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This study introduces the prostate cancer linear energy transfer sensitivity index (PCLSI) as a novel method to predict relative biological effectiveness (RBE) in prostate cancer using linear energy transfer (LET) in proton therapy based on screening for DNA repair mutations.
Materials and Methods:
Five prostate cancer cell lines with DNA repair mutations known to cause sensitivity to LET and DNA repair inhibitors were examined using published data. Relative Du145 LET sensitivity data were leveraged to deduce the LET equivalent of olaparib doses. The PCLSI model was built using three of the prostate cancer cell lines (LNCaP, 22Rv1 and Du145) with DNA mutation frequency from patient cohorts. The PCLSI model was compared against two established RBE models, McNamara and McMahon, for LET-optimized prostate cancer treatment plans.
Results:
The PCLSI model relies on the presence of eight DNA repair mutations: AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, which are most likely to predict increased LET sensitivity and RBE in proton therapy. In the LET-optimized plan, the PCLSI model indicates that prostate cancer cells with these DNA repair mutations are more sensitive to increased LET than the McNamara and McMahon RBE models, with expected RBE increases ranging from 11%–33% at 2keV/µm.
Conclusions:
The PCLSI model predicts increasing RBE as a function of LET in the presence of certain genetic mutations. The integration of LET-optimized proton therapy and genetic mutation profiling could be a significant step toward the use of individualized medicine to improve outcomes using RBE escalation without the potential toxicity of physical dose escalation.
Transcranial direct current stimulation (tDCS) is a promising treatment for major depressive disorder (MDD). This study evaluated its antidepressant and cognitive effects as a safe, effective, home-based therapy for MDD.
Methods
This double-blind, sham-controlled, randomized trial divided participants into low-intensity (1 mA, n = 47), high-intensity (2 mA, n = 49), and sham (n = 45) groups, receiving 42 daily tDCS sessions, including weekends and holidays, targeting the dorsolateral prefrontal cortex for 30 minutes. Assessments were conducted at baseline and weeks 2, 4, and 6. The primary outcome was cognitive improvement assessed by changes in total accuracy on the 2-back test from baseline to week 6. Secondary outcomes included changes in depressive symptoms (HAM-D), anxiety (HAM-A), and quality of life (QLES). Adverse events were monitored. This trial was registered with ClinicalTrials.gov (NCT04709952).
Results
In the tDCS study, of 141 participants (102 [72.3%] women; mean age 35.7 years, standard deviation 12.7), 95 completed the trial. Mean changes in the total accuracy scores from baseline to week 6 were compared across the three groups using an F-test. Linear mixed-effects models examined the interaction of group and time. Results showed no significant differences among groups in cognitive or depressive outcomes at week 6. Active groups experienced more mild adverse events compared to sham but had similar rates of severe adverse events and dropout.
Conclusions
Home-based tDCS for MDD demonstrated no evidence of effectiveness but was safe and well-tolerated. Further research is needed to address the technical limitations, evaluate broader cognitive functions, and extend durations to evaluate its therapeutic potential.
Multidimensional scaling (MDS) models for the analysis of dominance data have been developed in the psychometric and classification literature to simultaneously capture subjects’ preference heterogeneity and the underlying dimensional structure for a set of designated stimuli in a parsimonious manner. There are two major types of latent utility models for such MDS models that have been traditionally used to represent subjects’ underlying utility functions: the scalar product or vector model and the ideal point or unfolding model. Although both models have been widely applied in various social science applications, implicit in the assumption of such MDS methods is that all subjects are homogeneous with respect to their underlying utility function; i.e., they all follow a vector model or an ideal point model. We extend these traditional approaches by presenting a Bayesian MDS model that combines both the vector model and the ideal point model in a generalized framework for modeling metric dominance data. This new Bayesian MDS methodology explicitly allows for mixtures of the vector and the ideal point models thereby accounting for both preference heterogeneity and structural heterogeneity. We use a marketing application regarding physicians’ prescription behavior of antidepressant drugs to estimate and compare a variety of spatial models.
