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Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene–environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
ABSTRACT IMPACT: This work identifies host immune perturbations in sepsis mortality that suggests targets for a precision medicine paradigm in the host response to infection. OBJECTIVES/GOALS: To compare the early whole blood transcriptome during sepsis between 30-day survivors and non-survivors in the Intensive Care Unit (ICU), and to evaluate for pathway enrichment that might explain sepsis lethality. METHODS/STUDY POPULATION: We enrolled 162 sepsis patients in the first 24 hours of ICU admission, particularly targeting individuals requiring vasopressors. Peripheral whole blood was collected in PAXgene vacutainers. Isolated RNA was analyzed with Affymetrix Human Genome ST 2.0 microarray. Differential gene expression was performed with Bioconductor/R/limma using log2 fold-change +/-0.6 as a threshold for differential expression, and a Benjamini-Hochberg adjusted p-value <0.05 to declare significance. Functional gene enrichment was performed using the Gene Ontology (GO) database with PANTHER overrepresentation test (Fisher’s Exact) on all transcripts with adjusted p-value <0.05. Pathways analysis was performed with the Reactome Project using the raw fold change and significance data to identify dysregulated pathways. RESULTS/ANTICIPATED RESULTS: There were 58 non-survivors (36% mortality). We identified 39 genes as differentially expressed between sepsis non-survivors and survivors; 31 were upregulated in non-survivors and 8 had reduced expression. Several of the most overexpressed transcripts are neutrophil-specific, including LCN, MPO, OLF4M4, DEFA3, and DEFA4. A functional gene overrepresentation test further supports this finding, as the most enriched gene ontologies were neutrophil-mediated killing, neutrophil cytotoxicity, neutrophil extravasation, and respiratory burst, all demonstrating higher than 10-fold enrichment and FDR < 0.02. Pathway analysis of the peripheral blood transcriptome was notable for immune response derangement, specifically downregulation of both innate and adaptive immune pathways (FDR < 0.00001). DISCUSSION/SIGNIFICANCE OF FINDINGS: We identified increased expression of neutrophil-related genes in sepsis non-survivors, replicating candidates previously identified in pediatric sepsis mortality and ARDS. These immune perturbations in sepsis mortality may represent key targets for eventually employing precision medicine strategies in sepsis.
Hydrogen lithography has been used to template phosphine-based surface chemistry to fabricate atomic-scale devices, a process we abbreviate as atomic precision advanced manufacturing (APAM). Here, we use mid-infrared variable angle spectroscopic ellipsometry (IR-VASE) to characterize single-nanometer thickness phosphorus dopant layers (δ-layers) in silicon made using APAM compatible processes. A large Drude response is directly attributable to the δ-layer and can be used for nondestructive monitoring of the condition of the APAM layer when integrating additional processing steps. The carrier density and mobility extracted from our room temperature IR-VASE measurements are consistent with cryogenic magneto-transport measurements, showing that APAM δ-layers function at room temperature. Finally, the permittivity extracted from these measurements shows that the doping in the APAM δ-layers is so large that their low-frequency in-plane response is reminiscent of a silicide. However, there is no indication of a plasma resonance, likely due to reduced dimensionality and/or low scattering lifetime.
In this paper, the generation of relativistic electron mirrors (REM) and the reflection of an ultra-short laser off the mirrors are discussed, applying two-dimension particle-in-cell simulations. REMs with ultra-high acceleration and expanding velocity can be produced from a solid nanofoil illuminated normally by an ultra-intense femtosecond laser pulse with a sharp rising edge. Chirped attosecond pulse can be produced through the reflection of a counter-propagating probe laser off the accelerating REM. In the electron moving frame, the plasma frequency of the REM keeps decreasing due to its rapid expansion. The laser frequency, on the contrary, keeps increasing due to the acceleration of REM and the relativistic Doppler shift from the lab frame to the electron moving frame. Within an ultra-short time interval, the two frequencies will be equal in the electron moving frame, which leads to the resonance between laser and REM. The reflected radiation near this interval and corresponding spectra will be amplified due to the resonance. Through adjusting the arriving time of the probe laser, a certain part of the reflected field could be selectively amplified or depressed, leading to the selective adjustment of the corresponding spectra.
