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Studies on humans that exploit contemporary data-intensive, high-throughput ‘omic’ assay technologies, such as genomics, transcriptomics, proteomics and metabolomics, have unequivocally revealed that humans differ greatly at the molecular level. These differences, which are compounded by each individual’s distinct behavioral and environmental exposures, impact individual responses to health interventions such as diet and drugs. Questions about the best way to tailor health interventions to individuals based on their nuanced genomic, physiologic, behavioral, etc. profiles have motivated the current emphasis on ‘precision’ medicine. This review’s purpose is to describe how the design and execution of N-of-1 (or personalized) multivariate clinical trials can advance the field. Such trials focus on individual responses to health interventions from a whole-person perspective, leverage emerging health monitoring technologies, and can be used to address the most relevant questions in the precision medicine era. This includes how to validate biomarkers that may indicate appropriate activity of an intervention as well as how to identify likely beneficial interventions for an individual. We also argue that multivariate N-of-1 and aggregated N-of-1 trials are ideal vehicles for advancing biomedical and translational science in the precision medicine era since the insights gained from them can not only shed light on how to treat or prevent diseases generally, but also provide insight into how to provide real-time care to the very individuals who are seeking attention for their health concerns in the first place.
In view of the cooperative guidance problem with time delay, this paper proposes a two-stage time-delay prescribed-time cooperative guidance law in the three-dimensional (3D) space. In the first stage, by introducing a time scaling function and time-delay consensus, the proposed cooperative guidance law can overcome the negative influence of time delay to guaranteed the desired convergence performance. Derived from the Lyapunov convergence analysis, the time-delay stability of the first stage can be ensured and the convergence time can be described as the relationship between delayed time and mission-assigned convergence time. Then, taking the prescribed-time-related convergence time as the switching point, the second stage begins with suitable initial conditions and all interceptors are governed by proportional navigation guidance. Finally, comparative simulations are performed to demonstrate the effectiveness and superiority of the proposed time-delay guidance law.
We report the experimental results of the commissioning phase in the 10 PW laser beamline of the Shanghai Superintense Ultrafast Laser Facility (SULF). The peak power reaches 2.4 PW on target without the last amplifying during the experiment. The laser energy of 72 ± 9 J is directed to a focal spot of approximately 6 μm diameter (full width at half maximum) in 30 fs pulse duration, yielding a focused peak intensity around 2.0 × 1021 W/cm2. The first laser-proton acceleration experiment is performed using plain copper and plastic targets. High-energy proton beams with maximum cut-off energy up to 62.5 MeV are achieved using copper foils at the optimum target thickness of 4 μm via target normal sheath acceleration. For plastic targets of tens of nanometers thick, the proton cut-off energy is approximately 20 MeV, showing ring-like or filamented density distributions. These experimental results reflect the capabilities of the SULF-10 PW beamline, for example, both ultrahigh intensity and relatively good beam contrast. Further optimization for these key parameters is underway, where peak laser intensities of 1022–1023 W/cm2 are anticipated to support various experiments on extreme field physics.
OBJECTIVES/GOALS: In a familial case where 10 of 17 members inherited EA/LVNC in an autosomal dominant pattern, we discovered a novel, damaging missense variant in the gene KLHL26 that segregates with disease and comprises an altered electrostatic surface profile, likely decoupling the CUL3-interactome. We hypothesize that this KLHL26 variant is etiologic of EA/LVNC. METHODS/STUDY POPULATION: We differentiated a family trio (a heart-healthy daughter and EA/LVNC-affected mother and daughter) of induced pluripotent stem cells into cardiomyocytes (iPSC-CMs) in a blinded manner on three iPSC clones per subject. Using flow cytometry, immunofluorescence, and biomechanical, electrophysiological, and automated contraction methods, we investigated iPSC-CM differentiation efficiency between D10-20, contractility analysis and cell cycle regulation at D20, and sarcomere organization at D60. We further conducted differential analyses following label-free protein and RNA-Seq quantification at D20. Via CRISPR-Cas9 gene editing, we plan to characterize KLHL26 variant-specific iPSC-CM alterations and connect findings to discoveries from patient-specific studies. RESULTS/ANTICIPATED RESULTS: All iPSC lines differentiated into CMs with an increased percentage of cTnT+ cells in the affected daughter line. In comparison to the unaffected, affected iPSC-CMs had fewer contractions per minute and altered calcium transients, mainly a higher amount of total calcium release, faster rate of rise and faster rate of fall. The affected daughter line further had shorter shortening and relaxation times, higher proliferation, lower apoptosis, and a smaller cell surface area per cardiac nucleus. The affected mother line trended in a similar direction to the affected daughter line. There were no gross differences in sarcomere organization between the lines. We also discovered differential expression of candidate proteins such as kinase VRK1 and collagen COL5A1 from proteomic profiling. DISCUSSION/SIGNIFICANCE: These discoveries suggest that EA/LVNC characteristics or pathogenesis may result from decreased contractile ability, altered calcium transients, and cell cycle dysregulation. Through the KLHL26 variant correction and introduction in the daughter lines, we will build upon this understanding to inform exploration of critical clinical targets.
