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Heterogeneity in the number of secondary tuberculosis (TB) cases per source case, the effective reproductive number, R, is important in modelling prevention strategies' impact on incidence.
We estimated mean R (Rm) and calculate the dispersion parameter of this distribution, k, using surveillance and genotyping data for U.S. cases during 2009–2018. We modelled transmission assuming cases in a cluster have matching genotypes and share characteristics related to geography, temporal proximity (i.e. serial interval) and time since U.S. arrival among non-U.S.-born persons.
Complete data were available for 55 330/85 958 cases. Varying the serial interval and geographic proximity used to derive clusters, we consistently estimated Rm<1.0 and k < 0.08; the low value of k indicates a small number of source cases produce a disproportionate number of secondary cases.
U.S. TB reproductive number has a highly skewed distribution, indicating a minority of source cases disproportionately contribute to transmission.
One of the most perplexing and characteristic symptoms of the schizophrenia (SZ) patients is hallucination. The occurrence of hallucinations to be associated with altered activity in the auditory and visual cortex but is not well understood from the brain functional network dynamics in SZ.
To explore the brain abnormal basis of hallucinations in SZ with the dynamic functional connectivity (dFC).
Using magnetic resonance imaging for 83 SZ patients and 83 matched healthy controls and independent component analysis, 52 independent components (ICs) were identified as nodes and assigned into eight intrinsic connectivity networks (Figure 1A). Subsequently, we established dFC matrices and clustered them into four discrete states (Figure 1B) and three state transition metrics were obtained. To further explore the changes in the centrality of each component, eigenvector centrality (EC) was calculated and its time-varying was evaluated.
Compared to controls with FDR correction, we found that patients had more mean dwell times and fractional time in state 1 (P=0.0081 and P=0.0018), mainly with hypoconnectivity between auditory and visual network and other networks and hyperconnectivity between language and default-mode network (DMN). While, patients had less dwell times and fractional time in state 3 (P=0.0018 and P=0.0009), and decreased FC between visual network and executive control network (ECN) and increased FC between ECN and DMN than controls (Figure 2).
EC statistics showed that SZs displayed increased temporal dynamics in visual-related regions (Figure 3).
SZ was mainly manifested as altered dFC and temporal variability of nodal centrality in auditory and visual networks.
Though schizophrenia (SZ) and obsessive-compulsive disorder (OCD) are conceptualized as distinct clinical entities, they do have notable symptom overlap and a tight association. Graph-theoretical analysis of the brain connectome provides more indicators to describe the functional organization of the brain, which may help us understand the shared and disorder-specific neural basis of the two disorders.
To explore the static and dynamic topological organization of OCD and SZ as well as the relationship between topological metrics and clinical variables.
Resting state functional magnetic resonance imaging data of 31 OCD patients, 49 SZ patients, and 45 healthy controls (HC) were involved in this study (Table 1). Using independent component analysis to obtain independent components (ICs) (Figure 1), which were defined as nodes for static and dynamic topological analysis.
Static analysis showed the global efficiency of SZ was higher than HC. For nodal degree centrality, OCD exhibited decreased degree centrality in IC59 (located in visiual network) (P = 0.03) and increased degree centrality in IC38 (located in salience network) (P = 0.002) compared with HC. Dynamic analysis showed OCD exhibited decreased dynamics of degree centrality in IC38 (P = 0.003) compared with HC, which showed a negative correlation with clinical scores in OCD. While SZ showed decreased dynamics of degree centrality in IC76 (located in sensory motor network) compared with OCD (P=0.009), which showed a positive correlation with clinical scores in SZ (Figure 2).
These changes are suggestive of disorder-specific alternation of static and dynamic brain topological organization in OCD and SZ.
Obsessive-compulsive disorder (OCD) and schizophrenia (SZ) are both severe psychiatric disorders. Though these two disorders have distinct typical symptoms, there are partial polygenic overlap and comorbidity between the two disorders. However, few studies have explored the shared and disorder-specific brain function underlying the neural pathophysiology of the two disorders, especially in the aspect of dynamics.
