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ABSTRACT IMPACT: Urine tumor DNA non-invasively detects minimal residual disease and infers tumor mutational burden in locally advanced bladder cancer prior to radical cystectomy, which may potentially enable the selection of patients for bladder-sparing treatment or facilitate personalized adjuvant immunotherapy. OBJECTIVES/GOALS: Standard-of-care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. The inability to assess minimal residual disease (MRD) non-invasively limits our ability to offer bladder-sparing treatment. We sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS/STUDY POPULATION: We applied uCAPP-Seq, a targeted sequencing method for detecting utDNA, to urine cell-free DNA samples acquired on the day of radical cystectomy from 42 patients with bladder cancer. utDNA variant-calling was performed non-invasively without prior tumor mutational knowledge. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. Tumor mutational burden (TMB) was inferred from the number of non-silent mutations detected in urine cell-free DNA by applying a linear relationship derived from TCGA whole exome sequencing of 409 MIBC tumors. RESULTS/ANTICIPATED RESULTS: utDNA levels were significantly higher in patients with residual disease detected in their surgical pathology compared to those who achieved a pathologic complete response (P = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD significantly predicted the absence of pathologic complete response with a sensitivity of 81% and specificity of 81%. Positive utDNA MRD also portended significantly worse progression-free survival (HR = 7.4; P = 0.03) compared to negative utDNA MRD. Furthermore, we applied a linear relationship (Pearson r = 0.84; P < 0.0001) to identify patients with high inferred TMB who may have been candidates for early immune checkpoint blockade. DISCUSSION/SIGNIFICANCE OF FINDINGS: utDNA MRD analysis prior to surgery correlated significantly with pathologic response and progression-free survival, which may help select patients for bladder-sparing treatment. utDNA can also non-invasively infer TMB, which could facilitate personalized adjuvant therapy for patients in the future.
More than 50% patients with major depressive disorder (MDD) have severe functional impairment. The restoration of patient functioning is a critical therapeutic goal among patients with MDD. We conducted a systematic review and network meta-analysis to evaluate the efficacy of pharmacological treatments on self-rated functional outcomes using the Sheehan Disability Scale in adults with MDD in randomized clinical trials.
PubMed, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched from inception to December 10, 2019. Summary statistics are reported as weighted mean differences with 95% confidence intervals. Interventions were ranked using the surface under the cumulative ranking probabilities.
We included 42 randomized controlled trials (RCTs) (n = 18 998) evaluating the efficacy of 13 different pharmacological treatments on functional outcomes, as measured by the Sheehan Disability Scale (SDS). Duloxetine was the most effective pharmacological agent on functional outcomes, followed by (ranked by efficacy): paroxetine, levomilnacipran, venlafaxine, quetiapine, desvenlafaxine, agomelatine, escitalopram, amitriptyline, bupropion, sertraline, vortioxetine, and fluoxetine. Serotonin and norepinephrine reuptake inhibitors were more effective than other drug classes. Additionally, the comparison-adjusted funnel plot suggested the publication bias between small and large studies was relatively low.
Our results indicate that there may be differences across antidepressant agents and classes with respect to self-reported functional outcomes. Validation and replication of these findings in large-scale RCTs are warranted. Our research results will be clinically useful for guiding psychiatrists in treating patients with MDD and functional impairment. PROSPERO registration number CRD42018116663.
Cognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.
While having social support can contribute to better health, those in poor health may be limited in their capacity to receive social support. We studied the health factors associated with social support among community-dwelling older adults in Singapore. We used data from the third follow-up interviews (2014–2016) of 16,943 participants of the Singapore Chinese Health Study, a population-based cohort of older Singapore Chinese. Participants were interviewed at a mean age of 73 years (range 61–96 years) using the Duke Social Support Scale (DUSOCS). We first applied ordinary least squares regression to DUSOCS scores and found that those with instrumental limitations, poor self-rated health, cognitive impairment and depression had lower social support scores. We then applied latent class analysis to DUSOCS answer patterns and revealed four groups of older adults based on the source and amount of social support. Among them, compared to the ‘overall supported’ group (17%) with the highest social support scores and broad support from family members and non-family individuals, the ‘family restricted’ (50%) group had the lowest social support scores and only received support from children. Health factors associated with being ‘family restricted’ were instrumental limitations (odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.19–1.49), poor self-rated health (OR = 1.40, 95% CI = 1.28–1.53), cognitive impairment (OR = 1.19, 95% CI = 1.04–1.37) and depression (OR = 2.50, 95% CI = 2.22–2.82). We found that while older adults in poor health have lower social support scores, they were more likely to receive a lot of support from children. Our results showed that lower social support scores among Singaporean older adults in poor health may not indicate lack of social support, but rather that social support is restricted in scope and intensified around children. These results may apply to other Asian societies where family plays a central role in elder-care.
