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The lower airways harbor a community of bacterial species which is altered in asthma. We examined whether the lower airway microbiota were related to measures of asthma severity. We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed. We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P = 2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR = 2.26; 95% CI = 1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR = 2.15; 95%CI = 1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia. Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.

Objective To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center. Methods We designed two iterations of a comprehensive targeted gene panel for neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used TargetSeqTM probe‐based hybridization for target enrichment followed by Ion Torrent sequencing. Targeted high‐coverage sequencing and analysis was performed on 2249 neurology patients from Australia and New Zealand (1054 Version 1, 1195 Version 2) from 2012 to 2015. No selection criteria were used other than referral from a suitable medical specialist (e.g., neurologist or clinical geneticist). Patients were classified into 15 clinical categories based on the clinical diagnosis from the referring clinician. Results Six hundred and sixty‐five patients received a genetic diagnosis (30%). Diagnosed patients were significantly younger that undiagnosed patients (26.4 and 32.5 years, respectively; P = 4.6326E‐9). The diagnostic success varied markedly between disease categories. Pathogenic variants in 10 genes explained 38% of the disease burden. Unexpected phenotypic expansions were discovered in multiple cases. Triage of unsolved cases for research exome testing led to the discovery of six new disease genes. Interpretation A comprehensive targeted diagnostic panel was an effective method for neuromuscular disease diagnosis within the context of an Australasian referral center. Use of smaller disease‐specific panels would have precluded diagnosis in many patients and increased cost. Analysis through a centralized laboratory facilitated detection of recurrent, but under‐recognized pathogenic variants.

To identify the molecular cause of the disease, either in one of the eight known nemaline myopathy genes not yet sequenced in the proband, or in a novel gene for nemaline myopathy, whole exome sequencing and data analysis were performed on DNA from the proband as described previously, including filtering against variants present in the 1000 Genomes Project and NIH Heart, Lung and Blood Institute (NHLBI) Exome Sequencing Project datasets. 1 After filtering, 36 homozygous variants matched the autosomal recessive and consanguineous pattern of inheritance of the family. A recent Cfl2 knockout mouse model (Cfl2-/-) displays similar histopathological features to patients with CFL2 mutations, reinforcing the association between cofilin-2 abnormalities and nemaline myopathy. 5 Genetically, the homozygous deletion in the family we describe is more similar to the Cfl2-/- knockout mice 5 than the missense mutations previously described in the two other families. 3 4 Clinically, the patients in the family reported here were more severely affected than the patients in the two published families, closer in severity to the disease in the Cfl2-/- mice, none of which survived past postnatal day 8.

Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.

BACKGROUND: Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. METHODS: Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. RESULTS: PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-alpha and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. CONCLUSION: In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.

Quantitative phenotypes correlated with a complex disorder offer increased power to detect linkage in comparison to affected-unaffected classifications. Asthma is a complex disorder characterized by periods of bronchial obstruction and increased bronchial hyper reactivity. In childhood and early adulthood, asthma is frequently associated also with quantitative measures of atopy. Genome wide quantitative multipoint linkage analysis was conducted for serum IgE levels and percentage of positive skin prick test (SPT(per)) using three large groups of families originally ascertained for asthma. In this report, 438 and 429 asthma families were informative for linkage using IgE and SPT(per) which represents 690 independent families. Suggestive linkage (LOD > or = 2) was found on chromosomes 1, 3, and 8q with maximum LODs of 2.34 (IgE), 2.03 (SPT(per)), and 2.25 (IgE) near markers D1S1653, D3S2322-D3S1764, and D8S2324, respectively. The results from chromosomes 1 and 3 replicate previous reports of linkage. We also replicate linkage to 5q with peak LODs of 1.96 (SPT(per)) and 1.77 (IgE) at or near marker D5S1480. Our results provide further evidence implicating chromosomes 1, 3, and 5q. The current report represents one of the biggest genome scans so far reported for asthma related phenotypes. This study also demonstrates the utility of increased sample sizes and quantitative phenotypes in linkage analysis of complex disorders.