A cyclical conditional maximum likelihood estimation procedure is developed for the multidimensional unfolding of two- or three-way dominance data (e.g., preference, choice, consideration) measured on ordered successive category rating scales. The technical description of the proposed model and estimation procedure are discussed, as well as the rather unique joint spaces derived. We then conduct a modest Monte Carlo simulation to demonstrate the parameter recovery of the proposed methodology, as well as investigate the performance of various information heuristics for dimension selection. A consumer psychology application is provided where the spatial results of the proposed model are compared to solutions derived from various traditional multidimensional unfolding procedures. This application deals with consumers intending to buy new luxury sport-utility vehicles (SUVs). Finally, directions for future research are discussed.
A variety of joint space multidimensional scaling (MDS) methods have been utilized for the spatial analysis of two- or three-way dominance data involving subjects’ preferences, choices, considerations, intentions, etc. so as to provide a parsimonious spatial depiction of the underlying relevant dimensions, attributes, stimuli, and/or subjects’ utility structures in the same joint space representation. We demonstrate that care must be taken with respect to a key assumption in existent joint space MDS models such that all estimated dimensions are utilized by each and every subject in the sample, as this assumption can lead to serious distortions with respect to the derived joint spaces. We develop a new Bayesian dimension selection methodology for the multidimensional unfolding model which accommodates heterogeneity with respect to such dimensional utilization at the individual subject level for the analysis of two or three-way dominance data. A consumer psychology application regarding the preference for Over-the-Counter (OTC) analgesics is provided. We conclude by discussing the practical implications of the results, as well as directions for future research.
This study examines the impact of COVID-19-induced policy environments on civil servants’ public service motivation (PSM), a topic not yet adequately researched. Using a vignette survey experiment, we investigate how four types of COVID-19 policy environment information – 1) total deduction of annual leave compensation, 2) a significant increase in working hours, 3) positive assessments of government responses from domestic audiences, and 4) positive assessments of government responses from other advanced democracies – shape civil servants’ PSM during the pandemic. We analyze original data from over 4,000 South Korean civil servants in central and local governments, gathered as part of a representative survey. Results show that reducing compensation to prepare the disaster relief fund has a negative impact, whereas recognition by advanced democracies has a positive impact on PSM. Our analysis suggests the importance of policy environments in both motivating and demotivating civil servants during a pandemic crisis.
We investigate the concentration fluctuations of passive scalar plumes emitted from small, localised (point-like) steady sources in a neutrally stratified turbulent boundary layer over a rough wall. The study utilises high-resolution large-eddy simulations for sources of varying sizes and heights. The numerical results, which show good agreement with wind-tunnel studies, are used to estimate statistical indicators of the concentration field, including spectra and moments up to the fourth order. These allow us to elucidate the mechanisms responsible for the production, transport and dissipation of concentration fluctuations, with a focus on the very near field, where the skewness is found to have negative values – an aspect not previously highlighted. The gamma probability density function is confirmed to be a robust model for the one-point concentration at sufficiently large distances from the source. However, for ground-level releases in a well-defined area around the plume centreline, the Gaussian distribution is found to be a better statistical model. As recently demonstrated by laboratory results, for elevated releases, the peak and shape of the pre-multiplied scalar spectra are confirmed to be independent of the crosswind location for a given downwind distance. Using a stochastic model and theoretical arguments, we demonstrate that this is due to the concentration spectra being directly shaped by the transverse and vertical velocity components governing the meandering of the plume. Finally, we investigate the intermittency factor, i.e. the probability of non-zero concentration, and analyse its variability depending on the thresholds adopted for its definition.
In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.
Methods:
A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.
Results:
We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.
Conclusion:
The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.