Adolescents have been largely neglected from tuberculosis control efforts. In low- to medium burden settings much of the tuberculosis burden in this age group occurs from school outbreaks. We report on a large tuberculosis outbreak in adolescents from a boarding high school in Jiangsu Province, China. From March to June 2018, a tuberculosis outbreak occurred in a boarding high school. We conducted an outbreak investigation involving clinical diagnostic tests and molecular analysis to determine the outbreak origin. Cases were detected through symptom screening, tuberculin skin testing (TST), chest radiography, sputum smear, solid sputum culture and GeneXpert MTB/RIF. Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) genotyping and spoligotyping methods were performed on Mycobacterium tuberculosis (M. tuberculosis) isolates to identify the outbreak origin. A total of 845 students and 131 teachers/staff attended a TST screening for tuberculosis infection. The prevalence of elevated tuberculin reactions at ≥5, ≥10 and ≥15 mm was 12.19% (119/976), 6.35% (62/976) and 3.28% (32/976), respectively. Radiographic abnormalities were present in 5.73% (56 of 976) individuals, 40 students and 16 teachers/staff. Of these, 12 students were diagnosed with confirmed tuberculosis. In total, 14 students (two index cases and 12 confirmed cases) were diagnosed and reported in the tuberculosis outbreak, an attack rate of 1.7% (14/847) among students (two index cases and 845 screened students). Results from MIRU-VNTR typing and spoligotyping analyses demonstrated that three M. tuberculosis strains belong to the Beijing family with corresponding MIRU-VNTR alleles. This school-based tuberculosis outbreak among adolescents demonstrates that transmission among individuals in this age group is common and must be prioritised. It suggests that identifying and timely diagnosis of smear-positive cases, especially in the early phase of outbreaks, is the key to preventing further spread among close contacts.
This study aimed to investigate endoscopic revision septoplasty with semi-penetrating straight and circular incisions in patients for whom septoplasty was unsuccessful.
Patients in this study (n = 14) had a deviation of the nasal septum after septoplasty. Pre-operative and post-operative assessments were performed using a visual analogue scale and nasal endoscope. Semi-penetrating straight and circular incisions in front of the caudal septum and at the margin of the nasal septal cartilage–bone defect, respectively, were made. The mucoperichondrium and mucoperiosteum were bilaterally dissected until interlinkage with the cartilage–bone defect was achieved. Mucous membranes within the circular incision as well as the right mucoperichondrium and mucoperiosteal flaps were protected by pushing them to the right. This exposed the osteocartilaginous framework and allowed correction of the residual deviation. The patients were followed up for 30–71 months.
For nasal obstruction and headaches, a significant improvement was noted in post-operative compared to pre-operative visual analogue scale scores. No patients had septal deviations, saddle nose, false hump nose or contracture of the nasal columella.
The technique allowed exposure of the septal osteocartilaginous framework and a broad operational vision, which enabled successful correction of various deformities of the nasal septum.
To compare the epidemiologic features (e.g. settings and transmission mode) and patient clinical characteristics associated with outbreaks of different norovirus (Nov) strains, we retrospectively analysed data of Nov outbreaks occurring in Guangzhou, China from 2012 to 2018. The results suggested that outbreaks of Nov GII.2, GII.17 and GII.4 Sydney exhibited different outbreak settings, transmission modes and symptoms. GII.2 outbreaks mainly occurred in kindergartens, elementary and high schools and were transmitted mainly through person-to-person contact. By contrast, GII.4 Sydney outbreaks frequently occurred in colleges and were primarily associated with foodborne transmission. Cases from GII.2 and GII.17 outbreaks reported vomiting more frequently than those from outbreaks associated with GII.4 Sydney.
To investigate a Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak event involving multiple healthcare facilities in Riyadh, Saudi Arabia; to characterize transmission; and to explore infection control implications.
Cases presented in 4 healthcare facilities in Riyadh, Saudi Arabia: a tertiary-care hospital, a specialty pulmonary hospital, an outpatient clinic, and an outpatient dialysis unit.
Contact tracing and testing were performed following reports of cases at 2 hospitals. Laboratory results were confirmed by real-time reverse transcription polymerase chain reaction (rRT-PCR) and/or genome sequencing. We assessed exposures and determined seropositivity among available healthcare personnel (HCP) cases and HCP contacts of cases.
In total, 48 cases were identified, involving patients, HCP, and family members across 2 hospitals, an outpatient clinic, and a dialysis clinic. At each hospital, transmission was linked to a unique index case. Moreover, 4 cases were associated with superspreading events (any interaction where a case patient transmitted to ≥5 subsequent case patients). All 4 of these patients were severely ill, were initially not recognized as MERS-CoV cases, and subsequently died. Genomic sequences clustered separately, suggesting 2 distinct outbreaks. Overall, 4 (24%) of 17 HCP cases and 3 (3%) of 114 HCP contacts of cases were seropositive.
