We aimed to evaluate the effects of switching to faecal immunochemical testing (FIT) on the cumulative 2-year incidence rate of interval cancers, interval cancer rate and test sensitivity within a ...mature population-based colorectal cancer screening programme consisting of six rounds of biennial guaiac faecal occult blood testing (gFOBT).
The FIT results were compared with those of gFOBT used in each of the previous two rounds. For the three rounds analysed, 279,041 tests were performed by 156,186 individuals. Logistic regression analysis was used to determine interval cancer risk factors (Poisson regression) and to compare the sensitivity of FIT to gFOBT.
There were 612 cases of screen-detected cancers and 209 cases of interval cancers. The sex- and age-adjusted cumulative 2-year incidence rates of interval cancers were 55.7 (95% CI, 45.3-68.5), 42.4 (95% CI, 32.6-55.2) and 15.8 (95% CI, 10.9-22.8) per 100,000 person-years after the last two rounds of gFOBT and FIT, respectively. The FIT/gFOBT incidence rate ratio was 0.38 95% CI, 0.27-0.54 (P < 0.001). Sex- and age-adjusted sensitivity was significantly higher with FIT than with gFOBT (OR = 6.70 95% CI, 4.48-10.01, P < 0.0001).
This population-based study revealed a dramatic decrease in the cumulative incidence rates of interval cancers after switching from gFOBT to FIT. These data provide an additional incentive for countries still using gFOBT to switch to FIT.
For patients at high risk of anal cancer, annual screening strategies using invasive evaluation methods are stressful. According to a normal examination at baseline using simple and non invasive ...tests, the aim of the work was to quantify neoplastic events.
Data from patients with a normal evaluation at the first visit were retrospectively extracted from a prospective database. The individual follow-up period was at least two years and three evaluations. Patients with abnormal cytology were assessed using high-resolution anoscopy and targeted biopsies.
A total of 182 subjects (F/M: 10/90, aged 48.1(10.6) years, HIV: 81%) were followed for 41(11) months. Anal cytology remained normal in 94 patients (52%), but high-grade anal neoplasms occurred in 28 patients (15%). Patients with a negative HPV16 status at baseline had cumulative probabilities of high-grade AIN of 0.4%(0.1%-1.9%), 2.6%(1.2%-5.9%) and 7.5%(4.5%-12.2%) after 1 year, 2 years and 3 years of follow-up, respectively. These probabilities were lower than those of patients with a positive HPV16 at baseline and those with a previous history of AIN.
In patients with normal cytology and negative HPV16 at baseline, a three-year interval screening may be a less cumbersome alternative to traditional annual screening.
Little is known about the pathophysiological mechanisms of solitary rectal ulcer syndrome (SRUS).
We aim to identify the different phenotypes, taking into account complaints, anatomy and anorectal ...physiology.
Complaints, endoscopy results, and physiology data of patients with histologically proven SRUS were collected and analysed. The associated anorectal diseases were faecal incontinence and obstructed defecation. The clinical aspects of SRUS were compared, and factors associated with anorectal diseases were identified.
Overall, 102 consecutive patients were included. The predominant lesion was a rectal ulcer (66%), and inflammation of the rectal wall was present in 42% of patients. Abnormal rectal capacities and/or rectal perception was observed in more than half. Nearly half (52%) of the patients met the criteria for obstructed defecation and they tended to more frequently have psychiatric disease (66.7% vs 33.3%; p=0.07). Patients with faecal incontinence (17%) reported more self-perception of anal procidentia (p=0.01) and were more likely to have inflammation of the rectal wall (p=0.02), high-grade internal rectal procidentia (p=0.06) and anal hypotonia (p=0.004); their maximum tolerable volume was lower (p=0.004).
The characteristics of patients with SRUS suggest different phenotypes. This may be a way to develop a comprehensive treatment strategy.