To explore the abnormal characteristics of the dynamic functional connectivity (dFC) in OCD and SZ as well as the association between dFC metrics and symptom severity.
The resting state functional magnetic resonance imaging data of 31 patients with OCD, 49 patients with SZ, and 45 healthy controls were analyzed using independent component analysis to obtain independent components (ICs) and assigned them into eight brain networks (Figure 1), then used the sliding-window approach to generate dFC matrices. Using k-means clustering, we obtained three reoccurring dFC states (Figure 2), and state transition metrics were obtained
In a sparsely connected state (state 1), SZ showed both increased fractional time and mean dwell time than controls (P=0.047 and P=0.033) and OCD (P=0.001 and P=0.003). In a state characterized by negative FC between networks (state 2), OCD showed both increased fractional time and mean dwell time than controls (P=0.032 and P=0.013) and SZ (P=0.005 and P=0.003). Moreover, the fractional time of state 2 was positively correlated with anxiety scores in OCD (r=0.535, P=0.021, FDR corrected) (Figure 3).
OCD and SZ patients showed distinct alternations of brain functional dynamics.
We use a continuous wavelet transform to analyse the daily hemispheric sunspot area data from the Greenwich Royal Observatory during cycles 12–24 and then study the cause of the appearance or disappearance of the Rieger-type periodicity in the northern and southern hemispheres during a certain cycle. The Rieger-type periodicity in the northern and southern hemispheres should be developed independently in the two hemispheres. This periodicity in the northern hemisphere is generally anti-correlated with the long-term variations in the mean solar cycle strength of hemispheric activity, but the correlation of the two parameters in the southern hemisphere shows a weak correlation. The appearance or disappearance of Rieger-type periodicity in the northern and southern hemispheres during a certain solar cycle is not directly correlated with their corresponding hemispheric mean activity strength but should be related to the strength of the hemispheric activity during sunspot maximum times, which hints the Rieger-type periodicity is more related to temporal evolution of toroidal magnetic field. The Rieger-type periodicity in the two hemispheres disappears in those solar cycles with relatively weak hemispheric activity during sunspot maximum times. The reason for the disappearance of this periodicity may be due to the combined influence of relatively weak toroidal magnetic fields and torsional oscillations, the differential rotation parameters vary through the solar cycle and may not remain more or less unchanged during some time, which does not permit the strong growth of magnetic Rossby waves.
In 829 hospital encounters for patients with COVID-19, 73.2% included orders for antibiotics; however, only 1.8% had respiratory cultures during the first 3 hospital days isolating bacteria. Case–control analysis of 30 patients and 96 controls found that each antibiotic day increased the risk of isolating multidrug-resistant gram-negative bacteria (MDR-GNB) in respiratory cultures by 6.5%.
The aim of this study was to identify factors associated with distress experienced by physicians during their first coronavirus disease 2019 (COVID-19) triage decisions.
An online survey was administered to physicians licensed in New York State.
Of the 164 physicians studied, 20.7% experienced severe distress during their first COVID-19 triage decisions. The mean distress score was not significantly different between physicians who received just-in-time training and those who did not (6.0 ± 2.7 vs 6.2 ± 2.8; P = 0.550) and between physicians who received clinical guidelines and those who did not (6.0 ± 2.9 vs 6.2 ± 2.7; P = 0.820). Substantially increased odds of severe distress were found in physicians who reported that their first COVID-19 triage decisions were inconsistent with their core values (adjusted odds ratio, 6.33; 95% confidence interval, 2.03-19.76) and who reported having insufficient skills and expertise (adjusted odds ratio 2.99, 95% confidence interval 0.91-9.87).