Shark vertebrae and their centra (vertebral bodies) are high-performance structures able to survive millions of cycles of high amplitude strain despite lacking a repair mechanism for accumulating damage. Shark centra consist of mineralized cartilage, a biocomposite of bioapatite (bAp), and collagen, and the nanocrystalline bAp's contribution to functionality remains largely uninvestigated. Using the multiple detector energy-dispersive diffraction (EDD) system at 6-BM-B, the Advanced Photon Source, and 3D tomographic sampling, the 3D functionality of entire centra were probed. Immersion in ethanol vs phosphate-buffered saline produces only small changes in bAp d-spacing within a great hammerhead centrum. EDD mapping under in situ loading was performed an entire blue shark centrum, and 3D maps of bAp strain showed the two structural zones of the centrum, the corpus calcareum and intermedialia, contained opposite-signed strains approaching 0.5%, and application of ~8% nominal strain did not alter these strain magnitudes and their spatial distribution.
Prevented planting payments reimburse crop producers for losses from not being able to plant. These payments provide critical protection to producers; however, these payments, which are determined using a nationwide, crop-specific coverage factor, have been questioned to induce moral hazard. Depending on the region and crop insurance coverage, payments from this provision exceed producers’ losses. This paper estimates the prevented planting coverage factor by coverage level and region that would equitably reimburse corn and soybean producers for their losses. We find the prevented planting coverage factor has significant variation across coverage levels and location within our study region. The prevented planting coverage factor was found to decline as the policy coverage level increases. The further north in the study region the higher the coverage factor, likely due to increased land rent expenses. The results provide a unique perspective of how these coverage factors would vary to equitably compensate producers for losses, which addresses the moral hazard concerns with prevented planting.
Accordingly, the Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) working committee, composed of domestic experts, developed Korea’s first KMAP-BP in 2002 and later in 2006, 2010, and 2010. A revised version of KMAP-BP was announced every four years four times in 2014 and 2018.6-10). The treatment strategy considering the safety and tolerability of KMAP-BP 2022 was developed by collecting opinions from domestic bipolar disorder experts.
Objectives
Safety and tolerability of drugs are very important factors in the treatment of bipolar disorder. An expert opinion survey was conducted on treatment strategies in various special clinical situations, such as significant weight gain, characteristic drug side effects, low drug adherence, pregnant and reproductive women, and genetic counseling.
Methods
A written survey about treatment strategies related to safety and tolerability was prepared and focused on significant weight gain, characteristic drug side effects, low drug adherence, pregnant and reproductive women, and genetic counseling. Ninety-three experts of the review committee completed the survey.
Results
In the case of weight gain occurring during drug treatment, it was preferred to replace it with a drug that caused less weight gain, such as lamotrigine, aripiprazole, or ziprasidone. If there was a significant weight gain due to the treatment drug, it was preferred to intervene as soon as possible. In the case of hyperprolactinemia, it was selected to change the medication and discontinue it for benign rash caused by lamotrigine. In improving drug adherence, the preference for long-acting injections increased. Antipsychotics can be used with great caution in pregnant or reproductive women.
Conclusions
Treatment strategies in various clinical situations related to safety and tolerability in drug treatment for bipolar disorder were described. It is hoped that it will be useful in practical clinical situations.
Shape deformation during fossilization can prevent accurate reconstruction of an organism's form during life, hampering areas of paleontology ranging from functional morphology to systematics. Retrodeformation attempts to restore the original shape of deformed fossil specimens and requires an adequate knowledge of the deformation process. Although tectonic processes and retrodeformation are relatively well understood, research on quantifying the effect of compressive deformation on fossil morphology is scant. Here we investigate the factors that can cause changes in the shape of fossil specimens during compressive deformation. Three-dimensional (3D) models of trilobite cranidia/cephala are subjected to simulated deposition and compaction using rigid body simulation and scaling features of the open-source 3D software Blender. The variation in pitch and roll angle is lowest on flat surfaces, intermediate on tilted surfaces, and highest on irregular surfaces. These trends are reflected in the morphological differences captured by principal component scores in geometric morphometric analyses using landmarks. In addition, the different shapes of trilobite cranidia/cephala according to their systematic affinity influence the degree of angular variation, which in turn affects their posture—normal or inverted. Inverted cranidia/cephala show greater morphological variability than those with normal postures.
