Understanding the nature of high-redshift dusty galaxies requires a comprehensive view of their interstellar medium (ISM) and molecular complexity. However, the molecular ISM at high redshifts is ...commonly studied using only a few species beyond
12
C
16
O, limiting our understanding. In this paper, we present the results of deep 3 mm spectral line surveys using the NOrthern Extended Millimeter Array (NOEMA) targeting two strongly lensed dusty galaxies observed when the Universe was less than 1.8 Gyr old: APM 08279+5255, a quasar at redshift
z
= 3.911, and NCv1.143 (
H
-ATLAS J125632.7+233625), a
z
= 3.565 starburst galaxy. The spectral line surveys cover rest-frame frequencies from about 330 to 550 GHz for both galaxies. We report the detection of 38 and 25 emission lines in APM 08279+5255 and NCv1.143, respectively. These lines originate from 17 species, namely CO,
13
CO, C
18
O, CN, CCH, HCN, HCO
+
, HNC, CS, C
34
S, H
2
O, H
3
O
+
, NO, N
2
H
+
, CH, c-C
3
H
2
, and the vibrationally excited HCN and neutral carbon. The spectra reveal the chemical richness and the complexity of the physical properties of the ISM. By comparing the spectra of the two sources and combining the analysis of the molecular gas excitation, we find that the physical properties and the chemical imprints of the ISM are different: the molecular gas is more excited in APM 08279+5255, which exhibits higher molecular gas temperatures and densities compared to NCv1.143; the molecular abundances in APM 08279+5255 are akin to the values of local active galactic nuclei (AGN), showing boosted relative abundances of the dense gas tracers that might be related to high-temperature chemistry and/or the X-ray-dominated regions, while NCv1.143 more closely resembles local starburst galaxies. The most significant differences between the two sources are found in H
2
O: the 448 GHz ortho-H
2
O(4
23
− 3
30
) line is significantly brighter in APM 08279+5255, which is likely linked to the intense far-infrared radiation from the dust powered by AGN. Our astrochemical model suggests that, at such high column densities, far-ultraviolet radiation is less important in regulating the ISM, while cosmic rays (and/or X-rays and shocks) are the key players in shaping the molecular abundances and the initial conditions of star formation. Both our observed CO isotopologs line ratios and the derived extreme ISM conditions (high gas temperatures, densities, and cosmic-ray ionization rates) suggest the presence of a top-heavy stellar initial mass function. From the ∼330–550 GHz continuum, we also find evidence of nonthermal millimeter flux excess in APM 08279+5255 that might be related to the central supermassive black hole. Such deep spectral line surveys open a new window into the physics and chemistry of the ISM and the radiation field of galaxies in the early Universe.
No data exist on risks of infection with
Mycobacterium tuberculosis in travellers. We studied incidences of and risk factors for tuberculin skin-test conversion among Dutch long-term travellers to ...countries of high tuberculosis endemicity.
In a multicentre, prospective cohort study based in travel and tuberculosis clinics in the Netherlands, 1072 BCG-naïve immunocompetent travellers to countries with an estimated annual risk of
M tuberculosis infection of at least 1% were skin tested before departure with 1 tuberculin unit purified protein derivative (PPD) of
M tuberculosis in Tween-80. Those with results less than 2 mm were retested 2–4 months after their return with simultaneous testing for cross-sensitivity to environmental mycobacteria (1 tuberculin unit PPD of
M scrofulaceum in Tween-80).
M tuberculosis infection was defined as a post-travel
M tuberculosis tuberculin skin-test result of at least 10 mm that was 3 mm or more larger than the
M scrofulaceum result.
Post-travel skin-test results were available for 656 (66%) of 988 individuals who were eligible for follow-up. Among these, 12
M tuberculosis infections were identified (1·8%). The overall incidence rate was 3·5 per 1000 person-months of travel (95% Cl 2·0–6·2), and 2·8 per 1000 person-months of travel (1·2–5·5) after exclusion of health-care workers. Two had active tuberculosis at the time of testing (incidence rate 0·6 per 1000 person-months of travel 0·3–2·3). Work in patient care abroad was an independent risk factor (adjusted rate ratio 5·34, p=0·015).
