Population Analysis Research Articles

Spatial Accessibility and Social Inequality to Health Care in Urban System: A Case Study in Tianjin, China

In recent years, the issue of medical security has received more and more attention from the government, and ensuring people's health is an important task that cannot be ignored. In some areas, medical resources are relatively scarce, and they cannot provide a good guarantee for people's daily medical treatment. In the current paper, the spatial accessibility of medical resources and facilities in Tianjin was analyzed using the Gini coefficients, network technique, and Two-step floating catchment area. The results show that based on 2SFCA analysis, the medical facilities in Tianjin are not evenly distributed. Most of them are concentrated in the south and central parts of the city, while some areas have fewer medical resources. Most of the medical facilities are concentrated in the city center. Based on the network and population analysis, Citizens living in areas with almost complete coverage of medical resources can receive better health care. Some citizens living in an area that can be partially covered by medical resources can accept medical insurance. Living in areas where medical resources are extremely scarce, almost the majority of citizens do not have access to proper health insurance. Based on the Gini coefficients, the results show that the medical resources within 30 km and 20 km are relatively unequal, but the medical resources within 30 km are more equal in the two cases.

Identification of the optimal candidates to benefit from surgery and chemotherapy among elderly female breast cancer patients with bone metastases

Breast cancer is currently the most common malignant tumor affecting women’s health worldwide. The rise in breast cancer metastases among patients is attributed to the inherent variability in metastatic behavior. In breast cancer, bones are the primary location for distant metastases, significantly impacting the survival rates of elderly (≥ 65) patients. The use of surgery and chemotherapy in this population is controversial. This study seeks to create a tool for forecasting overall survival (OS) in older breast cancer patients with bone metastases and to determine the optimal candidates for surgery and chemotherapy. Elderly female breast cancer patients with bone metastases from the Surveillance, Epidemiology, and End Results (SEER) database were included in this study and categorized into a training cohort and a validation cohort using R software. To identify independent predictors of OS in this population, both univariate and multivariate Cox regression analyses were conducted. Subsequently, a prognostic nomogram was created to estimate OS at 12, 24, and 36 months. The nomogram’s accuracy and practical value were assessed using a calibration curve, area under the curve (AUC), and decision curve analysis (DCA). At the same time, a mortality risk classification system based on the nomogram was created to divide the population into high and low mortality risk categories, and subgroups were analyzed to determine the optimal candidates for surgery and chemotherapy. This study encompassed 2257 elderly female breast cancer patients with bone metastases, divided into 1581 participants for the training cohort and 676 for the validation cohort. Both univariate and multivariate Cox regression analyses validated those variables such as age, race, marital status, histological type, tumor grade, ER status, PR status, breast subtype, distant metastases (lung, liver, and brain), and treatment methods (surgery and chemotherapy) independently predicted OS in elderly female breast cancer patients with bone metastases (p < 0.05). Utilizing these independent predictors, a prognostic nomogram was developed to estimate OS at 12, 24, and 36 months. The calibration curves indicated that the nomogram’s predictions closely matched the observed outcomes. The nomogram’s AUC for forecasting OS at 12, 24, and 36 months was 0.753, 0.748, and 0.745 in the training cohort, and 0.744, 0.723, and 0.723 in the validation cohort. Additionally, the nomogram’s AUC surpassed that of any individual independent predictor. DCA showed that the nomogram could achieve more net clinical benefit over a broader range of threshold probabilities. The nomogram-based risk classification system effectively sorted patients into two categories: low risk (≤ 820) and high risk (> 820). Subgroup analysis indicated that individuals classified as low-risk experienced the greatest advantage from surgery and chemotherapy (p < 0.05), whereas the high-risk group did not exhibit a statistically significant difference (p > 0.05). Drawing from the clinicopathological characteristics of elderly female breast cancer patients with bone metastases, this study developed a novel prognostic nomogram to forecast OS at 12, 24, and 36 months, enabling precise survival predictions. In addition, this study also constructed a mortality risk classification system, which can effectively help clinicians screen out the optimal candidates to benefit from surgery and chemotherapy and rationalize the allocation of medical resources.

Model-Informed Selection of the Recommended Phase 2 Dosage for Anti-TIGIT Immunotherapy Leveraging co-Expressed PD-1 Inhibitor Target Engagement.