Background: After a transient ischemic attack (TIA) or minor stroke, the long-term risk of subsequent stroke is uncertain. Methods: Electronic databases were searched for observational studies reporting subsequent stroke during a minimum follow-up of 1 year in patients with TIA or minor stroke. Unpublished data on number of stroke events and exact person-time at risk contributed by all patients during discrete time intervals of follow-up were requested from the authors of included studies. This information was used to calculate the incidence of stroke in individual studies, and results across studies were pooled using random-effects meta-analysis. Results: Fifteen independent cohorts involving 129794 patients were included in the analysis. The pooled incidence rate of subsequent stroke per 100 person-years was 6.4 events in the first year and 2.0 events in the second through tenth years, with cumulative incidences of 14% at 5 years and 21% at 10 years. Based on 10 studies with information available on fatal stroke, the pooled case fatality rate of subsequent stroke was 9.5% (95% CI, 5.9 – 13.8). Conclusions: One in five patients is expected to experience a subsequent stroke within 10 years after a TIA or minor stroke, with every tenth patient expected to die from their subsequent stroke.
Police employees may experience high levels of stress due to the challenging nature of their work which can then lead to sickness absence. To date, there has been limited research on sickness absence in the police. This exploratory analysis investigated sickness absence in UK police employees.
Methods
Secondary data analyses were conducted using data from the Airwave Health Monitoring Study (2006–2015). Past year sickness absence was self-reported and categorised as none, low (1–5 days), moderate (6–19 days) and long-term sickness absence (LTSA, 20 or more days). Descriptive statistics and multinomial logistic regressions were used to examine sickness absence and exploratory associations with sociodemographic factors, occupational stressors, health risk behaviours, and mental health outcomes, controlling for rank, gender and age.
Results
From a sample of 40,343 police staff and police officers, forty-six per cent had no sickness absence within the previous year, 33% had a low amount, 13% a moderate amount and 8% were on LTSA. The groups that were more likely to take sick leave were women, non-uniformed police staff, divorced or separated, smokers and those with three or more general practitioner consultations in the past year, poorer mental health, low job satisfaction and high job strain.
Conclusions
The study highlights the groups of police employees who may be more likely to take sick leave and is unique in its use of a large cohort of police employees. The findings emphasise the importance of considering possible modifiable factors that may contribute to sickness absence in UK police forces.
The purpose of this study was to compare single- and multi-frequency bioimpedance (BIA) devices against dual-energy X-ray absorptiometry (DXA) for appendicular lean mass (ALM) and muscle quality index (MQI) metrics in Hispanic adults. One hundred thirty-one Hispanic adults (18–55 years) participated in this study. ALM was measured with single-frequency bioimpedance analysis (SFBIA), multi-frequency bioimpedance analysis (MFBIA) and DXA. ALMTOTAL (left arm + right arm + left leg + right leg) and ALMARMS (left arm + right arm) were computed for all three devices. Handgrip strength (HGS) was measured using a dynamometer. The average HGS was used for all MQI models (highest left hand + highest right hand)/2. MQIARMS was defined as the ratio between HGS and ALMARMS. MQITOTAL was established as the ratio between HGS and ALMTOTAL. SFBIA and MFBIA had strong correlations with DXA for all ALM and MQI metrics (Lin’s concordance correlation coefficient values ranged from 0·86 (MQIMFBIA-ARMS) to 0·97 (Arms LMSFBIA); all P < 0·001). Equivalence testing varied between methods (e.g. SFBIA v. DXA) when examining the different metrics (i.e. ALMTOTAL, ALMARMS, MQITOTAL and MQIARMS). MQIARMS was the only metric that did not differ from the line of identity and had no proportional bias when comparing all the devices against each other. The current study findings demonstrate good overall agreement between SFBIA, MFBIA and DXA for ALMTOTAL and ALMARMS in a Hispanic population. However, SFBIA and MFBIA have better agreement with DXA when used to compute MQIARMS than MQITOTAL.