The risk of
M tuberculosis infection in long-term travellers to high-endemicity countries, even if not engaged in health-care work, is substantial and of similar magnitude to the average risk for the local population. BCG vaccination or post-travel tuberculin skin-testing of high-risk travellers should be considered.
Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening.
In a multicenter, prospective, randomized crossover ...study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, The Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence.
The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D(4)/D(0) glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2-3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads.
Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.
The choice between posterior cervical foraminotomy (posterior surgery) and anterior cervical discectomy with fusion (anterior surgery) for cervical foraminal radiculopathy remains controversial.
To ...investigate the noninferiority of posterior vs anterior surgery in patients with cervical foraminal radiculopathy with regard to clinical outcomes after 1 year.
This multicenter investigator-blinded noninferiority randomized clinical trial was conducted from January 2016 to May 2020 with a total follow-up of 2 years. Patients were included from 9 hospitals in the Netherlands. Of 389 adult patients with 1-sided single-level cervical foraminal radiculopathy screened for eligibility, 124 declined to participate or did not meet eligibility criteria. Patients with pure axial neck pain without radicular pain were not eligible. Of 265 patients randomized (132 to posterior and 133 to anterior), 15 were lost to follow-up and 228 were included in the 1-year analysis (110 in posterior and 118 in anterior).
Patients were randomly assigned 1:1 to posterior foraminotomy or anterior cervical discectomy with fusion.
Primary outcomes were proportion of success using Odom criteria and decrease in arm pain using a visual analogue scale from 0 to 100 with a noninferiority margin of 10% (assuming advantages with posterior surgery over anterior surgery that would justify a tolerable loss of efficacy of 10%). Secondary outcomes were neck pain, disability, quality of life, work status, treatment satisfaction, reoperations, and complications. Analyses were performed with 2-proportion z tests at 1-sided .05 significance levels with Bonferroni corrections.
Among 265 included patients, the mean (SD) age was 51.2 (8.3) years; 133 patients (50%) were female and 132 (50%) were male. Patients were randomly assigned to posterior (132) or anterior (133) surgery. The proportion of success was 0.88 (86 of 98) in the posterior surgery group and 0.76 (81 of 106) in the anterior surgery group (difference, -0.11 percentage points; 1-sided 95% CI, -0.01) and the between-group difference in arm pain was -2.8 (1-sided 95% CI, -9.4) at 1-year follow-up, indicating noninferiority of posterior surgery. Decrease in arm pain had a between-group difference of 3.4 (1-sided 95% CI, 11.8), crossing the noninferiority margin with 1.8 points. All secondary outcomes had 2-sided 95% CIs clustered around 0 with small between-group differences.
In this randomized clinical trial, posterior surgery was noninferior to anterior surgery for patients with cervical radiculopathy regarding success rate and arm pain at 1 year. Decrease in arm pain and secondary outcomes had small between-group differences. These results may be used to enhance shared decision-making.
Netherlands Trial Register Identifier: NTR5536.
Short-term neck pain after posterior cervical foraminotomy (posterior surgery) compared with anterior cervical discectomy with fusion (anterior surgery) treating cervical radiculopathy has only been ...assessed once, retrospectively, to our knowledge. The aim of this study was to prospectively evaluate the course of neck pain for 6 weeks after both treatments.
This is a secondary analysis of the multicenter Foraminotomy ACDF Cost-Effectiveness Trial (FACET), conducted from January 2016 to May 2020. Of 389 patients who had single-level, 1-sided cervical radiculopathy and were screened for eligibility, 265 were randomly assigned to undergo posterior surgery (n = 132) or anterior surgery (n = 133). The primary outcome of the present analysis was neck pain, assessed weekly for 6 weeks using the visual analog scale (VAS), on a scale of 0 to 100. The secondary outcomes were arm pain, neck disability, work ability, quality of life, treatment satisfaction, motor and sensory changes, and hospital length of stay. Data were analyzed with mixed model analysis in intention-to-treat samples using 2-sided 95% confidence intervals (CIs).