Approximately 1 in 5 physicians in New York experienced severe distress during their first COVID-19 triage decisions. Physicians with insufficient skills and expertise, and core values misaligned to triage decisions are at heightened risk of experiencing severe distress. Just-in-time training and clinical guidelines do not appear to alleviate distress experienced by physicians during their first COVID-19 triage decisions.
To assess the potential for contamination of personnel, patients, and the environment during use of contaminated N95 respirators and to compare the effectiveness of interventions to reduce contamination.
Simulation study of patient care interactions using N95 respirators contaminated with a higher and lower inocula of the benign virus bacteriophage MS2.
In total, 12 healthcare personnel performed 3 standardized examinations of mannequins including (1) control with suboptimal respirator handling technique, (2) improved technique with glove change after each N95 contact, and (3) control with 1-minute ultraviolet-C light (UV-C) treatment prior to donning. The order of the examinations was randomized within each subject. The frequencies of contamination were compared among groups. Observations and simulations with fluorescent lotion were used to assess routes of transfer leading to contamination.
With suboptimal respirator handling technique, bacteriophage MS2 was frequently transferred to the participants, mannequin, and environmental surfaces and fomites. Improved technique resulted in significantly reduced transfer of MS2 in the higher inoculum simulations (P < .01), whereas UV-C treatment reduced transfer in both the higher- and lower-inoculum simulations (P < .01). Observations and simulations with fluorescent lotion demonstrated multiple potential routes of transfer to participants, mannequin, and surfaces, including both direct contact with the contaminated respirator and indirect contact via contaminated gloves.
Reuse of contaminated N95 respirators can result in contamination of personnel and the environment even when correct technique is used. Decontamination technologies, such as UV-C, could reduce the risk for transmission.
Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).
Materials and Methods
Patients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.
Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.
These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.
ABSTRACT IMPACT: It is our hope that a better understanding of the relationship between genetic variants that influence heart failure precursor traits will not only inform clinical care, but enable better assessment of inherited risk and will identify new biological targets for drug development. OBJECTIVES/GOALS: In this project, using a large-scale human genomic dataset with extensive phenotype data available, we intend to interrogate the known MTSS1 variants that have been associated with heart failure (HF) in previous GWAS studies in order to understand the directionality and mechanisms of their effects. METHODS/STUDY POPULATION: Data was obtained from the UK Biobank, a large prospective cohort of ˜500,000 patients across the United Kingdom with extensive phenotype data, including ˜50,000 patients with cardiac MRI and ˜200,000 with whole exome sequencing. We test for associations between genetic variants at the MTSS1 locus and HF precursor traits using logistic regression or linear regression, adjusting for age, gender, and principal components (PCs) of ancestry. For rare variant analyses we ‘bin’ rare variants (MAF < 0.01) using the software tool BioBin to aggregate low frequency genetic variants into single genetic units. RESULTS/ANTICIPATED RESULTS: Preliminary data have shown that variants in the known MTSS1 enhancer region which reduce MTSS1 expression are associated with smaller, more contractile hearts. We anticipate that common variants known to reduce enhancer activity will attenuate heart failure precursor traits, will be associated with a reduced risk clinical heart failure, and will favorably impact clinical outcomes once HF is established. We also anticipate that rare exonic variants predicted to impair MTSS1 function will attenuate heart failure precursor traits. DISCUSSION/SIGNIFICANCE OF FINDINGS: Through this work, we intend to take advantage of multiple novel approaches to better understand a complex disease process, identify a new potential therapeutic target (namely one that targets cardiac function), and to determine which patient subgroups will benefit from this our therapeutic interventions and why.