Optical parametric chirped-pulse amplification implemented using multikilojoule Nd:glass pump lasers is a promising approach for producing ultra-intense pulses (>1023 W/cm2). We report on the MTW-OPAL Laser System, an optical parametric amplifier line (OPAL) pumped by the Nd:doped portion of the multi-terawatt (MTW) laser. This midscale prototype was designed to produce 0.5-PW pulses with technologies scalable to tens of petawatts. Technology choices made for MTW-OPAL were guided by the longer-term goal of two full-scale OPALs pumped by the OMEGA EP to produce 2 × 25-PW beams that would be co-located with kilojoule−nanosecond ultraviolet beams. Several MTW-OPAL campaigns that have been completed since “first light” in March 2020 show that the laser design is fundamentally sound, and optimization continues as we prepare for “first-focus” campaigns later this year.
The FNDC5 gene encodes the fibronectin type III domain-containing protein 5 that is a membrane protein mainly expressed in skeletal muscle, and the FNDC5 rs3480 polymorphism may be associated with liver disease severity in non-alcoholic fatty liver disease (NAFLD). We investigated the influence of the FNDC5 rs3480 polymorphism on the relationship between sarcopenia and the histological severity of NAFLD. A total of 370 adult individuals with biopsy-proven NAFLD were studied. The association between the key exposure sarcopenia and the outcome liver histological severity was investigated by binary logistic regression. Stratified analyses were undertaken to examine the impact of FNDC5 rs3480 polymorphism on the association between sarcopenia and the severity of NAFLD histology. Patients with sarcopenia had more severe histological grades of steatosis and a higher prevalence of significant fibrosis and definite non-alcoholic steatohepatitis than those without sarcopenia. There was a significant association between sarcopenia and significant fibrosis (adjusted OR 2·79, 95 % CI 1·31, 5·95, P = 0·008), independent of established risk factors and potential confounders. Among patients with sarcopenia, significant fibrosis occurred more frequently in the rs3480 AA genotype carriers than in those carrying the FNDC5 rs3480 G genotype (43·8 v. 17·2 %, P = 0·031). In the association between sarcopenia and liver fibrosis, there was a significant interaction between the FNDC5 genotype and sarcopenia status (P value for interaction = 0·006). Sarcopenia is independently associated with significant liver fibrosis, and the FNDC5 rs3480 G variant influences the association between sarcopenia and liver fibrosis in patients with biopsy-proven NAFLD.
Synchrotron x-rays are a powerful tool to probe real-time changes in the microstructure of materials as they respond to an external stimulus, such as phase transformations that take place in response to a change in temperature. X-ray imaging techniques include radiography and tomography, and have been steadily improved over the last decades so that they can now resolve micrometer-scale or even finer structural changes in bulk specimens over time scales of a second or less. Under certain conditions, these imaging approaches can also give spatially resolved chemical information. In this article, we focus on the liquid to solid transformation of metallic alloys and the temporal and spatial resolution of the accompanying segregation of alloying elements. The solidification of alloys provides an excellent case study for x-ray imaging because it is usually accompanied by the progressive, preferential segregation of one or more of the alloying elements to either the solid or the liquid, and gives rise to surprisingly complex chemical segregation patterns. We describe chemical mapping investigations of binary and quasi-binary alloys using radiography and tomography, and recent developments in x-ray fluorescence imaging that offer the prospect of a more general, multielement mapping technique. Future developments for synchrotron-based chemical mapping are also considered.
Increasing crop diversity has been highly recommended because of its environmental and economic benefits. However, the impacts of crop diversity on soil properties are not well documented. Thus, the present study was conducted to assess the impacts of crop diversity on selected soil quality indicators. The cropping systems investigated here included wheat (Triticum aestivum L.) grown continuously for 5 years as mono-cropping (MC), and a 5-year cropping sequence [(wheat–cover crop (CC)–corn (Zea mays L.)–pea (Pisum sativum L.) and barley (Hordeum vulgare L.)–sunflower (Helianthus annuus L.)]. Each crop was present every year. This study was conducted in the northern Great Plains of North America, and soil quality data were collected for 2016 and 2017. Selected soil quality indicators that include: soil pH, organic carbon (SOC), cold water-extractable C (CWC) and N (CWN), hot water-extractable C (HWC) and N (HWN), microbial biomass carbon (MBC), bulk density (BD), water retention (SWR), wet soil aggregate stability (WAS), and urease and β-glucoside enzyme activity were measured after the completion of 5-year rotation cycle and the following year. Crop diversity did not affect soil pH, CWC, CWN, HWC, HWN and SWR. Cropping systems that contained CC increased SOC at shallow depths compared to the systems that did not have CC. Crop diversity increased WAS, MBC, and urease and β-glucoside enzyme activity compared with the MC. Comparison of electrical conductivity (EC) measured in this study to the baseline values at the research site prior to the establishment of treatments revealed that crop rotation decreased EC over time. Results indicate that crop diversity can improve soil quality, thus promoting sustainable agriculture.