In the first postoperative week, the mean VAS for neck pain was 56.2 mm (95% CI, 51.7 to 60.8 mm) after posterior surgery and 46.7 mm (95% CI, 42.2 to 51.2 mm) after anterior surgery. The mean between-group difference was 9.5 mm (95% CI, 3.3 to 15.7 mm), which gradually decreased to 2.3 mm (95% CI, -3.6 to 8.1 mm) at postoperative week 6. As of postoperative week 5, there was no significant difference between groups. Responder analyses confirmed this result. Secondary outcomes showed small differences between groups.
Insight into the course of neck pain during the first 6 weeks after posterior compared with anterior surgery is provided. Despite initially more neck pain after posterior surgery, patients swiftly improved and, as of postoperative week 5, results similar to those after anterior surgery were observed. Our findings should enable improved patient counseling and enhanced shared decision-making between physicians and patients with cervical radiculopathy, where more neck pain in the first postoperative weeks should be balanced against the benefits of posterior surgery.
Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.
Patients' initial beliefs about the success of a given pain treatment are shown to affect final treatment outcome. The Credibility/Expectancy Questionnaire (CEQ) has recently been developed as ...measure of treatment credibility and expectancy.
The objectives of this study were (1) to investigate the factor structure of the CEQ in a sample of chronic low back pain (CLBP) patients by means of a confirmatory factor analysis, (2) to examine the association between treatment credibility and expectancy and patient characteristics, and (3) to assess whether treatment expectancy and credibility are associated with the outcome of rehabilitation treatment.
CLBP patients (n=167) were randomized to either active physical therapy (n=51), cognitive-behavioral therapy (n=57), or a combination therapy (n=59), and completed the CEQ after a careful explanation of the treatment rationale.
Confirmatory factor analysis supported the 2-factor structure (credibility/expectancy) of the CEQ. Lower credibility was associated with higher pain-related fear and lower internal control of pain, and lower expectancy with higher levels of pain-related fear and no radiating pain. Multiple linear regression analyses revealed that after controlling for age, sex, treatment center, pain-intensity at baseline, duration of disability, and irrespective of the treatment offered, expectancy was significantly associated with disability and satisfaction. Credibility was significantly associated with patient-specific symptoms and satisfaction. For global perceived effect, treatment expectancy was predictive in active physical therapy only, and treatment credibility was a significant predictor in combination therapy only.
Although the associations found were low to modest, these results underscore the importance of expectancy and credibility for the outcome of different active interventions for CLBP and might contribute to the development of more effective treatments.
Natural killer (NK) cells are innate immune cells, characterized by their cytotoxic capacity, and chemokine and cytokine secretion upon activation. Human NK cells are identified by CD56 expression. ...Circulating NK cells can be further subdivided into the CD56
(~10%) and CD56
NK cell subsets (~90%). NK cell-like cells can also be derived from human induced pluripotent stem cells (iPSC). To study the chemokine and cytokine secretion profile of the distinct heterogenous NK cell subsets, intracellular flow cytometry staining can be performed. However, this assay is challenging when the starting material is limited. Alternatively, NK cell subsets can be enriched, sorted, stimulated, and functionally profiled by measuring secreted effector molecules in the supernatant by Luminex. Here, we provide a rapid and straightforward protocol for the isolation and stimulation of primary NK cells or iPSC-derived NK cell-like cells, and subsequent detection of secreted cytokines and chemokines, which is also applicable for a low number of cells.
International travel may be a source of introduction of tuberculosis into low-incidence countries. We assessed whether, in The Netherlands, sensitivity to tuberculin was associated with a history of ...travel to countries with a high incidence of tuberculosis. Immunocompetent adults with no history of Bacille Calmette-Guérin vaccination or sensitivity to tuberculin were skin-tested simultaneously with 1-tuberculin unit (TU) purified protein derivative (PPD) of Mycobacterium tuberculosis and 1-TU sensitin of Mycobacterium scrofulaceum. Tuberculin sensitivity was defined as a reaction to PPD of ⩾10 mm that was ⩾3 mm larger than the reaction to M. scrofulaceum sensitin. Tuberculin sensitivity was found in 7 (0.7%) of 1014 participants (95% confidence interval CI, 0.3%–1.4%); it was independently associated with a cumulative history of >3-months' travel to high-incidence areas (odds ratio, 6.0; 95% CI, 1.2–31.2; P = .016) and increased in association with total duration of travel (P = .02). Travel to high-incidence areas increases the risk of tuberculin sensitivity and, consequently, of latent tuberculous infection. In countries with a low incidence of tuberculosis, cases of infection acquired during travel may account for a substantial proportion of new infections in the resident population.