The mini fungal lectin PhoSL was recombinantly produced and characterized. Despite a length of only 40 amino acids, PhoSL exclusively recognizes N‐glycans with α1,6‐linked fucose. Core fucosylation ...influences the intrinsic properties and bioactivities of mammalian N‐glycoproteins and its level is linked to various cancers. Thus, PhoSL serves as a promising tool for glycoprofiling. Without structural precedence, the crystal structure was solved using the zinc anomalous signal, and revealed an interlaced trimer creating a novel protein fold termed β‐prism III. Three biantennary core‐fucosylated N‐glycan azides of 8 to 12 sugars were cocrystallized with PhoSL. The resulting highly resolved structures gave a detailed view on how the exclusive recognition of α1,6‐fucosylated N‐glycans by such a small protein occurs. This work also provided a protein consensus motif for the observed specificity as well as a glimpse into N‐glycan flexibility upon binding.
Molecular prisms: The structure of rPhoSL unraveled a novel protein fold and the atomic basis for the exclusive recognition of α1,6‐core‐fucosylated N‐glycans by a mini recombinant lectin. Thus, PhoSL serves as a promising tool for glycoprofiling.
We assess cerebral integrity with cortical and subcortical FDG-PET and cortical electroencephalography (EEG) within the mesocircuit model framework in patients with disorders of consciousness (DoCs). ...The mesocircuit hypothesis proposes that subcortical activation facilitates cortical function. We find that the metabolic balance of subcortical mesocircuit areas is informative for diagnosis and is associated with four EEG-based power spectral density patterns, cortical metabolism, and α power in healthy controls and patients with a DoC. Last, regional electrometabolic coupling at the cortical level can be identified in the θ and α ranges, showing positive and negative relations with glucose uptake, respectively. This relation is inverted in patients with a DoC, potentially related to altered orchestration of neural activity, and may underlie suboptimal excitability states in patients with a DoC. By understanding the neurobiological basis of the pathophysiology underlying DoCs, we foresee translational value for diagnosis and treatment of patients with a DoC.
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•Biologically founded EEG spectral regimes are related to cortical glucose uptake•Subcortical metabolism correlates with cortical α power, glucose uptake, and consciousness•Cortical α is negatively and θ is positively related to cortical glucose uptake in controls•Cortical electrometabolic coupling is inverted in patients with a severe brain injury
Patients with disorders of consciousness are characterized by reduced cerebral function as measured by glucose uptake and electrical activity. Annen et al. characterize the role of subcortical areas in sustaining cortical function and quantify electrometabolic coupling in healthy conscious and reduced conscious states after coma.
Transcranial direct current stimulation (tDCS) is a non-invasive technique recently employed in disorders of consciousness, and determining a transitory recovery of signs of consciousness in almost ...half of minimally conscious state (MCS) patients. Although the rising evidences about its possible role in the treatment of many neurological and psychiatric conditions exist, no evidences exist about brain functional connectivity substrates underlying tDCS response. We retrospectively evaluated resting state functional Magnetic Resonance Imaging (fMRI) of 16 sub-acute and chronic MCS patients (6 tDCS responders) who successively received a single left dorsolateral prefrontal cortex (DLPFC) tDCS in a double-blind randomized cross-over trial. A seed-based approach for regions of left extrinsic control network (ECN) and default-mode network (DMN) was performed. tDCS responders showed an increased left intra-network connectivity for regions co-activated with left DLPFC, and significantly with left inferior frontal gyrus. Non-responders (NR) MCS patients showed an increased connectivity between left DLPFC and midline cortical structures, including anterior cingulate cortex and precuneus. Our findings suggest that a prior high connectivity with regions belonging to ECN can facilitate transitory recovery of consciousness in a subgroup of MCS patients that underwent tDCS treatment. Therefore, resting state-fMRI could be very valuable in detecting the neuronal conditions necessary for tDCS to improve behavior in MCS.