The location of the vertical segment of the facial nerve varies greatly among patients undergoing otological surgery. Its position relative to the incus determines facial recess width, which has implications for ease of cochlear implantation.
To investigate the variation in facial nerve depth, relative to the incus, on pre-operative computed tomography in patients undergoing cochlear implantation.
A retrospective cohort study was conducted of paediatric patients undergoing cochlear implantation at a tertiary referral centre. Distance between the incus short process and facial nerve, in the transverse (medial-lateral) dimension, was measured at six imaging slices, ranging from 1.25 to 7.25 mm below the tip of the incus short process.
Facial nerve depth relative to the incus short process demonstrated significant variability. Among all subjects and at all measurements taken inferior to the incus, the mean dimension between the facial nerve and the incus short process was 1.71 mm.
This paper presents a rapid, repeatable technique to assess the depth of the facial nerve vertical segment on pre-operative computed tomography, as measured relative to the tip of the incus short process. This allows the surgeon to anticipate facial recess width and round window access during cochlear implantation.
To investigate the association between parity and the risk of incident dementia in women.
We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)).
Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02–1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1–4 parities (HR = 1.30, 95% CI = 1.02–1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02–1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00–2.55), but the risk of AD was not significantly associated with parity.
Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.
A 2-year fertilization experiment was conducted to study the effect of different ratios of organic (pig) manure on wheat yield and nitrogen use efficiency (NUE). The four treatments were no nitrogen (N) (CK); 100% chemical fertilizer N (urea; T1); 70% chemical fertilizer N + 30% organic manure N (T2) and 50% chemical fertilizer N + 50% organic manure N (T3), with the same amount of applied nitrogen (120 kg/ha). The results showed the maximum grain yield (3049 kg/ha), crop nitrogen uptake (216 kg/ha), NUE (65.4%) and accumulated nitrate nitrogen (NO3−-N in 0–200 cm, 142 kg/ha) were observed in the T1 among all treatments in the first year. However, the largest grain yield (5074 kg/ha), crop nitrogen uptake (244 kg/ha) and NUE (82.5%) were under T2 treatment in the second year. Furthermore, T2 had the maximum NO3−-N content in 0–100 cm layer (116 kg/ha), especially 0–40 cm layer, and the lowest NO3−-N content in 100–200 cm (58.8 kg/ha). However, 50% organic manure N in T3 increased apparent nitrogen loss by 39.0% compared to that in T2. Therefore, 30% organic manure N application was more conducive for enhancing wheat yield and NUE and promoting environmental safety after 1-year fertilization time.
Electroconvulsive therapy (ECT) remains irreplaceable in the treatment of several psychiatric conditions. However, evidence derived using data from a national database to support its safety is limited. The aim of this study was to investigate in-hospital mortality among patients with psychiatric conditions treated with and without ECT.
Using data from the Taiwan National Health Insurance Research Database from 1997 to 2013, we identified 828,899 inpatients with psychiatric conditions, among whom 0.19% (n = 1571) were treated with ECT.
We found that ECT recipients were more frequently women, were younger and physically healthier, lived in more urbanized areas, were treated in medical centers, and had longer hospital stays. ECT recipients had lower odds of in-hospital mortality than did those who did not receive ECT. Moreover, no factor was identified as being able to predict mortality in patients who underwent ECT. Among all patients, ECT was not associated with in-hospital mortality after controlling for potential confounders.