Successful behavior requires actively acquiring and representing information about the environment and people, and manipulating and using those acquired representations flexibly to optimally act in and on the world. The frontal lobes have figured prominently in most accounts of flexible or goal-directed behavior, as evidenced by often-reported behavioral inflexibility in individuals with frontal lobe dysfunction. Here, we propose that the hippocampus also plays a critical role by forming and reconstructing relational memory representations that underlie flexible cognition and social behavior. There is mounting evidence that damage to the hippocampus can produce inflexible and maladaptive behavior when such behavior places high demands on the generation, recombination, and flexible use of information. This is seen in abilities as diverse as memory, navigation, exploration, imagination, creativity, decision-making, character judgments, establishing and maintaining social bonds, empathy, social discourse, and language use. Thus, the hippocampus, together with its extensive interconnections with other neural systems, supports the flexible use of information in general. Further, we suggest that this understanding has important clinical implications. Hippocampal abnormalities can produce profound deficits in real-world situations, which typically place high demands on the flexible use of information, but are not always obvious on diagnostic tools tuned to frontal lobe function. This review documents the role of the hippocampus in supporting flexible representations and aims to expand our understanding of the dynamic networks that operate as we move through and create meaning of our world.

Empirical evidence suggests data and insights from the clinical practice guidelines and clinical quality registries are not being fully utilised, leaving health service managers, clinicians and providers without clear guidance on how best to improve healthcare delivery. This lack of uptake of existing research knowledge represents low value to the healthcare system and needs to change. Five electronic databases (MEDLINE, Embase, CINAHL, Cochrane Central and Cochrane Database of Systematic Reviews) were systematically searched. Included studies were published between 2000 and 2020 reporting on the attributes, evidence usage and impact of clinical practice guidelines and clinical quality registries on health service delivery. Twenty-six articles including one randomised controlled trial, eight before-and-after studies, eight case studies/reviews, five surveys and four interview studies, covering a wide range of medical conditions and conducted in the USA, Australia and Europe, were identified. Five complementary strategies were derived to maximise the likelihood of best practice health service delivery: (1) feedback and transparency, (2) intervention sustainability, (3) clinical practice guideline adherence, (4) productive partnerships and (5) whole-of-team approach. These five strategies, used in context-relevant combinations, are most likely to support the application of existing high-quality data, adding value to health service delivery. The review highlighted the limitations of study design in opportunistic registry studies that do not produce clear, usable evidence to guide changes to health service implementation practices. Recommendations include exploration of innovative methodologies, improved coordination of national registries and the use of incentives to encourage guideline adherence and wider dissemination of strategies used by successful registries.

Communication is aided greatly when speakers and listeners take advantage of mutually shared knowledge (i.e., common ground). How such information is represented in memory is not well known. Using a neuropsychological-psycholinguistic approach to real-time language understanding, we investigated the ability to form and use common ground during conversation in memory-impaired participants with hippocampal amnesia. Analyses of amnesics' eye fixations as they interpreted their partner's utterances about a set of objects demonstrated successful use of common ground when the amnesics had immediate access to common-ground information, but dramatic failures when they did not. These findings indicate a clear role for declarative memory in maintenance of common-ground representations. Even when amnesics were successful, however, the eye movement record revealed subtle deficits in resolving potential ambiguity among competing intended referents; this finding suggests that declarative memory may be critical to more basic aspects of the on-line resolution of linguistic ambiguity.

Abstract Objective To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. Design Randomised controlled trial. Setting Participants’ homes and communities at five sites in the United Kingdom. Participants 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. Intervention The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. Main outcome measures The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. Results 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference −1.3, 95% confidence interval −5.2 to 2.6; Cohen’s d effect size −0.06, 95% confidence interval −0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). Conclusion The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia. Trial registration ISRCTN Registry ISRCTN15320670 .