Explore the vast range of titles available.

Achromobacter species are increasingly isolated from the respiratory tract of cystic fibrosis patients and often a chronic infection is established. How Achromobacter sp. adapts to the human host remains uncharacterised. By comparing longitudinally collected isolates of Achromobacter sp. isolated from five CF patients, we have investigated the within-host evolution of clonal lineages. The majority of identified mutations were isolate-specific suggesting co-evolution of several subpopulations from the original infecting isolate. The largest proportion of mutated genes were involved in the general metabolism of the bacterium, but genes involved in virulence and antimicrobial resistance were also affected. A number of virulence genes required for initiation of acute infection were selected against, e.g. genes of the type I and type III secretion systems and genes related to pilus and flagellum formation or function. Six antimicrobial resistance genes or their regulatory genes were mutated, including large deletions affecting the repressor genes of an RND-family efflux pump and a beta-lactamase. Convergent evolution was observed for five genes that were all implicated in bacterial virulence. Characterisation of genes involved in adaptation of Achromobacter to the human host is required for understanding the pathogen-host interaction and facilitate design of future therapeutic interventions.

Achromobacter species are increasingly isolated from the respiratory tract of cystic fibrosis patients and often a chronic infection is established. How Achromobacter sp. adapts to the human host remains uncharacterised. By comparing longitudinally collected isolates of Achromobacter sp. isolated from five CF patients, we have investigated the within-host evolution of clonal lineages. The majority of identified mutations were isolate-specific suggesting co-evolution of several subpopulations from the original infecting isolate. The largest proportion of mutated genes were involved in the general metabolism of the bacterium, but genes involved in virulence and antimicrobial resistance were also affected. A number of virulence genes required for initiation of acute infection were selected against, e.g. genes of the type I and type III secretion systems and genes related to pilus and flagellum formation or function. Six antimicrobial resistance genes or their regulatory genes were mutated, including large deletions affecting the repressor genes of an RND-family efflux pump and a beta-lactamase. Convergent evolution was observed for five genes that were all implicated in bacterial virulence. Characterisation of genes involved in adaptation of Achromobacter to the human host is required for understanding the pathogen-host interaction and facilitate design of future therapeutic interventions.

Cognitive deficits are already present in early stages of schizophrenia. P3a and P3b event-related potentials (ERPs) are believed to underlie the processes of attention and working memory (WM), yet limited research has been performed on the associations between these parameters. Therefore, we explored possible associations between P3a/b amplitudes and cognition in a large cohort of antipsychotic-naïve, first-episode schizophrenia (AN-FES) patients and healthy controls (HC). Seventy-three AN-FES patients and 93 age- and gender-matched HC were assessed for their P3a/b amplitude with an auditory oddball paradigm. In addition, subjects performed several subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). AN-FES patients had significantly reduced P3a/b amplitudes, as well as significantly lower scores on all cognitive tests compared with HC. Total group correlations revealed positive associations between P3b amplitude and WM and sustained attention and negative associations with all reaction time measures. These associations appeared mainly driven by AN-FES patients, where we found a similar pattern. No significant associations were found between P3b amplitude and cognitive measures in our HC. P3a amplitude did not correlate significantly with any cognitive measures in either group, nor when combined. Our results provide further evidence for P3a/b amplitude deficits and cognitive deficits in AN-FES patients, which are neither due to antipsychotics nor to disease progress. Furthermore, our data showed significant, yet weak associations between P3b and cognition. Therefore, our data do not supply evidence for deficient P3a/b amplitudes as direct underlying factors for cognitive deficits in schizophrenia.

Despite recent advances in cross-cultural neuropsychological test development, suitable tests for cross-linguistic assessment of language functions are not widely available. The aims of this study were to develop and validate a brief naming test, the Copenhagen Cross-Linguistic Naming Test (C-CLNT), for the assessment of culturally, linguistically, and educationally diverse older adult populations in Europe. The C-CLNT was based on a set of standardized color drawings. Items for the C-CLNT were selected by considering name agreement and frequency across five European and two non-European languages. Ambiguities in some of the selected items and scoring criteria were resolved after pilot testing in 10 memory clinic patients. The final 30-item C-CLNT was validated by verifying its psychometric properties in 24 controls and 162 diverse memory clinic patients with affective disorder, mild cognitive impairment, and with dementia. The C-CLNT had acceptable scale reliability (coefficient alpha = .67) and good construct validity, with moderate to strong correlations with traditional language tests ( = .42- .75). Diagnostic accuracy for dementia was good and significantly better than that of the Boston Naming Test (areas under the curve of .80 vs .64, < .001), but was poor for mild cognitive impairment. Only 3% of the variance in C-CLNT test scores was explained by immigrant background, while 6% was explained by age and years of education. In comparison, these proportions were 34 and 22% for the BNT. The C-CLNT has promising clinical utility for cross-linguistic assessment of naming impairment in culturally, linguistically, and educationally diverse older adults.

Background X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient’s lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry. Results The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately − 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH. Conclusion The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21–28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15–0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron. The SARS-CoV-2 Omicron variant is associated with high rates of vaccine breakthrough infections, but the immunological basis for this is not well characterised. Here, the authors show that increased anti-Spike IgG antibody levels are associated with a reduced risk of infection with the Delta variant, but not with Omicron.