ECT was indicated to be safe and did not increase the odds of in-hospital mortality. However, ECT appeared to be administered only on physically healthy but psychiatrically compromised patients, a pattern that is in opposition with the scientific evidence supporting its safety. Moreover, our data suggest that ECT is still used as a treatment of last resort in the era of modern psychiatry.
Guangxi, a province in southwestern China, has the second highest reported number of HIV/AIDS cases in China. This study aimed to develop an accurate and effective model to describe the tendency of HIV and to predict its incidence in Guangxi. HIV incidence data of Guangxi from 2005 to 2016 were obtained from the database of the Chinese Center for Disease Control and Prevention. Long short-term memory (LSTM) neural network models, autoregressive integrated moving average (ARIMA) models, generalised regression neural network (GRNN) models and exponential smoothing (ES) were used to fit the incidence data. Data from 2015 and 2016 were used to validate the most suitable models. The model performances were evaluated by evaluating metrics, including mean square error (MSE), root mean square error, mean absolute error and mean absolute percentage error. The LSTM model had the lowest MSE when the N value (time step) was 12. The most appropriate ARIMA models for incidence in 2015 and 2016 were ARIMA (1, 1, 2) (0, 1, 2)12 and ARIMA (2, 1, 0) (1, 1, 2)12, respectively. The accuracy of GRNN and ES models in forecasting HIV incidence in Guangxi was relatively poor. Four performance metrics of the LSTM model were all lower than the ARIMA, GRNN and ES models. The LSTM model was more effective than other time-series models and is important for the monitoring and control of local HIV epidemics.
Giardia duodenalis is the most common intestinal parasite of humans in the USA, but the risk factors for sporadic (non-outbreak) giardiasis are not well described. The Centers for Disease Control and Prevention and the Colorado and Minnesota public health departments conducted a case-control study to assess risk factors for sporadic giardiasis in the USA. Cases (N = 199) were patients with non-outbreak-associated laboratory-confirmed Giardia infection in Colorado and Minnesota, and controls (N = 381) were matched by age and site. Identified risk factors included international travel (aOR = 13.9; 95% CI 4.9–39.8), drinking water from a river, lake, stream, or spring (aOR = 6.5; 95% CI 2.0–20.6), swimming in a natural body of water (aOR = 3.3; 95% CI 1.5–7.0), male–male sexual behaviour (aOR = 45.7; 95% CI 5.8–362.0), having contact with children in diapers (aOR = 1.6; 95% CI 1.01–2.6), taking antibiotics (aOR = 2.5; 95% CI 1.2–5.0) and having a chronic gastrointestinal condition (aOR = 1.8; 95% CI 1.1–3.0). Eating raw produce was inversely associated with infection (aOR = 0.2; 95% CI 0.1–0.7). Our results highlight the diversity of risk factors for sporadic giardiasis and the importance of non-international-travel-associated risk factors, particularly those involving person-to-person transmission. Prevention measures should focus on reducing risks associated with diaper handling, sexual contact, swimming in untreated water, and drinking untreated water.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
The current experiment was conducted to evaluate the effects of different dietary protein levels and rumen-protected folic acid (RPFA) supplementation on ruminal fermentation, microbial enzyme activity, bacterial populations and urinary excretion of purine derivatives (PD) in growing beef steers. Low-protein (LP) or high-protein (HP) diets were fed to eight ruminally cannulated first-generation cross-bred (Blonde d'Aquitaine × Simmental) beef steers with or without RPFA supplementation. Steers were fed a total mixed ration, and dietary concentrate to maize silage ratio was 50 : 50 (dry matter (DM) basis). No interaction between dietary crude protein (CP) levels and RPFA supplementation was observed during the experiment. Ruminal pH was unaffected by RPFA supplementation, but decreased with increasing dietary CP levels. Ruminal total volatile fatty acid concentration increased with increasing dietary CP levels or RPFA supplementation. Molar proportion of acetate increased with RPFA supplementation, but tended to decrease with increasing dietary CP levels. The proportion of propionate decreased with RPFA supplementation, but was unaffected by dietary CP levels. As a result, the acetate to propionate ratio increased with RPFA supplementation, but tended to be lower for the HP diets than the LP diets. Ammonia-nitrogen content decreased with RPFA supplementation, but increased with increasing dietary CP levels. In situ ruminal degradability of maize straw and concentrate increased with increasing dietary CP levels or RPFA supplementation. Microbial enzyme (carboxymethyl-cellulase, cellobiase, xylanase, pectinase, α-amylase and protease) activity, bacterial populations (Ruminococcus albus, Ruminococcus flavefaciens, Butyrivibrio fibrisolvens, Prevotella ruminicola, Fibrobacter succinogenes and Ruminobacter amylophilus) and urinary PD excretion increased with increasing dietary CP levels or RPFA supplementation. The current study showed that increasing dietary CP levels from 109·1 to 130·7 g/kg DM or supplementing 75 mg RPFA improved ruminal fermentation and microbial protein synthesis by increasing bacterial population and microbial enzyme activity.