The purposes of this study were to determine the prevalence of and the association between shoulder contracture and osseous deformity in a cohort of children with an obstetrical brachial plexus ...injury and to identify the risk factors for these complications.
In a retrospective cohort study, all children with an obstetrical brachial plexus injury who had been born between January 1991 and January 1998 at one academic medical center and all those with the same diagnosis who had been born elsewhere during the same period and were referred to the medical center within six weeks after delivery were evaluated at fixed time-intervals by one examiner. The patients underwent a final orthopaedic, neurological, and radiographic examination at a mean age of 3.7 years (range, one to seven years). Shoulder contracture was defined as a decrease in the passive range of motion in one or more directions compared with the range on the unaffected side. Osseous deformity was defined as a nonspherical humeral head or an abnormal glenoid.
The prevalence of a shoulder contracture of >10 degrees was 56% (twenty-nine of fifty-two patients), and the prevalence of an osseous deformity was 33% (sixteen of forty-eight patients with complete radiographic follow-up). In the children in whom complete neurological recovery was delayed (i.e., recovery was more than three weeks after birth), the prevalence of shoulder contracture was 54% (thirteen of twenty-four patients) and the prevalence of osseous deformity was 26% (six of twenty-three patients). A strong association was noted between shoulder contracture and osseous deformity (p = 0.004). Directly after birth, the presence of a clavicular fracture was the only factor that was associated (p = 0.016) with the development of an osseous deformity (but not with a shoulder contracture). At a later stage, speed and extent of neurological recovery were related to shoulder contracture and osseous deformity. An asymmetric appearance was noticed in children who had a contracture, including those who had complete neurological recovery.
The prevalence of shoulder contracture and osseous deformity in children with obstetrical brachial plexus injury was high, even in those with complete neurological recovery. These complications were strongly associated with one another. No symptom that appeared immediately after birth was identified as a factor that would predict the development of future shoulder contracture. A clavicular fracture was found to be significantly associated with the development of an osseous deformity at a later stage.
Estrogen Receptor alpha (ERα)-positive breast cancer patients receive endocrine therapy, often in the form of tamoxifen. However, resistance to tamoxifen is frequently observed. A signalling cascade ...that leads to tamoxifen resistance is dictated by activation of the Protein Kinase A (PKA) pathway, which leads to phosphorylation of ERα on Serine 305 and receptor activation, following tamoxifen binding. Thus far, it remains elusive what protein complexes enable the PKA-ERα interaction resulting in ERα Serine 305 phosphorylation.
We performed immunohistochemistry to detect ERαSerine 305 phosphorylation in a cohort of breast cancer patients who received tamoxifen treatment in the metastatic setting. From the same tumor specimens, Agilent 44 K gene expression analyses were performed and integrated with clinicopathological data and survival information. In vitro analyses were performed using MCF7 breast cancer cells, which included immunoprecipitations and Fluorescence Resonance Energy Transfer (FRET) analyses to illustrate ERα complex formation. siRNA mediated knockdown experiments were performed to assess effects on ERαSerine 305 phosphorylation status, ERα/PKA interactions and downstream responsive gene activity.
Stratifying breast tumors on ERα Serine 305 phosphorylation status resulted in the identification of a gene network centered upon AKAP13. AKAP13 mRNA expression levels correlate with poor outcome in patients who received tamoxifen treatment in the metastatic setting. In addition, AKAP13 mRNA levels correlate with ERαSerine 305 phosphorylation in breast tumor samples, suggesting a functional connection between these two events. In a luminal breast cancer cell line, AKAP13 was found to interact with ERα as well as with a regulatory subunit of PKA. Knocking down of AKAP13 prevented PKA-mediated Serine 305 phosphorylation of ERα and abrogated PKA-driven tamoxifen resistance, illustrating that AKAP13 is an essential protein in this process.
We show that the PKA-anchoring protein AKAP13 is essential for the phosphorylation of ERαS305, which leads to tamoxifen resistance both in cell lines and tamoxifen-treated breast cancer patients.
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