Large carnivores have extensive spatial requirements, with ranges that often span geopolitical borders. Consequently, management of transboundary populations is subject to several political jurisdictions, often with heterogeneity in conservation challenges. In continental Asia there are four threatened leopard subspecies with transboundary populations spanning 23 countries: the Persian Panthera pardus saxicolor, Indochinese P. pardus delacouri, Arabian P. pardus nimr and Amur P. pardus orientalis leopards. We reviewed the status of these subspecies and examined the challenges to, and opportunities for, their conservation. The Amur and Indochinese leopards have the majority (58–100%) of their remaining range in borderlands, and the Persian and Arabian leopards have 23–26% of their remaining ranges in borderlands. Overall, in 18 of 23 countries the majority of the remaining leopard range is in borderlands, and thus in most countries conservation of these subspecies is dependent on transboundary collaboration. However, we found only two transboundary initiatives for Asian leopards. Overall, we highlighted three key transboundary landscapes in regions that are of high importance for the survival of these subspecies. Recent listing of the leopard in the Bonn Convention on the Conservation of Migratory Species of Wild Animals is important, but more international collaboration is needed to conserve these subspecies. We provide a spatial framework with which range countries and international agencies could establish transboundary cooperation for conserving threatened leopards in Asia.
Leg weakness (LW) issues are a great concern for pig breeding industry. And it also has a serious impact on animal welfare. To dissect the genetic architecture of limb-and-hoof firmness in commercial pigs, a genome-wide association study was conducted on bone mineral density (BMD) in three sow populations, including Duroc, Landrace and Yorkshire. The BMD data were obtained by ultrasound technology from 812 pigs (including Duroc 115, Landrace 243 and Yorkshire 454). In addition, all pigs were genotyped using genome-by-sequencing and a total of 224 162 single-nucleotide polymorphisms (SNPs) were obtained. After quality control, 218 141 SNPs were used for subsequent genome-wide association analysis. Nine significant associations were identified on chromosomes 3, 5, 6, 7, 9, 10, 12 and 18 that passed Bonferroni correction threshold of 0.05/(total SNP numbers). The most significant locus that associated with BMD (P value = 1.92e−14) was detected at approximately 41.7 Mb on SSC6 (SSC stands for Sus scrofa chromosome). CUL7, PTK7, SRF, VEGFA, RHEB, PRKAR1A and TPO that are located near the lead SNP of significant loci were highlighted as functionally plausible candidate genes for sow limb-and-hoof firmness. Moreover, we also applied a new method to measure the BMD data of pigs by ultrasound technology. The results provide an insight into the genetic architecture of LW and can also help to improve animal welfare in pigs.
The modelling of edge carbon transport and emission on EAST tokamak under resonant magnetic perturbation (RMP) fields has been conducted with the three-dimensional edge transport code EMC3-EIRENE. The measured vertical distribution of CVI emission by the extreme ultraviolet spectrometer system for the perturbed case shows a reduction in the CVI emission by 20 % compared to the equilibrium case. The chord-integrated CVI emission can be reconstructed by EMC3-EIRENE modelling, which presents an increase in the CVI emission with RMP fields. The discrepancy between experiments and simulations has been investigated by parameter study to examine the sensitivity of the simulation results on the edge plasma conditions and the impurity perpendicular transport. It is found that the variation of edge plasma conditions for the equilibrium case cannot resolve the discrepancy in the CVI emission between simulations and measurements. The simulations with enhanced impurity perpendicular transport coefficient allows a reasonable agreement with the measured reduction of CVI emission.
