Abstract
Microvascular dysfunction (MVD) is a common pathophysiological change that occurs in various diseases, such as type 2 diabetes mellitus (T2DM), heart failure, dementia, and depression. ...Recent technical advances have enabled noninvasive measurement and quantification of microvascular changes in humans. In this paper, we describe the protocols of the microvascular measurements applied in the Maastricht Study, an ongoing prospective, population-based cohort study of persons aged 40–75 years being carried out in the southern part of the Netherlands (baseline data assessment, November 2010–January 2020). The study includes a variety of noninvasive measurements in skin, retina, brain, and sublingual tissue, as well as plasma and urine biomarker assessments. Following this, we summarize our main findings involving these microvascular measurements through the end of 2018. Finally, we provide a brief perspective on future microvascular investigations within the framework of the Maastricht Study.
We present spectroscopic redshifts of mJy submillimeter galaxies (SMGs), which have been identified from the ALMA follow-up observations of 870 m detected sources in the Extended Chandra Deep Field ...South (the ALMA-LESS survey). We derive spectroscopic redshifts for 52 SMGs, with a median of z = 2.4 0.1. However, the distribution features a high-redshift tail, with ∼23% of the SMGs at . Spectral diagnostics suggest that the SMGs are young starbursts, and the velocity offsets between the nebular emission and UV ISM absorption lines suggest that many are driving winds, with velocity offsets of up to 2000 km s−1. Using the spectroscopic redshifts and the extensive UV-to-radio photometry in this field, we produce optimized spectral energy distributions (SEDs) using Magphys, and use the SEDs to infer a median stellar mass of = (6 1)× 1010 M for our SMGs with spectroscopic redshift. By combining these stellar masses with the star formation rates (measured from the far-infrared SEDs), we show that SMGs (on average) lie a factor of ∼5 above the so-called "main sequence" at . We provide this library of 52 template fits with robust and uniquely well-sampled SEDs as a resource for future studies of SMGs, and also release the spectroscopic catalog of ∼2000 (mostly infrared-selected) galaxies targeted as part of the spectroscopic campaign.
The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever ...worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.
•Infections, autoimmunity, and granuloma predispose to organ damage prior HSCT, thereby compromising survival and quality of immune reconstitution.•In patients with hypomorphic ...recombination-activating gene deficiency, HSCT with T-cell depleted grafts shows poor outcome.
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Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio HR = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.
Hypomorphic alleles for the recombination activation genes RAG1 and RAG2 lead to severe immunodeficiency syndromes. Schuetz et al report on a retrospective analysis of transplant outcomes in 60 patients with this rare disorder. Overall survival at 4 years was 67.5%, with poor survival predicted by active infection, organ damage, and T-cell depletion of the graft. Patients diagnosed by newborn screening with early transplant had 100% survival, supporting early transplantation for these patients.
Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In ...this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.
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•Human BCG vaccination induces a persistent innate immune training of CD14+ monocytes•BCG vaccination imprints a persistent transcriptomic myeloid bias on human HSPCs•Hepatic nuclear factors are regulators of BCG-induced trained immunity in HSPCs•BCG induces persistent epigenetic changes in peripheral CD14+ monocytes
Cirovic and de Bree et al. investigate the effects of BCG vaccination in humans and reveal the induction of a transcriptomic rewiring of human stem and progenitor cells toward the myeloid cell lineage, instructed by hepatic nuclear factors, resulting in epigenetic and functional changes within CD14+ peripheral monocytes.
We present detailed studies of a z = 2.12 submillimeter galaxy, ALESS67.1, using sub-arcsecond resolution ALMA, adaptive optics-aided VLT/SINFONI, and Hubble Space Telescope (HST)/CANDELS data to ...investigate the kinematics and spatial distributions of dust emission (870 m continuum), 12CO(J = 3-2), strong optical emission lines, and visible stars. Dynamical modeling of the optical emission lines suggests that ALESS67.1 is not a pure rotating disk but a merger, consistent with the apparent tidal features revealed in the HST imaging. Our sub-arcsecond resolution data set allows us to measure half-light radii for all the tracers, and we find a factor of 4-6 smaller sizes in dust continuum compared to all the other tracers, including 12CO; also, ultraviolet (UV) and H emission are significantly offset from the dust continuum. The spatial mismatch between the UV continuum and the cold dust and gas reservoir supports the explanation that geometrical effects are responsible for the offset of the dusty galaxy on the IRX-β diagram. Using a dynamical method we derive an , consistent with other submillimeter galaxies (SMGs) that also have resolved CO and dust measurements. Assuming a single value we also derive resolved gas and star formation rate surface densities, and find that the core region of the galaxy ( kpc) follows the trend of mergers on the Schmidt-Kennicutt relationship, whereas the outskirts ( kpc) lie on the locus of normal star-forming galaxies, suggesting different star formation efficiencies within one galaxy. Our results caution against using single size or morphology for different tracers of the star formation activity and gas content of galaxies, and therefore argue the need to use spatially resolved, multi-wavelength observations to interpret the properties of SMGs, and perhaps even for galaxies in general.
Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of ...treatment on the respiratory microbiome is unknown. Data are from children (
= 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test,
< 0.05 for each). Wilcoxon effect sizes were small for beta-lactam (
: 0.15; 95% confidence interval CI, 0.01 to 0.29) and medium for multidrug efflux RGPC (
: 0.23; 95% CI, 0.09 to 0.37). Analyses comparing the resistome at the beginning and end of the trial indicated that in contrast to the standard strategy group, the resistome significantly differed in children receiving the short course strategy. Relative abundances of commensals such as Neisseria subflava were higher in children receiving the standard strategy, and
species and Veillonella parvula were higher in children receiving the short course strategy. We conclude that children receiving 5 days of beta-lactam therapy for CAP had a significantly lower abundance of antibiotic resistance determinants than those receiving standard 10-day treatment. These data provide an additional rationale for reductions in antibiotic use when feasible.
Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. We examined relationships between the duration of antibiotic treatment and its impact on resistance genes and bacteria in the respiratory microbiome using data from a randomized controlled trial of beta-lactam therapy for pediatric pneumonia. The randomized design provides reliable evidence of the effectiveness of interventions and minimizes the potential for confounding. Children receiving 5 days of therapy for pneumonia had a lower prevalence of two different types of resistance genes than did those receiving the 10-day treatment. Our data also suggest that children receiving longer durations of therapy have a greater abundance of antibiotic resistance genes for a longer period of time than do children receiving shorter durations of therapy. These data provide an additional rationale for reductions in antibiotic use.
ABSTRACT
We analyse the physical properties of a large, homogeneously selected sample of ALMA-located sub-millimetre galaxies (SMGs). This survey, AS2UDS, identified 707 SMGs across the ∼1 deg2 ...field, including ∼17 per cent, which are undetected at K ≳ 25.7 mag. We interpret their ultraviolet-to-radio data using magphys and determine a median redshift of z = 2.61 ± 0.08 (1σ range of z = 1.8–3.4) with just ∼6 per cent at z > 4. Our survey provides a sample of massive dusty galaxies at z ≳ 1, with median dust and stellar masses of Md = (6.8 ± 0.3) × 108 M⊙ (thus, gas masses of ∼1011 M⊙) and M* = (1.26 ± 0.05) × 1011 M⊙. We find no evolution in dust temperature at a constant far-infrared luminosity across z ∼ 1.5–4. The gas mass function of our sample increases to z ∼ 2–3 and then declines at z > 3. The space density and masses of SMGs suggest that almost all galaxies with M* ≳ 3 × 1011 M⊙ have passed through an SMG-like phase. The redshift distribution is well fit by a model combining evolution of the gas fraction in haloes with the growth of halo mass past a critical threshold of Mh ∼ 6 × 1012 M⊙, thus SMGs may represent the highly efficient collapse of gas-rich massive haloes. We show that SMGs are broadly consistent with simple homologous systems in the far-infrared, consistent with a centrally illuminated starburst. Our study provides strong support for an evolutionary link between the active, gas-rich SMG population at z > 1 and the formation of massive, bulge-dominated galaxies across the history of the Universe.
IMPORTANCE: Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium. OBJECTIVE: To determine whether ...prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017. INTERVENTIONS: Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride. MAIN OUTCOME AND MEASURES: The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. RESULTS: All 1789 randomized patients (mean, age 66.6 years SD, 12.6; 1099 men 61.4%) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 0.3% for the 2-mg haloperidol group vs 1 0.1% for the placebo group). CONCLUSIONS AND RELEVANCE: Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01785290
The authors treated 676 patients with metastatic melanoma with an antibody to CTLA-4 (ipilimumab), the antibody plus a gp100 vaccine, or the vaccine alone. Patients who received ipilimumab with or ...without gp100 vaccine survived nearly 4 months longer than did those who received the gp100 vaccine alone. Adverse immune-related events were noted and some were severe, but most were reversible with appropriate treatment.
The incidence of metastatic melanoma has increased over the past three decades,
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and the death rate continues to rise faster than the rate with most cancers.
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The World Health Organization (WHO) estimates that worldwide there are 66,000 deaths annually from skin cancer, with approximately 80% due to melanoma.
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In the United States alone, an estimated 8600 persons died from melanoma in 2009.
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The median survival of patients with melanoma who have distant metastases (American Joint Committee on Cancer stage IV) is less than 1 year.
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No therapy is approved beyond the first-line therapy for metastatic melanoma, and enrollment . . .
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