Objectives/Goals: We aimed to discover treatment candidates for uterine fibroids, a common benign tumor with adverse impacts on quality of life. Repurposing already approved medications for fibroids can expedite treatment option expansion. Using genetic proxies, we identified novel fibroid drug candidates and estimated their effect on risk of fibroid diagnosis. Methods/Study Population: We performed a genetically predicted gene expression (GPGE) analysis using S-PrediXcan and GTEx tissue models with multi-ancestry genome-wide association study (GWAS) summary statistics of fibroids (cases  =  74,294, controls  =  465). There were 81 genes significantly associated with fibroid risk. Querying drug–gene interaction databases identified 56 approved medications that target these genes, including two antihypertensives, hydralazine, and spironolactone. Using independent multi-ancestry GWAS summary statistics (N  =  635,969) for systolic (SBP) and diastolic blood pressure (DBP), we conducted GPGE analyses. Blood pressure (exposure) and fibroids (outcome) GPGE summary statistics in the same tissues were used for two-sample Mendelian randomization (MR) analyses to proxy medication effects. Results/Anticipated Results: GPGE analyses identified hydralazine/tumor protein P53 (TP53) activity and spironolactone/thyroid hormone receptor beta (THRB) activity as drug-gene candidate pairs. Both drugs increase gene activity of their paired gene. Increased TP53 expression was associated with SBP in four tissues (exposure). The MR results indicated hydralazine use, proxied by increased TP53 expression, may reduce fibroid risk by 42% per standard deviation of gene expression (odds ratio [OR]  =  0.58, p  =  1.43E-12). Increased THRB expression was associated with DBP in eight tissues and were included in the MR (exposure). The MR results suggest spironolactone use, proxied by increased THRB expression, may reduce fibroid risk by 23% per standard deviation of gene expression (OR  =  0.77, p  = 5.94E-6). Discussion/Significance of Impact: We provide biologically plausible evidence for repurposing hydralazine and spironolactone for reducing risk of fibroid diagnosis. Repurposing these hypertension medications could provide novel preventative treatments for fibroids, particularly for individuals disproportionately affected by both conditions.

We investigate the effect of three-dimensionality on the synchronisation characteristics of the wake behind an oscillating circular cylinder at ${\textit {Re}} = 300$. Cylinder oscillations in rotation, transverse translation and streamwise translation are considered. We utilise phase-reduction analysis, which quantifies the phase-sensitivity function of periodic flows, to examine the synchronisation properties. Here, we present an ensemble-based framework for phase-reduction analysis to handle three-dimensional wakes that are not perfectly time-periodic. Based on the phase-sensitivity functions, synchronisability to three types of cylinder oscillations is evaluated. In spite of similar trends, we find that phase-sensitivity functions involving three-dimensional wakes are lower in magnitude compared with those of two-dimensional wakes, which leads to narrower conditions for synchronisation to weak cylinder oscillations. We unveil that the difference between the phase-sensitivity functions of two- and three-dimensional flows is strongly correlated to the amplitude variation of the three-dimensional flow by the cylinder motions. This finding reveals that the cylinder motion modifies the three-dimensionality of the wake as well as the phase of vortex shedding, which leads to reduced phase modulation. The synchronisation conditions of three-dimensional wakes, predicted by phase-reduction analysis, agree with the identification by parametric studies using direct numerical simulations for forced oscillations with small amplitudes. This study presents the potential capability of phase-reduction to study synchronisation characteristics of complex flows.

Tuberculosis (TB) is one of the deadliest infectious diseases globally, ranking as 13th leading cause of mortality and morbidity. According to the Global Tuberculosis Report 2022, TB claimed the lives of 1.6 million people worldwide in 2021. Among the casualties, 1 870 000 individuals with HIV co-infections contributed to 6.7% of the total fatalities, accounting TB as the second most lethal infectious disease following COVID-19. In the quest to identify biomarkers for disease progression and anti-TB therapy, microRNAs (miRNAs) have gained attention due to their precise regulatory role in gene expression in disease stages and their ability to distinguish latent and active TB, enabling the development of early TB prognostic signatures. miRNAs are stable in biological fluids and therefore will be useful for non-invasive and broad sample collection. However, their inherent lack of specificity and experimental variations may lead to false-positive outcomes. These limitations can be overcome by integrating standard protocols with machine learning, presenting a novel tool for TB diagnostics and therapeutics. This review summarizes, discusses and highlights the potential of miRNAs as a biomarker, particularly their differential expression at disease stages. The review assesses the advantages and obstacles associated with miRNA-based diagnostic biomarkers in pulmonary TB and facilitates rapid, point-of-care testing.

