•Local silt layer allows dry dock without dewatering in alignment of immersed tunnel.•Dry dock used for elements 1 & 2, then 3 & 4 and for further cast in situ tunnel.•Uplift silt layer and water ...levels require use of lock in trench for elements 1 & 2.•Water level require unusually small draft for elements 3 & 4.•Element 4 ends in dock: no closure joint, locking system and watertight sealing off.
The construction of the A73 highway from Venlo to Maastricht (the Netherlands) involved the construction of the 2.4 km long, dual two lane Roertunnel near the city of Roermond. The Roertunnel consists of a somewhat deeper part crossing the quite small River Roer and its 1 km wide flood Valley, continued by a 1.4 km long shallow tunnel alongside the southern part of Roermond. The water levels in the River Roer vary from low water (summer conditions) to high water levels and possibly flooding of the Valley (spring conditions). Environmental conditions were severe, prohibiting amongst other for dewatering.
The project was tendered the Ministry of Public Works and Water Management (Rijkswaterstaat RWS as a design and build contract. The tender documents included a reference design developed by the client for the crossing of the Roer Valley. This design consisted of a cast in situ piled cut and cover tunnel constructed in a building pit formed by temporary sheet piles and closed off at its bottom by a unreinforced concrete slab supported by tie down piles. This concept was designed to avoid dewatering of the building pit.
In view of the ground conditions, an immersed tunnel was a more cost effective solution compared to the proposed reference design. However, an immersed tunnel appeared at a first glance not to be feasible as the small depth and width of the River Roer does not allow transportation of tunnel elements over the River from any remote dry dock, and as a dry dock in the vicinity of the tunnel location could not be created as dewatering was not allowed. The careful analysis of the geotechnical data indicated the local presence of a 5 m thick silt layer of low permeability over a length of 350 m along the tunnel alignment at the eastern side of the Roer Valley. This offered the opportunity to create a dry dock of length of about 350 m along the alignment of the tunnel by means of sheet piles reaching into the silt layer, avoiding any dewatering. The dry dock has been used for the construction of the four immersed elements of a total length of about 600 m in two batches. Finally the dock was used to construct the remaining part of the crossing of the Valley as a cast in situ tunnel.
A gravel bed foundation consisting of nine berms per tunnel segment has been preferred above sand flow to mitigate the risk of weakening of loose sand in case of earthquake.
The paper describes the concept and the various aspects of the design of the immersed tunnel constructed in a dry dock along the tunnel alignment. A section of the paper is devoted to the interaction of structural design and gravel bed design.
•Immersion trench very close and below existing immersed tunnel.•Severe requirements to displacements of existing tunnel.•Criteria for design and execution of partition wall.•Monitoring of tunnel ...during execution according to observational method (71).
In the framework of the improvement of the traffic around Amsterdam, a new immersed tunnel has been constructed very close and somewhat deeper along the existing immersed tunnel built in the 1960s. A partition (retaining) wall is needed to maintain the existing tunnel while performing the dredging works for the immersion trench of the new tunnel. Due to the quite poor state of the tunnel and the short distance between the new and existing tunnels, the construction of the partition wall and the dredging works were considered as a main project risk.
During one year, the movements of the existing tunnel have been monitored to understand its behaviour. A detailed analysis of possible causes of deformation of the existing tunnel and of the displacements at its immersion joints during installation of the partition wall and the dredging works has been performed. Requirements to the allowable displacement at the immersion joints and hence to the design and construction of the partition wall have been derived from these observations and analyses. Extensive monitoring has been performed during the installation of the partition wall applying the principles of the observational method. Based on this monitoring, criteria were re-evaluated during the works and a safe and damage free operation has been continuously monitored all along the construction period.
This paper describes the approach applied to the design, execution and monitoring of the existing tunnel and focusses on the analysis and mitigation of main design and construction risks, as well as the monitoring system and threshold values applied. The difficulties encountered during the installation and the corrective methods are described.