Fossil charcoals from archaeological sites provide direct evidence for the relationship between environmental change and ancient peoples’ livelihoods in the past. Our identification of 5811 fossil charcoal fragments from 84 samples suggested temperate deciduous and mixed conifer-broadleaved forests as the dominant vegetation at the Erdaojingzi site in northeastern China ca. 3500 cal yr BP; the major representative taxa were Quercus, Pinus, and Ulmus. Four woody plants probably supplied humans with food resources at the Erdaojingzi site, including Quercus, Ulmus, Amygdalus/Armeniaca, and Ziziphus. The nuts of Quercus were utilized as staple foods because of their rich starch content. The leaves of Ulmus may have been used by humans because of their massive dietary fibre. Amygdalus/Armeniaca and Ziziphus probably provided fruits for humans. Based on the coexistence approach (CA) used on the fossil charcoals, we found that the MAT anomaly was 7.9 ± 5.9°C at ca. 3500 cal yr BP, which is almost the same as the modern one (7.8°C), while the MAP was halved from 772 ± 301 mm at ca. 3500 cal yr BP to 370 mm currently. The wet climate might have facilitated significant development of rain-fed agriculture, promoted the emergence of large settlements, and eventually facilitated the birth of civilization.
Poroelastic effects have been of great interest in the seismic literature as they have been identified as a major cause of wave attenuation in heterogeneous porous media. The observed attenuation in the seismic wave can be explained in part by energy loss to fluid motion in the pores. On the other hand, it is known that the attenuation is particularly pronounced in stratified structures where the scale of spatial heterogeneity is much smaller than the seismic wavelength. Understanding of poroelastic effects on seismic wave attenuation in heterogeneous porous media has largely relied on numerical experiments. In this work, we present a homogenisation technique to obtain an upscaled viscoelastic model that captures seismic wave attenuation when the sub-seismic scale heterogeneity is periodic. The upscaled viscoelastic model directly relates seismic wave attenuation to the material properties of the heterogeneous structure. We verify our upscaled viscoelastic model against a full poroelastic model in numerical experiments. Our homogenisation technique suggests a new approach for solving coupled equations of motion.
The compressibility effects on energy exchange mechanisms in a three-dimensional, spatially developing plane free shear layer are investigated via data produced by direct numerical simulation. The compressible shear layer is simulated using a high-order discontinuous spectral element method for convective Mach numbers $M_c = 0.3$, 0.5 and 0.7. The energy exchange mechanisms in the flow are examined by analysing the budget terms of mean kinetic, internal and turbulent kinetic energy transport equations, in both transition and turbulent regions. The results show that turbulent production, turbulent viscous dissipation, mean viscous dissipation, pressure dilatation and enthalpic production are the main mechanisms responsible for energy exchange among different forms of energy. The effects of compressibility on energy transfer mechanisms are studied based on the analyses of those five budget terms. The primary budget terms evolve differently in the transition and turbulent regions and change significantly for varying compressibility. In the transition region, a double-peak variation becomes a single peak in the streamwise profile of the turbulent production as $M_c$ increases from 0.3 to 0.7, due to significant changes in the vortex pairing structures. The shear layer centre slightly shifts to the high-speed side due to the appearance of the velocity deficit. The velocity deficit presence distance (VDPD) becomes longer as compressibility increases. However, in the turbulent region, the cross-stream profiles of the main budget terms significantly shift to the low-speed side because of the asymmetric mass entrainment and shift even further as $M_c$ increases.
It is important to understand the temporal trend of the paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in schools and communities. We determined the differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. Serial cycle threshold values of SARS-CoV-2 from the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral loads (mean cycle threshold on day 7 of illness 28.6 vs. 36.7, P = 0.02). Peak SARS-CoV-2 viral loads occurred around day 2 of illness in infected children. Although we were unable to directly demonstrate infectivity, the detection of significant amount of virus in the upper airway of asymptomatic children suggest that they have the potential to shed and transmit SARS-CoV-2. Our study highlights the importance of contact tracing and screening for SARS-CoV-2 in children with epidemiological risk factors regardless of their symptom status, in order to improve containment of the virus in the community, including educational settings.
Maternal migraine may contribute to mental heath problems in offspring but empirical evidence has been available only for bipolar disorders. Our objective was to examine the association between maternal migraine and the risk of any and specific psychiatric disorders in offspring.