We describe 2 distinct healthcare-associated outbreaks, each initiated by a unique index case and characterized by multiple superspreading events. Delays in recognition and in subsequent implementation of control measures contributed to secondary transmission. Prompt contact tracing, repeated testing, HCP furloughing, and implementation of recommended transmission-based precautions for suspected cases ultimately halted transmission.
Lymphatic filariasis is a neglected tropical disease caused by roundworm parasites such as Brugia malayi that spread via a mosquito vector. In vitro culture of these parasites provides controlled conditions to understand parasite biology and provides a cheaper way to screen potential micro- and macrofilaricides. Published studies have used a wide array of approaches and metrics regarding in vitro cultures of B. malayi; as a result, drawing comparisons and identifying the reasons why inability to reproduce outcomes are difficult. This study sought to determine conditions that ensure reproducible outcomes and used evaluation metrics that are easily measured and can be automated to ensure objectivity. We found culturing B. malayi third-stage larvae (L3) in endothelial basal media supplemented with 20% fetal bovine serum and 75 µm ascorbic acid in a temperature- and humidity-controlled incubator produced better survival and molting rates as well as longer and more motile parasites than previously reported. The benefit of ascorbic acid seemed to be unique to L3 parasites, as the addition of ascorbic acid to adult parasites had no significant impact on survival or motility. The methods reported in this study will help in designing experiments for both parasite behaviour studies and drug screening applications for disease eradication.
Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other.
We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes.
Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility.
Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.
The Central Molecular Zone (CMZ), the inner 450 pc of our Galaxy, is an exceptional region where the volume and column densities, gas temperatures, velocity dispersions, etc. are much higher than in the Galactic plane. It has been suggested that the formation of stars and clusters in this area is related to the orbital dynamics of the gas. The complex kinematic structure of the molecular gas was revealed by spectral line observations. However, these results are limited to the line-of-sight-velocities. To fully understand the motions of the gas within the CMZ, we have to know its location in 6D space (3D location + 3D motion). Recent orbital models have tried to explain the inflow of gas towards and its kinematics within this region. With parallax and proper motion measurements of masers in the CMZ we can discriminate among these models and constrain how our Galactic Center is fed with gas.
Vortex-induced vibration (VIV) is an important physical phenomenon as one design a riser or a cylindrical structure in ocean. As the riser or the cylindrical structure is adjacent to a seabed, the boundary effect on VIV is not fully understood yet. The direct-forcing immersed boundary (DFIB) method is used to investigate a two-degree-of-freedom VIV of a flexible supported circular cylinder adjacent to a plane boundary in this study. Furthermore, the effect of the VIV of cylinder on skin friction of the plane boundary is investigated. The effects of varying reduced velocity and gap ratio on VIV are discussed. Only a single vortex street is found when the cylinder is close to plane boundary. Hydrodynamic coefficients of the freely vibrating cylinder are analyzed in time and spectral domains. Furthermore, nearly round oval-shaped motion is observed as the so-called lock-in phenomenon occurs. The skin friction of the plane boundary is predicted by the DFIB model. Results show that the vibrating cylinder in the boundary layer flow can reduce the friction effectively. This proposed DFIB model can be useful for the investigation of VIV of the structures under the plane boundary effect even for a small gap between the cylinder and the boundary.
Auditory verbal hallucinations (AVHs) are one of the most common and severe symptoms of schizophrenia, but the neuroanatomical abnormalities underlying AVHs are not well understood. The present study aims to investigate whether AVHs are associated with cortical thinning.
Participants were schizophrenia patients from four centers across China, 115 with AVHs and 93 without AVHs, as well as 261 healthy controls. All received 3 T T1-weighted brain scans, and whole brain vertex-wise cortical thickness was compared across groups. Correlations between AVH severity and cortical thickness were also determined.
The left middle part of the middle temporal gyrus (MTG) was significantly thinner in schizophrenia patients with AVHs than in patients without AVHs and healthy controls. Inferences were made using a false discovery rate approach with a threshold at p < 0.05. Left MTG thickness did not differ between patients without AVHs and controls. These results were replicated by a meta-analysis showing them to be consistent across the four centers. Cortical thickness of the left MTG was also found to be inversely correlated with hallucination severity across all schizophrenia patients.
The results of this multi-center study suggest that an abnormally thin left MTG could be involved in the pathogenesis of AVHs in schizophrenia.
The transient impact hypothesis was extended, and the oblique collision model was established by considering the tangential slip. In order to solve this problem, the oblique-impact equations for cam-follower were transformed into a linear complementarity problem. Impulsive control method was employed to control or anti-control the nonlinear responses. The simulation results show that the cam-follower system performs very complex nonlinear characteristics, such as period, quasi-period and chaos responses. Using the impulsive control method, the nonlinear responses of the cam-follower system can be controlled to P(n, n) and P(∞, n) or anti-controlled to chaos.