From December 2019, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has spread rapidly, leading to a global pandemic. Little is known about possible relationships between ...SARS‐CoV‐2 and other viruses in the respiratory system affecting patient prognosis and outcomes. This study aims to characterize respiratory virome profiles in association with SARS‐CoV‐2 infection and disease severity, through the analysis in 89 nasopharyngeal swabs collected in a patient's cohort from the Campania region (Southern Italy). Results show coinfections with viral species belonging to Coronaviridae, Retroviridae, Herpesviridae, Poxviridae, Pneumoviridae, Pandoraviridae, and Anelloviridae families and only 2% of the cases (2/89) identified respiratory viruses.
Key Points
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The severe acute respiratory syndrome coronavirus 2 infection is considered a major global threat that is still spreading around the world.
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Nasopharyngeal swabs samples were collected from the Campania region cohort of 89 Covid‐19 patients.
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Descriptive analysis of respiratory virome was carried out with the HOME‐BIO pipeline, that performed viral taxonomy profiling.
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It detected coinfections with viral species belonging to Coronaviridae, Retroviridae, Herpesviridae, Poxviridae, Pneumoviridae, Pandoraviridae, and Anelloviridae family.
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Only 2% of the cases (2/89) identified respiratory viruses.
The development of multicellular organisms requires the precisely coordinated regulation of an evolutionarily conserved group of signaling pathways. Temporal and spatial control of these signaling ...cascades is achieved through networks of regulatory proteins, segregation of pathway components in specific subcellular compartments, or both. In vertebrates, dysregulation of primary cilia function has been strongly linked to developmental signaling defects, yet it remains unclear whether cilia sequester pathway components to regulate their activation or cilia-associated proteins directly modulate developmental signaling events. To elucidate this question, we conducted an RNAi-based screen in Drosophila non-ciliated cells to test for cilium-independent loss-of-function phenotypes of ciliary proteins in developmental signaling pathways. Our results show no effect on Hedgehog signaling. In contrast, our screen identified several cilia-associated proteins as functioning in canonical Wnt signaling. Further characterization of specific components of Intraflagellar Transport complex A uncovered a cilia-independent function in potentiating Wnt signals by promoting β-catenin/Armadillo activity.
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•Ciliary proteins can modulate the canonical Wnt pathway independently of the cilium•IFT-A protein knockdown leads to loss of canonical Wnt-specific target gene expression•IFT-A proteins modulate Wnt signaling through the stabilization of β-cat/Arm
Intraflagellar transport (IFT) proteins form multi-subunit protein complexes to ensure bidirectional transport within the cilium. Balmer et al. identify through a reverse genetic screen that a subset of IFT complex A proteins promotes canonical Wnt signaling independent of their ciliary function by modulation of β-catenin/Armadillo activity.
JunD regulates genes involved in antioxidant defence. We took advantage of the chronic oxidative stress resulting from junD deletion to examine the role of reactive oxygen species (ROS) in tumour ...development. In a model of mammary carcinogenesis, junD inactivation increased tumour incidence and revealed an associated reactive stroma. junD‐inactivation in the stroma was sufficient to shorten tumour‐free survival rate and enhance metastatic spread. ROS promoted conversion of fibroblasts into highly migrating myofibroblasts through accumulation of the hypoxia‐inducible factor (HIF)‐1α transcription factor and the CXCL12 chemokine. Accordingly, treatment with an antioxidant reduced the levels of HIF and CXCL12 and numerous myofibroblast features. CXCL12 accumulated in the stroma of HER2‐human breast adenocarcinomas. Moreover, HER2 tumours exhibited a high proportion of myofibroblasts, which was significantly correlated to nodal metastases. Interestingly, this subset of tumours exhibited a significant nuclear exclusion of JunD and revealed an associated oxido‐reduction signature, further demonstrating the relevance of our findings in human cancers. Collectively, our data uncover a new mechanism by which oxidative stress increases the migratory properties of stromal fibroblasts, which in turn potentiate tumour dissemination.
Abstract
Objectives
ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients ...are still incompletely understood.
Methods
We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative).
Results
A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age female 50%; mean age 48.4 years (s.d. 12.6) and 34% had disease onset at ≥65 years female 54%; mean age 73.6 years (s.d. 6). ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03.
Conclusion
Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.
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