Background: Multiplex molecular tests for infectious diseases can provide highly sensitive results rapidly; however, these tests may more readily detect asymptomatic colonization. There are reports of non-FDA approved laboratory-developed multiplex tests for the diagnosis of urinary tract infections (UTI). Differentiating UTI from asymptomatic bacteriuria is challenging, especially in older adults. The increased sensitivity of multiplex tests may exacerbate this challenge. We sought to describe the use of multiplex testing for UTIs in Medicare claims. Methods: Multiplex testing was identified using carrier claims submitted by non-institutional providers using the Chronic Conditions Warehouse for 2016 – 2022. Because there are no CPT-4 codes specifying UTI multiplex testing, we included claims as described in Figure 1 and categorized claims based on the primary ICD-10-CM diagnosis. The payment amounts for line items related to testing for infectious agents were summed. Laboratories were counted using CLIA numbers listed on corresponding claims. Beneficiaries residing in a nursing home at the time of their claim were identified using stay information derived from the Minimum Dataset 3.0. For comparison, similar characteristics among carrier claims with a CPT-4 code indicating urine culture were also described. Results: Claims for unspecified multiplex molecular tests overall have increased, driven by increases in claims with a primary UTI diagnosis (from 8,521 in 2016 to 386,943 in 2022), while urine cultures have not (Figure 1). In 2022, 65% of all unspecified multiplex tests were linked to a diagnosis of UTI; UTI multiplex claims were associated with 647 laboratories. For UTI claims, the median cost per claim for line items related to multiplex testing was $589 compared to $13 for urine culture-related line items. Overall, 8% of UTI multiplex claims were for beneficiaries residing in a nursing home. Conclusions: Claims for non-FDA approved unspecified multiplex tests associated with a primary diagnosis of UTI have increased >45-times between 2016-2021 and have >45-times higher median costs than urine cultures. The use of this testing in the Medicare population, including nursing home residents, is of potential concern given that inappropriate treatment of asymptomatic bacteriuria has been described to be common in older adults. Research is needed to outline use cases where UTI multiplex testing may be beneficial. Appropriate use of diagnostic testing is important to minimize diagnostic errors and avoid unnecessary antibiotic use.

We analyzed invasive group A streptococcal puerperal sepsis cases in a large health zone in Alberta, Canada between 2013 and 2022. Of the 21 cases, 85.7% were adjudicated as hospital/delivery-acquired, with 2 clusters having identical isolates found through whole genome sequencing. We implemented policy interventions across Alberta aimed at preventing future infections.

Two independent temporal-spatial clusters of hospital-onset Rhizopus infections were evaluated using whole-genome sequencing (WGS). Phylogenetic analysis confirmed that isolates within each cluster were unrelated despite epidemiological suspicion of outbreaks. The ITS1 region alone was insufficient for accurate analysis. WGS has utility for rapid rule-out of suspected nosocomial Rhizopus outbreaks.

The Ramsey number $R(F,H)$ is the minimum number N such that any N-vertex graph either contains a copy of F or its complement contains H. Burr in 1981 proved a pleasingly general result that, for any graph H, provided n is sufficiently large, a natural lower bound construction gives the correct Ramsey number involving cycles: $R(C_n,H)=(n-1)(\chi (H)-1)+\sigma (H)$ , where $\sigma (H)$ is the minimum possible size of a colour class in a $\chi (H)$ -colouring of H. Allen, Brightwell and Skokan conjectured that the same should be true already when $n\geq \lvert H\rvert \chi (H)$ .

We improve this 40-year-old result of Burr by giving quantitative bounds of the form $n\geq C\lvert H\rvert \log ^4\chi (H)$ , which is optimal up to the logarithmic factor. In particular, this proves a strengthening of the Allen–Brightwell–Skokan conjecture for all graphs H with large chromatic number.

