with hypomanic symptoms in a student population.

A self-report scale called the Hypomanic Attitudes and Positive Predictions Inventory (HAPPI) has been developed to assess cognitions that distinguish between bipolar disorder and nonclinical controls (Mansell, 2006; Mansell & Jones, 2006). We recruited 191 undergraduate students to assess the associations between the HAPPI and self-reported past (MDQ; Hirschfeld et al., 2000) and present (ISS; Bauer et al., 1991) bipolar symptoms, and to explore the factor structure of the scale. The HAPPI correlated with past and present symptoms independently of the BIS/BAS subscales (Carver & White, 1994) and the HPS (Eckblad & Chapman, 1986). Five factors of the HAPPI were identified: success activation and triumph over fear, activating response style, reduced social regulation, loss of control when activated, and catastrophic beliefs about internal states. The HAPPI factors showed specific relationships with current bipolar symptoms that largely fitted with predictions based on the model. Further work is required to establish whether they have a causal role.

Effects of global atrophy, white matter lesions, and cerebral blood flow on age-related changes in speed, memory, intelligence, vocabulary, and frontal function.

Brain images were obtained from 133 healthy people of ages 61-85 years who completed 20 tests of information processing speed, intelligence, frontal and executive function, memory, and vocabulary. Structural equation models examined relationships between cognitive test scores, ages and measurements of global age-associated atrophy, white matter lesions, and cerebral blood flow. These neurophysiological measures jointly account for all age-related variance in information processing speed. Speed entirely mediated relationships between neurophysiological measures and memory and partly mediated relationships between neurophysiological measures and intelligence and frontal function. Neurophysiological measures, but not calendar age, accounted for vocabulary scores. Cognitive slowing was responsible for some, but not all, age-related declines in mental function. Age-related declines in intelligence, frontal function, and speed were due to changes in different functional systems.

White matter lesions account for all age-related declines in speed but not in intelligence.

MRI scans measured white matter lesion prevalence (WMLP) in 65 people ages 65-84 years who also took 17 cognitive tests: 3 tests of general fluid intelligence, 3 of vocabulary, 2 of episodic and 3 of working memory, 2 of processing speed, and 4 of frontal and executive function. Entry of age with WMLP into regression equations as predictors of test scores showed that inferences about the functional relationships between markers of brain aging and cognitive impairments are seriously misleading if they are based on simple correlations alone. A new finding that WMLP accounts for all of the age-related variance between individuals in tests of speed and executive ability but for none of the age-related variance in intelligence revises current hypotheses that gross brain changes affect general fluid intelligence and other mental abilities solely through their effects on information-processing speed.

Neural basis of category-specific semantic deficits for living things: evidence from semantic dementia, HSVE and a neural network model.

Studies of patients with semantic impairments following brain damage offer key insights into the cognitive and neural organization of semantic memory. Especially important in this regard are studies of category-specific semantic impairment. We report a direct comparison of semantic deficits in two groups suffering from different diseases: semantic dementia (SD) and herpes simplex virus encephalitis (HSVE). Although pathology in both disorders is centred on the anterior temporal lobes bilaterally, category-specific semantic impairment is rarely observed in SD yet commonly found in HSVE. Using a combination of neuropsychology and computational neuroscience, we tested the possibility that category-specific deficits for living things depend not solely upon the location of damage within the cortical semantic network but also critically upon the type of impairment. When the semantic representations within the model are degraded or 'dimmed' then a generalized, global semantic impairment results (as found in SD) but when the representations are distorted then a category-specific pattern emerges (as per HSVE). Three novel predictions from this model were tested and confirmed, thereby adding weight to the hypothesis that both type and distribution of pathology can be critical in producing neuropsychological phenomena.

The effect of age on inhibition of return is independent of non-ocular response inhibition.

Inhibition of return (IOR) refers to the slowing of a response to a target stimulus presented in the same location as a previous stimulus. Increased IOR has been observed in older adults, despite a reduction in other 'inhibitory' processes. However, cue-target tasks have been used in all previous studies and because of this, IOR may have been overestimated due to non-ocular response inhibition associated with withholding a response from the cue. Could increased levels of response inhibition account for the observations of increased IOR in older adults? This confound can be circumvented by using a target-target paradigm, in which a response is made to all stimuli. We tested three groups of 24 subjects: young (mean 22.5 years), young-old (mean 61.9 years) and old-old (mean 74.8 years). Subjects completed both visual cue-target and target-target tasks with identical inter-stimulus intervals of 1400 and 1800ms. IOR magnitude increased with age in both the cue-target task and the target-target task. Furthermore, the magnitude of visual IOR was found to increase with age even when individual differences in baseline response speed were taken into account. Thus, there appears to be a genuine increase in IOR magnitude with age.