This population-based cohort study used individual-level linked Danish national health registers. Participants were all live-born singletons in Denmark during 1978–2012 (n = 2 069 785). Follow-up began at birth and continued until the onset of a psychiatric disorder, death, emigration or 31 December 2016, whichever came first. Cox proportional hazards model was employed to calculate the hazard ratios (HRs) of psychiatric disorders.
Maternal migraine was associated with a 26% increased risk of any psychiatric disorders in offspring [HR, 1.26; 95% confidence interval (CI), 1.22–1.30]. Increased rates of psychiatric disorders were seen in all age groups from childhood to early adulthood. Increased rates were also observed for most of the specific psychiatric disorders, in particular, mood disorders (HR, 1.53; 95% CI, 1.39–1.67), neurotic, stress-related and somatoform disorders (HR, 1.44; 95% CI, 1.37–1.52) and specific personality disorders (HR, 1.47; 95% CI, 1.27–1.70), but not for intellectual disability (HR, 0.84; 95% CI, 0.71–1.00) or eating disorders (HR, 1.10; 95% CI, 0.93–1.29). The highest risk was seen in the offspring of mothers with migraine and comorbid psychiatric disorders (HR, 2.13; 95% CI, 1.99–2.28).
Maternal migraine was associated with increased risks of a broad spectrum of psychiatric disorders in offspring. Given the high prevalence of migraine, our findings highlight the importance of better management of maternal migraine at childbearing ages for early prevention of psychiatric disorders in offspring.
The coronavirus disease 2019 (COVID-19) pandemic represents an unprecedented threat to mental health. Herein, we assessed the impact of COVID-19 on subthreshold depressive symptoms and identified potential mitigating factors.
Participants were from Depression Cohort in China (ChiCTR registry number 1900022145). Adults (n = 1722) with subthreshold depressive symptoms were enrolled between March and October 2019 in a 6-month, community-based interventional study that aimed to prevent clinical depression using psychoeducation. A total of 1506 participants completed the study in Shenzhen, China: 726 participants, who completed the study between March 2019 and January 2020 (i.e. before COVID-19), comprised the ‘wave 1’ group; 780 participants, who were enrolled before COVID-19 and completed the 6-month endpoint assessment during COVID-19, comprised ‘wave 2’. Symptoms of depression, anxiety and insomnia were assessed at baseline and endpoint (i.e. 6-month follow-up) using the Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder-7 (GAD-7) and Insomnia Severity Index (ISI), respectively. Measures of resilience and regular exercise were assessed at baseline. We compared the mental health outcomes between wave 1 and wave 2 groups. We additionally investigated how mental health outcomes changed across disparate stages of the COVID-19 pandemic in China, i.e. peak (7–13 February), post-peak (14–27 February), remission plateau (28 February−present).
COVID-19 increased the risk for three mental outcomes: (1) depression (odds ratio [OR] = 1.30, 95% confidence interval [CI]: 1.04–1.62); (2) anxiety (OR = 1.47, 95% CI: 1.16–1.88) and (3) insomnia (OR = 1.37, 95% CI: 1.07–1.77). The highest proportion of probable depression and anxiety was observed post-peak, with 52.9% and 41.4%, respectively. Greater baseline resilience scores had a protective effect on the three main outcomes (depression: OR = 0.26, 95% CI: 0.19–0.37; anxiety: OR = 1.22, 95% CI: 0.14–0.33 and insomnia: OR = 0.18, 95% CI: 0.11–0.28). Furthermore, regular physical activity mitigated the risk for depression (OR = 0.79, 95% CI: 0.79–0.99).
The COVID-19 pandemic exerted a highly significant and negative impact on symptoms of depression, anxiety and insomnia. Mental health outcomes fluctuated as a function of the duration of the pandemic and were alleviated to some extent with the observed decline in community-based transmission. Augmenting resiliency and regular exercise provide an opportunity to mitigate the risk for mental health symptoms during this severe public health crisis.