In the context of mortality forecasting, “rotation” refers to the phenomenon that mortality decline accelerates at older ages but decelerates at younger ages. Since rotation is typically subtle, it is difficult to be confirmed and modeled in a statistical, data-driven manner. In this paper, we attempt to overcome this challenge by proposing an alternative modeling approach. The approach encompasses a new model structure, which includes a component that is devoted to measuring rotation. It also features a modeling technique known as ANCOVA, which allows us to statistically detect rotation and extrapolate the phenomenon into the future. Our proposed approach yields plausible mortality forecasts that are similar to those produced by Li et al. [Extending the Lee-Carter method to model the rotation of age patterns of mortality decline for long-term projections. Demography 50 (6), 2037–205, and may be considered more advantageous than the approach of Li et al. in the sense that it is able to generate not only static but also stochastic forecasts.

This article examines the phenomenal growth of Korean cultural industries and their export to East Asia and other parts of the world. In the early years of industrialisation, culture was used by the authoritarian regime as a form of ideological support. Strict controls were exercised over cultural production and presentation. Controls were later relaxed as the regime used entertainment and sport as popular distractions. However, the increase in television ownership, the growth of domestic electronics and home appliance industries, and rising incomes (especially among the middle class) provided the material base for the growth of cultural industries following democratisation in the 1990s. Cultural industries became key drivers of economic growth, innovation and employment, and were strongly promoted and supported by government in the style of the developmental state. The result was burgeoning production and international trade across a wide spectrum of cultural industries – film, television drama, animation, video games and music. As a reflection of the increasing integration of Korea into world markets, the government also had to ensure compliance with international trade regulations and clamp down on piracy. Today, the Korean Wave of popular culture has reached consumers in all parts of the world and makes a significant contribution to Korean gross domestic product and exports.

We describe a large outbreak of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) involving an acute-care hospital emergency department during December 2020 and January 2021, in which 27 healthcare personnel worked while infectious, resulting in multiple opportunities for SARS-CoV-2 transmission to patients and other healthcare personnel. We provide recommendations for improving infection prevention and control.

People with late-stage Alzheimer’s disease and related dementias (ADRD) who are assumed to have lost coherent cognitive capacity may exhibit unexpected episodes of spontaneous, meaningful, and relevant communication or behavior. Most reports of paradoxical lucidity or “episodes of lucidity” (EL) are anecdotal or case studies. Given the transient nature and lack of scientific explanation of the phenomenon, EL is under-investigated and poorly understood.

To develop an operational definition of and typologies for EL, we conducted a pilot study of former and current family caregivers from UsAgainstAlzheimer’s A-LIST® (N = 480). Over sixty percent of caregivers (n = 294, 61%) reported witnessing at least one EL with their care recipient over the course of dementia. Most episodes happened in late stages of dementia (71%). Only 10% happened within 7 days before death. The majority of episodes (71%) lasted <30 minutes. About half the episodes were characterized by uncharacteristic speech and communication. Caregivers perceived these experiences positively (M = 4.1; range = 1–5), but also expressed desire to know why/when EL occurs and how to respond to it.

We plan to use these data to refine definitions and typologies to incorporate into a prospective, demographically diverse survey to family caregivers to assess predictors of EL and linking EL to caregiver well-being and bereavement response. Precise and robust operationalizations of EL will allow future research to assess if EL has different effects on ADRD prognosis or alters how family members understand, manage and adapt to a PLWD’s dementia progression.

In the auto insurance industry, a Bonus-Malus System (BMS) is commonly used as a posteriori risk classification mechanism to set the premium for the next contract period based on a policyholder's claim history. Even though the recent literature reports evidence of a significant dependence between frequency and severity, the current BMS practice is to use a frequency-based transition rule while ignoring severity information. Although Oh et al. [(2020). Bonus-Malus premiums under the dependent frequency-severity modeling. Scandinavian Actuarial Journal 2020(3): 172–195] claimed that the frequency-driven BMS transition rule can accommodate the dependence between frequency and severity, their proposal is only a partial solution, as the transition rule still completely ignores the claim severity and is unable to penalize large claims. In this study, we propose to use the BMS with a transition rule based on both frequency and size of claim, based on the bivariate random effect model, which conveniently allows dependence between frequency and severity. We analytically derive the optimal relativities under the proposed BMS framework and show that the proposed BMS outperforms the existing frequency-driven BMS. Later, numerical experiments are also provided using both hypothetical and actual datasets in order to assess the effect of various dependencies on the BMS risk classification and confirm our theoretical findings.