In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to ...receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4
T-cell responses (
< 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8
T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (
= 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8
T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (
= 0.004) and CD27/CD57 (
= 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log
copies cp/ml; interquartile range IQR, 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.)
In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4
and CD8
T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.
Background. Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization is a well-established risk factor for subsequent infection and a key event in interindividual transmission. Some ...studies have showed an association between fluoroquinolones and MRSA colonization or infection. The present study was performed to identify specific risk factors for MRSA acquisition in long-term care facilities (LTCFs). Methods. A prospective cohort of patients naive for S. aureus colonization was established and followed (January 2008 through October 2010) in 4 French LTCFs. Nasal colonization status and potential risk factors were assessed weekly for 13 weeks after inclusion. Variables associated with S. aureus acquisition were identified in a nested-matched case-case-control study using conditional logistic regression models. Cases were patients who acquired MRSA (or methicillin-sensitive S. aureus MSSA). Patients whose nasal swab samples were always negative served as controls. Matching criteria were center, date of first nasal swab sample, and exposure time. Results. Among 451 included patients, 76 MRSA cases were matched to 207 controls and 112 MSSA cases to 208 controls. Multivariable analysis retained fluoroquinolones (odds ratio, 2.17; 95% confidence interval, 1.01–4.67), male sex (2.09; 1.10–3.98), and more intensive care at admission (3.24; 1.74–6.04) as significantly associated with MRSA acquisition, and body-washing assistance (2.85; 1.27–6.42) and use of a urination device (1.79; 1.01–3.18) as significantly associated with MSSA acquisition. Conclusions. Our results suggest that fluoroquinolones are a risk factor for MRSA acquisition. Control measures to limit MRSA spread in LTCFs should also be based on optimization of fluoroquinolone use.
Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic ...underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h
of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.
Long-term remitted Cushing's disease (LTRCD) patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Although previous ...studies have conducted gray matter volume analyses, assessing cortical thickness and surface area of LTRCD patients may offer further insight into the neuroanatomical substrates of Cushing's disease. Structural 3T magnetic resonance images were obtained from 25 LTRCD patients, and 25 age-, gender-, and education-matched healthy controls (HCs). T1-weighted images were segmented using FreeSurfer software to extract mean cortical thickness and surface area values of 68 cortical gray matter regions and two whole hemispheres. Paired sample t tests explored differences between the anterior cingulate cortex (ACC; region of interest), and the whole brain. Validated scales assessed psychiatric symptomatology, self-reported cognitive functioning, and disease severity. After correction for multiple comparisons, ROI analyses indicated that LTRCD-patients showed reduced cortical thickness of the left caudal ACC and the right rostral ACC compared to HCs. Whole-brain analyses indicated thinner cortices of the left caudal ACC, left cuneus, left posterior cingulate cortex, right rostral ACC, and bilateral precuneus compared to HCs. No cortical surface area differences were identified. Cortical thickness of the left caudal ACC and left cuneus were inversely associated with anxiety symptoms, depressive symptoms, and disease duration, although certain associations did not persist after correction for multiple testing. In six of 68 regions examined, LTRCD patients had reduced cortical thickness in comparison to HCs. Cortical thickness of the left caudal ACC was inversely associated with disease duration. This suggests that prolonged and excessive exposure to glucocorticoids may be related to cortical thinning of brain structures involved in emotional and cognitive processing.
Cushing’s disease (CD) is a rare and severe endocrine disease characterized by hypercortisolemia. Previous studies have found structural brain alterations in remitted CD patients compared to healthy ...controls, specifically in the anterior cingulate cortex (ACC). However, potential mechanisms through which these persistent alterations may have occurred are currently unknown.
Structural 3T MRI’s from 25 remitted CD patients were linked with gene expression data from neurotypical donors, derived from the Allen Human Brain Atlas. Differences in gene expression between the ACC and an unaffected control cortical region were examined, followed by a Gene Ontology (GO) enrichment analysis. A cell type enrichment analysis was conducted on the differentially expressed genes, and a disease association enrichment analysis was conducted to determine possible associations between differentially expressed genes and specific diseases. Subsequently, cortisol sensitivity of these genes in existing datasets was examined.