The inner few hundred parsecs of the Milky Way, the Central Molecular Zone (CMZ), is our closest laboratory for understanding star formation in the extreme environments (hot, dense, turbulent gas) that once dominated the universe. We present an update on the first large-area survey to expose the sites of star formation across the CMZ at high-resolution in submillimeter wavelengths: the CMZoom survey with the Submillimeter Array (SMA). We identify the locations of dense cores and search for signatures of embedded star formation. CMZoom is a three-year survey in its final year and is mapping out the highest column density regions of the CMZ in dust continuum and a variety of spectral lines around 1.3 mm. CMZoom combines SMA compact and subcompact configurations with single-dish data from BGPS and the APEX telescope, achieving an angular resolution of about 4″ (0.2 pc) and good image fidelity up to large spatial scales.
The late-type stellar population in the Galactic Center was first predicted to reside in a dynamically relaxed cusp (power law slope ranging from 3/2 to 7/4). However, other works - which rely on models to correct for projection effects - have suggested a flat distribution instead. The need for this correction is due to the lack of information regarding the line-of-sight distances. With a two decade long baseline in astrometric measurements, we are now able to measure significant projected radial accelerations, six of which are newly reported here, which directly constrain line-of-sight distances. Here we present a statistical approach to take advantage of this information and more accurately constrain the shape of the radial density profile of the late-type stellar population in the Galactic Center.
The compact radio and near-infrared (NIR) source Sagittarius A* has been observed in the context of two NIR triggered global VLT and VLBA campaigns at 43 GHz (7 mm) on May 16-18 2012 and October 4 2014. While on October 4 2014 Sgr A* remained in a quiescent state, a NIR flare on May 17 2012 is accompanied by an increase in flux density of 0.22 Jy at 7 mm delayed by 4.5±0.5 h. Additionally, Sgr A* seems to develop a weak secondary radio off-core component of 0.02 Jy at a position angle of 140° and an angular distance of 1.5 mas shortly before the peak of the flare. This spatial extension and the time delay are in the range of expected values for events casually connected by adiabatic expansion.
Epitaxial Ge films are useful as a substrate for high-efficiency solar cell applications. It is possible to grow epitaxial Ge films on low cost, cube textured Ni(001) sheets using CaF2(001) as a buffer layer. Transmission electron microscopy (TEM) analysis indicates that the CaF2(001) lattice has a 45o in-plane rotation relative to the Ni(001) lattice. The in-plane epitaxy relationships are CaF2//Ni and CaF2[$\bar 1$10]//Ni. Energy dispersive spectroscopy (EDS) shows a sharp interface between Ge/CaF2 as well as between CaF2/Ni. Electron backscatter diffraction (EBSD) shows that the Ge(001) film has a large grain size (∼50 μm) with small angle grain boundaries (< 8o). The epitaxial Ge thin film has the potential to be used as a substrate to grow high quality III-V and II-VI semiconductors for optoelectronic applications.
Intra-individual variability (IIV) and the change of attentional functions have been reported to be susceptible to both healthy ageing and pathological ageing. The current study aimed to evaluate the IIV of attention and the age-related effect on alerting, orienting, and executive control in cognitively healthy older adults.
We evaluated 145 Chinese older adults (age range of 65–80 years, mean age of 72.41 years) with a comprehensive neuropsychological battery and the Attention network test (ANT). A two-step strategy of analytical methods was used: Firstly, the IIV of older adults was evaluated by the intraindividual coefficient of variation of reaction time (ICV-RT). The correlation between ICV-RT and age was used to evaluate the necessity of subgrouping. Further, the comparisons of ANT performance among three age groups were performed with processing speed adjusted.
Person's correlation revealed significant positive correlations between age and IIV (r = 0.185, p = 0.032), age and executive control (r = 0.253, p = 0.003). Furthermore, one-way ANOVA comparisons among three age groups revealed a significant age-related disturbance on executive control (F = 4.55, p = 0.01), in which oldest group (group with age >75 years) showed less efficient executive control than young-old (group with age 65–70 years) (Conventional score, p = 0.012; Ratio score, p = 0.020).
Advancing age has an effect on both IIV and executive attention in cognitively healthy older adults, suggesting that the disturbance of executive attention is a sensitive indicator to reflect healthy ageing. Its significance to predict further deterioration should be carefully evaluated with prospective studies.