Losses in gross brain volume and cerebral blood flow account for age-related differences in speed but not in fluid intelligence.

Age-related gross head size; adjusted age-related change in brain volume and carotid and basilar blood flow; as well as scores on 3 tests of fluid intelligence (gf), 2 tests of information-processing speed, 2 memory tests, and 3 tests of executive function were obtained from 69 volunteers aged from 62 to 84 years. Brain volume negatively predicted scores on all 10 cognitive tasks, accounting for up to 78% of age-related variance in scores on the speed tasks and on 1 executive task. Cerebral blood flow (CBF) negatively predicted scores on 8 cognitive tasks, accounting for up to 36% of age-related variance in speed scores. However, neither brain volume nor CBF accounted for significant age-related variance between individuals on any of 3 gf tests. We conclude that speed, but not gf, is an exceptionally sensitive behavioral index of the progress of gross brain changes that affect cognition in old age and that speed and gf do not reflect integrity of the same functional systems.

Vaccination with novel combinations of anti-HER2/neu cytokines fusion proteins and soluble protein antigen elicits a protective immune response against HER2/neu expressing tumors.

We have previously demonstrated that anti-HER2/neu IgG3-(IL-2), (IL-12)-IgG3, or IgG3-(GM-CSF) antibody fusion proteins (mono-AbFPs) elicit anti-tumor activity against murine tumors expressing HER2/neu when used as adjuvants of extracellular domain of HER2/neu (ECD(HER2)) protein vaccination. We have now studied the effect of combinations of IL-2 and IL-12 or IL-12 and GM-CSF mono-AbFPs during vaccination with ECD(HER2). In addition, we developed two novel anti-HER2/neu IgG3-cytokine fusion proteins in which IL-2 and IL-12 or IL-12 and GM-CSF were fused to the same IgG3 molecule (bi-AbFPs). (IL-12)-IgG3-(IL-2) and (IL-12)-IgG3-(GM-CSF) were properly assembled and retained both cytokine activity and the ability to bind antigen. Vaccination of mice with ECD(HER2) and a combination of cytokines as either bi-AbFPs or two mono-AbFPs activated both Thl and Th2 immune responses and resulted in significant protection against challenge with a HER2/neu expressing tumor. Our results suggest that this approach will be effective in the prevention and/or treatment of HER2/neu expressing tumors.

Overgenerality of autobiographical memory in Alzheimer's disease.

OBJECTIVES: Overgenerality of autobiographical memory (ABM) is well documented in a range of clinical conditions, particularly in depressed and parasuicidal patients (e.g., Williams, 1996; Williams & Broadbent, 1986). This study extended the investigation to Alzheimer's disease (AD), and attempted to identify whether ABM overgenerality in the AD group is specifically expressed through an excess of categoric memories. DESIGN: AD sufferers and control participants were compared on their ABM specificity in a cued-recall task. METHOD: Ten AD patients and 10 controls, matched for age, gender and educational level, were administered an ABM specificity measure following their mental status assessment. A battery of neuropsychological tests provided an independent estimate of cognitive deficit severity in the following areas: long-term memory, IQ, working memory, processing speed, and verbal fluency. A control for depression was also employed. RESULTS: Compared to control participants, AD participants produced significantly fewer specific autobiographical memories. Additionally, the number of produced categoric overgeneral memories was significantly greater in the AD group in comparison with the controls. CONCLUSION: This study demonstrates the existence of ABM overgenerality in AD, manifested through an excess of categoric memories. Consistent with the mnemonic interlock theory (Williams, 1996), AD sufferers seem to lack cognitive resources to conduct a directed search for a specific memory, and stop at the categoric descriptions stage. This may contribute to lack of specificity in ABM retrieval.

Concordance of Cornell medical index self-reports to structured clinical assessment for the identification of physical health status.

Self-reported questionnaires are frequently used to assess health status in epidemiological studies. The Cornell medical index is one such tool used to determine the presence of physical and psychiatric illness but its accuracy and value have been questioned. In this study we have assessed the ability of the CMI to predict health status in two separate patient populations (n = 101, 88) by comparison to a structured medical assessment based on the SENIEUR protocol by two physicians. There was good agreement between medication use reported on the CMI and on medical assessment (k = 0.79; CI: 0.70-0.88). Accuracy of prediction of the CMI for specific medical conditions was good 89-99%. A threshold score from the CMI was not predictive of health as determined by the SENIEUR protocol. In our older populations, we conclude that the CMI accurately predicted health status. The determination of normal health by a threshold score was poorly predictive of heath status. Self-reported medication use was the best predictor of health status.