The gene expression analysis identified 300 differentially expressed genes in the ACC compared to the cortical control region. GO analyses found underexpressed genes to represent immune function. The cell type specificity analysis indicated that underexpressed genes were enriched for deactivated microglia and oligodendrocytes. Neither significant associations with diseases, nor evidence of cortisol sensitivity with the differentially expressed genes were found.
Underexpressed genes in the ACC, the area vulnerable to permanent changes in remitted CD patients, were often associated with immune functioning. The specific lack of deactivated microglia and oligodendrocytes implicates protective effects of these cell types against the long-term effects of cortisol overexposure.
•Underexpressed genes in the ACC of CD patients associated with immune functioning.•Fewer deactivated microglia and oligodendrocytes markers in the ACC of CD patients.•These cell types may protect against the effects of chronic cortisol overexposure.
Abstract Background Clinical observations suggest that Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) may affect cystic fibrosis (CF) patients with different ...characteristics and risk factors, but this has never been demonstrated within a single prospective cohort. Methods We studied 50 MABSC-positive and 23 MAC-positive patients from a French prevalence study of non‐tuberculous mycobacteria (NTM) in CF. Risk factors specifically associated with MABSC and MAC were analyzed by nested case–control studies, with two NTM-negative controls matched by age, sex and center for each case. Results MAC-positive patients were significantly older than MABSC-positive patients (mean SD age, 23.1 10.2 vs 17.4 8.3 years, p = 0.013), and were also older at CF diagnosis (mean SD age, 12.9 16.1 vs 3.1 7.7 years, p = 0.015); they tended to be less frequent of the ΔF508/ΔF508 genotype (33.3 vs 61.1%, p = 0.17) and to use pancreatic extracts less frequently (82.4 vs 97.6%, p = 0.07). Risk factors identified by multivariate analysis were: i) in the MAC case–control study, an older age at CF diagnosis (p = 0.004); ii) in the MABSC case–control study, at least one course of intravenous antibiotics (p = 0.01) and more frequent isolation of Aspergillus (p = 0.03). Conclusions MAC affects adult patients with a mild form of CF, whereas MABSC affects younger patients with more severe CF and more frequent intravenous antimicrobial treatment.
•Patients with MDD have elevated awakening salivary alpha-amylase (sAA) levels.•sAA levels are higher in patients with MDD than in other common psychiatric disorders.•Evening salivary cortisol levels ...are elevated in patients with MDD.
Specific Major Depressive Disorder (MDD) biomarkers could help improve our understanding of MDD pathophysiology and aid in the refinement of current MDD criteria. While salivary cortisol (SC) can differentiate between healthy controls and patients with psychiatric disorders, salivary alpha amylase (sAA), may be a putative candidate biomarker for MDD specifically.
In a naturalistic cohort of consecutive out-patients and healthy controls, sAA and SC were determined in 833 participants (97 MDD patients, 142 patients with other mood, anxiety, and/or somatoform (MAS-) disorders, and 594 healthy controls). Samples were collected at 7 different time points (at awakening, after 30, 45, and 60 min, at 10:00 p.m., at 11:00 p.m., and at awakening on day 2).
The mean age of the sample was 43.8 years (SD = 12.9; 63.9% female). Concerning sAA, MDD patients had higher sAA levels upon awakening on two consecutive days (p = 0.04, p = 0.01 respectively), as well as a higher area under the curve with respect to the increase (AUCi; p = 0.04) in comparison to both controls and the other MAS-disorders group. Regarding SC, mean levels of evening SC were elevated in MDD patients (p = 0.049) in comparison to both controls and the other MAS-disorders group. SC values on day 2 after ingestion of dexamethasone were elevated in both MDD patients and the other MAS-disorders group (p = 0.04, p = 0.047 respectively).
sAA at awakening and not cortisol differentiates MDD from other psychiatric disorders in outpatients. This suggests that sAA may be a valuable candidate biomarker specifically for MDD.
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