We present a long-term seasonal tree ring cellulose oxygen isotope (δ18Oc) time series created by analyzing four segments (S1, S2, S3, and S4) per year during the period of 1951–2009 from southeastern Tibetan Plateau. This intraseasonal δ18Oc reveals the onset and mature phase of the summer monsoon precipitation in this region. Analysis indicates that the δ18Oc of S1 has the strongest correlation with precipitation during the regional monsoon onset (29–33 pentads, May 21–June 10, r = −0.69), and the δ18Oc values for S2, S3, and S4 correlate strongly with June, July, and August precipitation, respectively. Combined δ18Oc of S2, S3, and S4 shows the most robust correlation (r = −0.82) with the mature-phase monsoon precipitation (June-July-August, JJA), passing rigorous statistical tests for calibration and verification in dendroclimatology. These results demonstrate the feasibility in using long-term intraseasonal δ18Oc to reconstruct the Asian summer monsoon's intraseasonal variations.
Deep-brain magnetic stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of DMS on the brain remain unclear. Studies have reported abnormalities in the white matter of depressive brains, suggesting the involvement of myelin and oligodendrocyte pathologies in the development of major depressive disorder. In this study, we use a cuprizone induced demyelination animal model to generate depressive like behaviours and white matter and oligodendrocyte damages. Meanwhile, we treated the animal with DMS 20 minutes daily during the cuprizone challenge or recovery period. Behavioural tests, including nesting, new objective recognition, working memory and depression-like behaviours were tested periodically. Histological staining and western blotting were used to examine the underlying mechanism of DMS. We found that DMS reverse cuprizone induced behavioural deficits in acute demyelination but not during the recovery period. DMS alleviated demyelination and inflammation induced by cuprizone. During the recovery period, DMS had no impacts on overall neural progenitor cell proliferation, but enhanced the maturation of oligodendrocyte. This data suggest that DMS may be a promising treatment option for improving white matter function in psychiatric disorders and neurological diseases in future.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Although alienation toward parents is important for children (for current mental health status or later interpersonal relationships in adulthood), it is undervalued and even lacks a standardized tool of assessment. Moreover, the large number of left-behind children in China is a cause of public concern. However, their experienced alienation toward their parents remains unclear, which may be important for early detection or intervention for behavioral problems in this population. Hence, the current study aimed to develop an alienation inventory for children and then use it to investigate the experienced alienation toward parents in Chinese left-behind children.
Two studies were carried out. Study 1 was designed to develop a standard inventory of alienation toward parents (IAP). In study 2, 8361 children and adolescents (6704 of them were left-behind status) of the Chongqing area, aged between 8 and 19 years old, were recruited for investigation. All participants were surveyed with a standard sociodemographic questionnaire, children's cognitive style questionnaire, children's depression inventory, adolescent self-rating life events checklist, and newly built IAP in study 1.
In study 1, we developed a two-component (communication and emotional distance) and 18-item (9 items for maternal or paternal form, respectively) IAP questionnaire. In study 2, exploratory factor analysis indicated an expected two-factor structure of IAP, which was confirmed by confirmatory factor analysis. The Cronbach's alpha coefficients showed a good reliability (0.887 and 0.821 for maternal and paternal form, respectively). Children with absent mother experienced the highest alienation toward parents. Boys as well as children aged 8–10 years old experienced higher alienation toward parents. Poor communication with parents (sparse or no connection), level of left-behind condition (parents divorced, been far away from parents), and psychosocial vulnerability (stressful life events, negative cognitive style) were risk factors of alienation toward parents.
The current study develops a two-factor (communication and emotional distance) IAP, which offers a reliable tool to assess experienced alienation of affection toward parents in children aged between 8 and 19 years old. Our result is the first investigation of experienced alienation and potential influential factors in Chinese left-behind children. The findings that children with absent mother experience higher alienation toward parents, as well as three recognized risk factors for alienation of affection toward parents (poor communication with absent parents, worse left-behind condition, and psychosocial vulnerability), give valuable guidance for parents who intend to leave or who are already leaving as well as for government policymaking.
Although numerous studies have investigated the individual effects of salinity, irrigation and fertilization on soil microbial communities, relatively less attention has been paid to their combined influences, especially using molecular techniques. Based on the field of orthogonal designed test and deoxyribonucleic acid sequencing technology, the effects of saline water irrigation amount, salinity level of irrigation water and nitrogen (N) fertilizer rate on soil bacterial community structure were investigated. The results showed that the irrigation amount was the most dominant factor in determining the bacterial richness and diversity, followed by the irrigation water salinity and N fertilizer rate. The values of Chao1 estimator, abundance-based coverage estimator and Shannon indices decreased with an increase in irrigation amount while increased and then decreased with an increase in irrigation water salinity and N fertilizer rate. The highest soil bacterial richness and diversity were obtained under the least irrigation amount (25 mm), medium irrigation water salinity (4.75 dS/m) and medium N fertilizer rate (350 kg/ha). However, different bacterial phyla were found to respond distinctively to these three factors: irrigation amount significantly affected the relative abundances of Proteobacteria and Chloroflexi; irrigation water salinity mostly affected the members of Actinobacteria, Gemmatimonadetes and Acidobacteria; and N fertilizer rate mainly influenced the Bacteroidetes' abundance. The results presented here revealed that the assessment of soil microbial processes under combined irrigation and fertilization treatments needed to be more careful as more variable consequences would be established by comparing with the influences based on an individual factor, such as irrigation amount or N fertilizer rate.