Faecal examinations for helminth eggs were performed on 1869 people from two riverside localities, Vientiane Municipality and Saravane Province, along the Mekong River, Laos. To obtain adult flukes, 42 people positive for small trematode eggs (Opisthorchis viverrini, heterophyid, or lecithodendriid eggs) were treated with a 20–30 mg kg−1 single dose of praziquantel and purged. Diarrhoeic stools were then collected from 36 people (18 in each area) and searched for helminth parasites using stereomicroscopes. Faecal examinations revealed positive rates for small trematode eggs of 53.3% and 70.8% (average 65.2%) in Vientiane and Saravane Province, respectively. Infections with O. viverrini and six species of intestinal flukes were found, namely, Haplorchistaichui, H. pumilio, H. yokogawai, Centrocestus caninus,Prosthodendrium molenkampi, and Phaneropsolus bonnei. The total number of flukes collected and the proportion of fluke species recovered were markedly different in the two localities; in Vientiane, 1041 O. viverrini (57.8 per person) and 615 others (34.2 per person), whereas in Saravane, 395 O. viverrini (21.9 per person) and 155207 others (8622.6 per person). Five people from Saravane harboured no O. viverrini but numerous heterophyid and/or lecithodendriid flukes. The results indicate that O. viverrini and several species of heterophyid and lecithodendriid flukes are endemic in these two riverside localities, and suggest that the intensity of infection and the relative proportion of fluke species vary by locality along the Mekong River basin.
OBJECTIVES/GOALS: Metastasis to regional areas decreases invasive breast cancer (IBC) survival rate by 13%. Despite the clinical importance of lymph node involvement, the role of extracellular matrix (ECM) remodeling in metastases is unknown. We hypothesize that the spatial dysregulation of the collagen proteome facilitates pro-tumorigenic immune infiltration. METHODS/STUDY POPULATION: Lymph node metastases were compared to patient-matched primary tumor and normal lymph nodes using tissue microarrays (TMA) from 31 generational South Carolina women with IBC (black women, BW n=10, white women, WW n=21) and lumpectomies from 5 triple-negative breast cancer (TNBC) patients (BW n=3; WW n=2) by ECM-targeted mass spectrometry imaging. RESULTS/ANTICIPATED RESULTS: Between metastatic and normal lymph nodes, 10% of peptides, primarily from fibrillar collagens, were significantly different by area under the receiver operating curve (AUROC>70%; p-value< 0.01) within the TMAs. In a subsequent preliminary study of the TNBC metastatic niche, a segmentation analysis of 152 putatively identified peptides and 117,909 pixels revealed 10 uniquely localized proteomic groups. 12 peptides were found to have significantly decreased relative peak intensities in lymph node metastases compared to the primary tumor and normal lymph nodes by a one-way ANOVA test (p< 0.05). 7 peptides could discriminate between metastatic and normal lymph nodes, while 22 peptides could discriminate between metastatic lymph nodes and the primary tumor (AUROC>0.70; p-value < 0.05). DISCUSSION/SIGNIFICANCE: Our preliminary interrogation highlights emerging differences between lymph node metastases, the primary tumor, and normal lymph nodes. Future work is needed to connect these discrete ECM proteomes to immune infiltration alterations, which could contribute to disparate patient outcomes.