This paper will present a dynamic Variable Rate Irrigation System developed by the University of Georgia. The system consists of the EZZone management zone delineation tool, the UGA Smart Sensor Array (UGA SSA) and an irrigation scheduling decision support tool. An experiment was conducted in 2015 and 2016 in two different peanut fields to evaluate the performance of using the UGA SSA to dynamically schedule Variable Rate Irrigation (VRI). For comparison reasons strips were designed within the fields. These strips were irrigated according to either UGA SSA or Irrigator Pro recommendations. The results showed that Irrigator Pro is a conservative irrigation method which results in high yields. On the other hand the UGA SSA recommendations worked very well with the VRI system and in both years it recommended an average of 25% less irrigation water than the Irrigator Pro.
crAssphage is a newly discovered gut bacteriophage. However, its pathogenicity and molecular epidemiology in humans are as yet unclear. In this study, we investigated the association between crAssphage and diarrhoea, as well as the molecular epidemiology of crAssphage in Chinese patients from our hospital. Our results indicated that there were no significant differences in the crAssphage-positive ratio and viral loads in faecal supernatants between adults with diarrhoea and healthy adults. Of infants and children with diarrhoea, 2·8% were found to be crAssphage-positive, including two infants aged <1 month. Markedly, of all confirmed crAssphage-positive strains, 100% had the ORF00039 deletion and 77·8% had low identity of ORF00018 compared to crAssphage (GenBank accession no. NC_024711, designated genotype 1). Thus, crAssphage was not associated with diarrhoea and most strains of crAssphage in Chinese patients (designated genotype 2) were characterized by the ORF00039 deletion and low identity of ORF00018.
A new approach for the analysis of stress intensity factors (SIFs) for cracked plane plate is proposed based on the wavelet finite element method using the scaling functions of B-spline wavelet on the interval (BSWI). The performance of the method is investigated through the comparison of the results with the available numerical examples in the literate. It is shown that the solution quality is much better than that of the traditional adaptive finite element method. Though the method is applied to plane structures in this paper, it can be extended to solving problems for other classes of structures.
Biased assessment of tillage impacts on soil organic carbon (SOC) sequestration are often associated with a lack of information on the initial level of SOC stocks. The present study reported the changes in SOC concentrations and stocks following 10-year different tillage practices relative to the initial SOC levels. The tillage trial included no tillage (NT), ridge tillage (RT) and mouldboard plough (MP) on a Black soil (Hapludolls) in Northeast China. Results showed that tillage, soil depth and time significantly affected SOC concentration and SOC stock. Tillage and crop residue retention had great impacts on the SOC concentrations in the top 0·1 m layer. Compared with MP and NT, RT resulted in higher SOC concentration and SOC stock in the plough layer (0–0·2 m), which became more obvious with time. The soil under NT and RT had higher stratification ratios (SR) of SOC (SR, the ratio of SOC concentration in 0–0·05 m to that in 0·1–0·2 m) than under MP. Significant positive and nearly identical linear relationships between the SR of SOC and the duration of tillage practices occurred for both NT and RT soils; the increased SR in NT resulted from both SOC increase in surface and SOC decrease in subsurface soils, but in RT, the increased SR was only from a substantial SOC increase in surface soil. Accordingly, the present study highlights that RT was more helpful than NT in carbon sequestration for the studied Black soil in Northeast China.