Quantifying reasonable crop yield gaps and determining potential regions for yield improvement can facilitate regional plant structure adjustment and promote crop production. The current study attempted to evaluate the yield gap in a region at multi-scales through model simulation and farmer investigation. Taking the winter wheat yield gap in the Huang-Huai-Hai farming region (HFR) for the case study, 241 farmers’ fields in four typical high-yield demonstration areas were surveyed to determine the yield limitation index and attainable yield. In addition, the theoretical and realizable yield gap of winter wheat in 386 counties of the HFR was assessed. Results showed that the average field yield of the demonstration plots was 8282 kg/ha, accounting for 0.72 of the potential yield, which represented the highest production in the region. The HFR consists of seven sub-regions designated 2.1–2.7: the largest attainable yield gap existed in the 2.6 sub-region, in the southwest of the HFR, while the smallest was in the 2.2 sub-region, in the northwest of the HFR. With a high irrigated area rate, the yield gap in the 2.2 sub-region could hardly be reduced by increasing irrigation, while a lack of irrigation remained an important limiting factor for narrowing the yield gap in 2.3 sub-region, in the middle of the HFR. Therefore, a multi-scale yield gap evaluation framework integrated with typical field survey and crop model analysis could provide valuable information for narrowing the yield gap.
With growing demand for better fuel economy for automobiles, multimaterial solutions are increasingly being utilized in the automotive industry for reducing weight in the vehicle body structure. This poses challenges in terms of joining dissimilar metals, especially those with vastly different properties such as aluminum to steel joining. General Motors has developed a new resistance spot-welding technique for dissimilar materials using a multi-ring domed (MRD) electrode and multiple solidification weld schedules to address this challenge. Originally developed for aluminum to aluminum resistance spot welding, this technology is being deployed as the mainstream aluminum joining solution to leverage existing infrastructure and workforce competency in resistance spot welding. With the recent expansion of MRD technology to aluminum to steel resistance spot welding, there is an ever-greater need to experimentally verify the quality of each aluminum to steel resistance spot-weld application with limited time and resources. Nondestructive evaluation (NDE) would enable the transfer of resistance spot-welding technology to dissimilar aluminum to steel joints. This article describes the current state of the art of aluminum to steel resistance spot welding and the challenges in developing a robust NDE process for this technology.
The strong-coupling mode, called the “quasimode”, is excited by stimulated Brillouin scattering (SBS) in high-intensity laser–plasma interactions. Also SBS of the quasimode competes with SBS of the fast mode (or slow mode) in multi-ion species plasmas, thus leading to a low-frequency burst behavior of SBS reflectivity. Competition between the quasimode and the ion-acoustic wave (IAW) is an important saturation mechanism of SBS in high-intensity laser–plasma interactions. These results give a clear explanation of the low-frequency periodic burst behavior of SBS and should be considered as a saturation mechanism of SBS in high-intensity laser–plasma interactions.
We propose an alternative to the prevailing framework for modelling tear-film breakup, which posits a layered structure with a mucus layer next to the cornea and an aqueous layer on top. Experimental evidence shows continuous variation of mucin concentration throughout the tear film, with no distinct boundary between the two layers. Thus, we consider a continuous-viscosity model that replaces the mucus and aqueous layers by a single liquid layer with continuous profiles of mucin concentration and viscosity, which are governed by advection–diffusion of mucin. The lipids coating the tear film are treated as insoluble surfactants as previously, and slip is allowed on the ocular surface. Using the thin-film approximation, we carry out linear stability analysis and nonlinear numerical simulations of tear-film breakup driven by van der Waals attraction. Results show that for the same average viscosity, having more viscous material near the ocular surface stabilizes the film and prolongs the breakup time. Compared with the layered models, the continuous-viscosity model predicts film breakup times that are in better agreement with experimental data. Finally, we also suggest a hydrodynamic explanation for how pathological loss of membrane-associated mucins may lead to faster breakup.