OBJECTIVES/GOALS: The correction of spinopelvic parameters is associated with better outcomes in patients with adult spinal deformity (ASD). This study presents a novel artificial intelligence (AI) tool that automatically predicts spinopelvic parameters from spine x-rays with high accuracy and without need for any manual entry. METHODS/STUDY POPULATION: The AI model was trained/validated on 761 sagittal whole-spine x-rays to predict the following parameters: Sagittal Vertical Axis (SVA), Pelvic Tilt (PT), Pelvic Incidence (PI), Sacral Slope (SS), Lumbar Lordosis (LL), T1-Pelvic Angle (T1PA), and L1-Pelvic Angle (L1PA). A separate test set of 40 x-rays was labeled by 4 reviewers including fellowship-trained spine surgeons and a neuroradiologist. Median errors relative to the most senior reviewer were calculated to determine model accuracy on test and cropped-test (i.e. lumbosacral) images. Intraclass correlation coefficients (ICC) were used to assess inter-rater reliability RESULTS/ANTICIPATED RESULTS: The AI model exhibited the following median (IQR) parameter errors: SVA[2.1mm (8.5mm), p=0.97], PT [1.5° (1.4°), p=0.52], PI[2.3° (2.4°), p=0.27], SS[1.7° (2.2°), p=0.64], LL [2.6° (4.0°), p=0.89], T1PA [1.3° (1.1°), p=0.41], and L1PA [1.3° (1.2°), p=0.51]. The parameter errors on cropped lumbosacral images were: LL[2.9° (2.6°), p=0.80] and SS[1.9° (2.2°), p=0.78]. The AI model exhibited excellent reliability at all parameters in both whole-spine (ICC: 0.92-1.0) and lumbosacral x-rays: (ICC: 0.92-0.93). DISCUSSION/SIGNIFICANCE: Our AI model accurately predicts spinopelvic parameters with excellent reliability comparable to fellowship-trained spine surgeons and neuroradiologists. Utilization of predictive AI tools in spine-imaging can substantially aid in patient selection and surgical planning.
High-quality evidence is lacking for the impact on healthcare utilisation of short-stay alternatives to psychiatric inpatient services for people experiencing acute and/or complex mental health crises (known in England as psychiatric decision units [PDUs]). We assessed the extent to which changes in psychiatric hospital and emergency department (ED) activity were explained by implementation of PDUs in England using a quasi-experimental approach.
Methods
We conducted an interrupted time series (ITS) analysis of weekly aggregated data pre- and post-PDU implementation in one rural and two urban sites using segmented regression, adjusting for temporal and seasonal trends. Primary outcomes were changes in the number of voluntary inpatient admissions to (acute) adult psychiatric wards and number of ED adult mental health-related attendances in the 24 months post-PDU implementation compared to that in the 24 months pre-PDU implementation.
Results
The two PDUs (one urban and one rural) with longer (average) stays and high staff-to-patient ratios observed post-PDU decreases in the pattern of weekly voluntary psychiatric admissions relative to pre-PDU trend (Rural: −0.45%/week, 95% confidence interval [CI] = −0.78%, −0.12%; Urban: −0.49%/week, 95% CI = −0.73%, −0.25%); PDU implementation in each was associated with an estimated 35–38% reduction in total voluntary admissions in the post-PDU period. The (urban) PDU with the highest throughput, lowest staff-to-patient ratio and shortest average stay observed a 20% (−20.4%, CI = −29.7%, −10.0%) level reduction in mental health-related ED attendances post-PDU, although there was little impact on long-term trend. Pooled analyses across sites indicated a significant reduction in the number of voluntary admissions following PDU implementation (−16.6%, 95% CI = −23.9%, −8.5%) but no significant (long-term) trend change (−0.20%/week, 95% CI = −0.74%, 0.34%) and no short- (−2.8%, 95% CI = −19.3%, 17.0%) or long-term (0.08%/week, 95% CI = −0.13, 0.28%) effects on mental health-related ED attendances. Findings were largely unchanged in secondary (ITS) analyses that considered the introduction of other service initiatives in the study period.
Conclusions
The introduction of PDUs was associated with an immediate reduction of voluntary psychiatric inpatient admissions. The extent to which PDUs change long-term trends of voluntary psychiatric admissions or impact on psychiatric presentations at ED may be linked to their configuration. PDUs with a large capacity, short length of stay and low staff-to-patient ratio can positively impact ED mental health presentations, while PDUs with longer length of stay and higher staff-to-patient ratios have potential to reduce voluntary psychiatric admissions over an extended period. Taken as a whole, our analyses suggest that when establishing a PDU, consideration of the primary crisis-care need that underlies the creation of the unit is key.