Parkinson's disease (PD) has been proposed to result from the interaction of aging and environment in susceptible individuals. Defective metabolism of debrisoquine, inherited as an autosomal recessive, has been associated with this susceptibility. In 35 PD patients and 19 age-matched controls, no significant differences in debrisoquine metabolism were found, although a trend to impaired metabolism was noted in patients with disease onset ≤40. Foci of PD patients were associated with rural living and well water drinking, or rural living coupled with market gardening or wood pulp mills. In a questionnaire survey, patients with PD onset ≤age 47 were significantly more likely to have lived in rural areas and to have drunk well water than those with onset ≥age 54 (p≤0.01). Because of population mobility in North America, a case-control study designed to test environmental, occupational, dietary and other proposed risk factors for PD was conducted in China, where the population is more stationary and the environment more stable. No significant differences in incidences of head trauma, smoking or childhood measles were found between patients and controls.
Saline-sodic soils are widely distributed in the western Songnen Plain of Northeast China and planting rice has been found to be an effective and feasible approach for improving saline-sodic soil and increasing food production. Assessment of the effectiveness and sustainability of this method requires monitoring of the changes in soil salinity and nutrient content. The objective of the current study was to investigate the changes of soil salinity and nitrogen (N) contents over 1, 3, 6 and 9 years of cultivation, four application rates of N (N0: no N, N1: 100 kg N/ha, N2: 200 kg N/ha and N3: 300 kg N/ha) and two irrigation water types: ground water irrigation (GWI) and river water irrigation (RWI). Salinity and N contents of soil and water samples were analysed before planting and after harvest throughout the experiments. Soil pH and electrical conductivity (EC), especially in the surface layer of 0–40 cm depth, decreased with years of cultivation with both GWI and RWI, while soil inorganic N and total N contents increased. Moreover, with increasing N application rates, soil inorganic N and total N contents increased significantly in the 0–20 cm soil layer. Increasing N application had little effect on soil pH and EC. Reclaiming and planting rice promoted desalination of the surface and formation of a fertile tillage layer in saline-sodic paddy fields. In terms of irrigation and drainage in saline-sodic paddy fields, both soil salinity and N contents increased. Soil total salinity increased annually by 34 and 12·8 kg/ha, and inorganic N contents increased annually by 9 and 13·5 kg/ha with GWI and RWI, respectively. Therefore, comprehensive agricultural practices should be adopted for improving and cropping rice in saline-sodic paddy fields.
We examine the roles of actuaries in UK life offices, along with trends, challenges to and opportunities for actuaries. We carry out an analysis of senior roles in life offices, a questionnaire survey and interviews with relevant senior personnel. We find that actuaries occupy many important roles in life offices and are regarded as having good industry knowledge and technical skills, especially in financial modelling. There are fewer executive directors and more non-executive directors of life offices who are actuaries compared with the position in 1990. A higher proportion of reserved roles is outsourced to consultants than was the case in 1990. Only a small number of Actuarial Function Holders are directors. Actuaries are more siloed than was the case in the past, although actuaries are well represented in the finance and risk functions of many offices. Although actuarial work in connection with the preparation for Solvency II will decline, there will be important ongoing requirements for actuaries following Solvency II implementation. We also see opportunities for actuaries in four areas: in risk management, in financial analysis and management based on Solvency II and international financial reporting standards, in connection with “big data”, and in product development and the customer proposition. There are implications for the examination syllabus, continuing professional development and research.
Tramadol hydrochloride (HCl) is a centrally acting synthetic opioid analgesic. Psychotic symptoms are relatively rare in reported adverse events. Here, we report a patient who presented with tramadol-related psychotic symptoms.
A 59-year-old female had underlying bipolar I disorder and received lithium treatment with stable affective status. 1 month before hospitalisation, she had been taking tramadol HCl/acetaminophen for joint pain. She then developed obvious persecutory delusion. However, her clinical picture did not meet the criteria of any mood episode. After treatment of risperidone in addition to lithium, she was discharged without any psychotic symptom. She remained euthymic without any psychotic symptom on monotherapy of lithium (300 mg) three tablets once daily.
Tramadol HCl is commonly prescribed in clinical practice and psychotic symptoms related to it are uncommon. We should be careful about the rare but important adverse events while prescribing tramadol HCl.