The membrane-anchored matrix metalloprotease MT1-MMP is a potent collagenolytic enzyme with a well-established role in extracellular matrix turnover and cellular invasion into collagen-rich tissues. MT1-MMP is highly expressed in various types of cancer and has been demonstrated to be directly involved in several stages of tumor progression, including primary tumor growth, angiogenesis, invasion and metastasis. Osteosarcoma is the most common type of primary bone cancer. This disease is characterized by invasive tumor growth, leading to extensive bone destruction, and metastasis to the lungs. The tumor cells in human osteosarcoma display a strong expression of MT1-MMP, but the role of MT1-MMP in osteosarcoma progression is currently unknown. In this study, we investigated the role of MT1-MMP during various stages of osteosarcoma development. We utilized an optimized orthotopic murine osteosarcoma model and human osteosarcoma cells in which the MT1-MMP gene was knocked out using CRISPR/Cas9. We observed a strong expression of MT1-MMP in wildtype cells of both primary tumors and lung metastases, but, surprisingly, MT1-MMP deficiency did not affect primary tumor growth, bone degradation or the formation and growth of lung metastases. We therefore propose that, unlike findings reported in other cancers, tumor-expressed MT1-MMP is dispensable for all stages of osteosarcoma progression.

Plant and animal perception of microbes through pathogen surveillance proteins leads to MAP kinase signalling and the expression of defence genes. However, little is known about how plant MAP kinases regulate specific gene expression. We report that, in the absence of pathogens, Arabidopsis MAP kinase 4 (MPK4) exists in nuclear complexes with the WRKY33 transcription factor. This complex depends on the MPK4 substrate MKS1. Challenge with Pseudomonas syringae or flagellin leads to the activation of MPK4 and phosphorylation of MKS1. Subsequently, complexes with MKS1 and WRKY33 are released from MPK4, and WRKY33 targets the promoter of PHYTOALEXIN DEFICIENT3 ( PAD3 ) encoding an enzyme required for the synthesis of antimicrobial camalexin. Hence, wrky33 mutants are impaired in the accumulation of PAD3 mRNA and camalexin production upon infection. That WRKY33 is an effector of MPK4 is further supported by the suppression of PAD3 expression in mpk4 – wrky33 double mutant backgrounds. Our data establish direct links between MPK4 and innate immunity and provide an example of how a plant MAP kinase can regulate gene expression by releasing transcription factors in the nucleus upon activation.

Background X-linked hypophosphataemia (XLH) is a rare, hereditary, progressive and lifelong phosphate wasting disorder characterised by pathological elevations in fibroblast growth factor (FGF) 23 concentration and activity; XLH has an incidence of approximately 1 in 20–25,000 individuals. Excess FGF23 activity leads to increased phosphate excretion in the kidneys – mediated by downregulation of renal tubular phosphate transporters – and reduced phosphate absorption in the intestines – due to impaired vitamin D activation. This results in impaired bone growth and mineralisation, short and disproportionate stature, leg bowing, musculoskeletal pain, spontaneous dental abscesses, rickets, and osteomalacia. The spectrum of manifestations differs between paediatric and adult patients. Those involved in the treatment of this condition face many challenges, including a lack of robust natural history and demographic data. This multicentre, international, rare-disease patient registry (XLH Registry) was established to address the paucity of data in XLH and to help inform future clinical practice. Results The XLH Registry collects standard diagnostic and monitoring practice data, including (where applicable) diagnosis and disease progression history, treatment regimens and family history; the protocol does not mandate any interventions or clinical assessments. The XLH Registry aims to recruit 1200 paediatric and adult patients with XLH over 10 years, and several data analyses and peer-reviewed publications are expected to be generated throughout this period. A post-authorisation safety study for Bburosumab, for which the registry Sponsor is the marketing authorisation holder, will be nested as a sub-study within the XLH Registry via a subsequent protocol amendment. Conclusion The data collected within this rare-disease patient registry will be utilised to synthesise real-world evidence to inform the management of XLH, to improve the quality of life and standard of care of patients living with this rare debilitating disease.

Inflammatory arthritis, including rheumatoid arthritis and psoriatic arthritis, is characterized by physical function impairment. This becomes apparent even before arthritis onset, as in psoriasis (PsO). Chronic inflammation triggers an accelerated remodeling of the extracellular matrix (ECM), resulting in released ECM fragments detectable in blood. We aimed to investigate levels of blood-based ECM biomarkers in patients with RA, PsA, PsO, and healthy controls and to explore the association of ECM biomarkers with hand function impairments. Patients with RA (n = 85), PsA (n = 115), PsO (n = 102) and controls (n = 110) were included in this cross-sectional study. ECM catabolic (C1M, C2M, C3M, C4M, PRO-C4, C6M, ARG), formation (PRO-C1, PRO-C3, PRO-C6) and inflammation biomarkers (VICM) were measured in serum from all patients. Objective hand function (fine motor skills (Moberg-Picking-Up Test), isometric grip strength (dynamometer) and patient-perceived hand function (Michigan Hand Questionnaire (MHQ)) were assessed. Patients with RA and PsA received treatment with disease-modifying anti-rheumatic drugs. VICM levels were higher in RA, PsA, and PsO than in controls (p < 0.0001). PsA and PsO showed higher C4M levels compared to controls (p < 0.0001, p < 0.0001), while C6M was lower in patients with RA, PsA and PsO than in controls (p < 0.0001, p < 0.001, p < 0.01). PsO presented with higher levels of C1M compared to controls and to RA (p < 0.001 and p < 0.0001). PRO-C6 correlated negatively with MHQ ( ρ  = -0.39, p < 0.01) and grip strength (ρ  = -0.31, p < 0.05) in PsO, while only weak correlations were observed between biomarkers and hand function scores for RA and PsA patients (all ρ  <  ± 0.2–0.3). Patients with RA, PsA, and PsO showed significant alterations in ECM remodeling biomarkers. Especially PsA and PsO had higher levels of inflammatory biomarkers compared to RA and controls, likely due to modulation by treatment. Predominantly in PsO, ECM formation biomarkers were associated with hand function impairments.