Refining dose projections requires a deep understanding of drug-target relationships at the site of action, which is often challenging to achieve. Here we present a case study of how one can refine dose projections for a TIGIT-targeted immunotherapy by leveraging information from the well-studied PD-1 pathway since the co-expression of PD-1 and TIGIT on immune cells provides a unique opportunity to extrapolate data from one target to inform the dosing strategy for the other. We develop a fit-for-purpose mathematical model that captures the experimentally observed relationship between the concentration of a mouse PD-1 antagonist in the plasma and PD-1 target engagement within the tumor microenvironment (TME). We then assess the applicability of this PD-1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti-TIGIT antibody, across various doses. This analysis aims to refine our understanding of the dose-response relationship for targeting TIGIT, a critical step in optimizing therapeutic efficacy, without conducting additional experiments. The approach is then extended to project efficacious doses for M6223, another anti-TIGIT antibody, using the established PD-1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug-target relationship at the site of action by leveraging established drug-target relationships. Through extrapolating information from a well-characterized pathway, we offer a method to inform dose optimization strategies with limited data using model-informed drug development.

Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology

Infection with enterohemorrhagic E. coli (EHEC) causes severe changes in the brain leading to angiopathy, encephalopathy and microglial activation. In this study, we investigated the role of tumour necrosis factor alpha (TNF-α) for microglial activation and brain pathology using a preclinical mouse model of EHEC infection. LC–MS/MS proteomics of mice injected with a combination of Shiga toxin (Stx) and lipopolysaccharide (LPS) revealed extensive alterations of the brain proteome, in particular enrichment of pathways involved in complement activation and coagulation cascades. Inhibition of TNF-α by the drug Etanercept strongly mitigated these changes, particularly within the complement pathway, suggesting TNF-α-dependent vasodilation and endothelial injury. Analysis of microglial populations using a novel human-in-the-loop deep learning algorithm for the segmentation of microscopic imaging data indicated specific morphological changes, which were reduced to healthy condition after inhibition of TNF-α. Moreover, the Stx/LPS-mediated angiopathy was significantly attenuated by inhibition of TNF-α. Overall, our findings elucidate the critical role of TNF-α in EHEC-induced brain pathology and highlight a potential therapeutic target for mitigating neuroinflammation, microglial activation and injury associated with EHEC infection.Graphical

The Current State of Breast Cancer Genetics in Populations of African Ancestry

Breast cancer (BC) constitutes a significant global health burden, particularly among women, with disparities observed across populations. Notably, women of African ancestry often experience BC at earlier ages and in more aggressive forms, with a higher prevalence of metastasis. Genetic studies, including those focused on BRCA1 and BRCA2 genes, have revealed population-specific variations in BC susceptibility. Despite efforts to investigate BC genetics in African and African-descendant populations, research remains limited compared to studies conducted in populations of European descent. Socioeconomic factors further compound the challenges faced by marginalized populations, influencing disease outcomes and treatment efficacy. This review explores the BC literature in African and African-descendant populations, highlighting population-specific genetic variants associated with the disease’s subtypes, treatment response, and disease evolution. Limited sample sizes and lack of data on genetic ancestry hinder the development of precise risk stratification and treatment strategies. Efforts to expand research, improve data collection, and enhance genetic analyses in diverse populations are crucial steps toward addressing racial disparities and advancing BC care on a global scale.

Burden of HPV-induced diseases and cost effectiveness of catch-up vaccination in Czech Republic: a model-based study

ObjectivesHuman papillomavirus (HPV) infections are highly prevalent sexually transmitted infections, notably associated with various cancers. This study analyses the health and economic impacts of HPV-associated diseases in the Czech Republic and evaluates the cost-effectiveness of a catch-up vaccination program.MethodsUtilizing a Markov multistate model, the study assesses the lifetime impacts and costs related to HPV infections. Cohorts of ages 15–21 were simulated to assess the impact of catch-up vaccination outside the 11-year-old age group.ResultsThe total quality-adjusted life years (QALYs) for the female and male cohorts (together 119,362 individuals) were higher in the vaccination scenario compared to the non-vaccination scenario. The increase in QALYs was 122,246 and 200,852 respectively, when considering the actual vaccination rates. Across both cohorts, 329 cancer-related deaths were prevented. In the probabilistic sensitivity analysis for the female population, vaccination was the dominant strategy in 99.3% of iterations. In the male population, vaccination was the dominant strategy in 80.3% of iterations. The implementation of catch-up vaccination for the 15–21 age group significantly increased QALY gains and reduced life-years-lost (LYLs). In the female cohort, all analysed rates of catch-up vaccination were the dominant strategy, while in the male cohort, the incremental cost-effectiveness ratios (ICERs) remained consistently below 42,000 CZK/QALY.ConclusionsThe catch-up vaccination program for 15-21-year-olds is cost-effective and can prevent a significant number of HPV-related cancers in both men and women.

Development and characterization of a double-fluorescent HIV-1 reporter cellular model to tackle the Rev-dependent export pathway.

The Rev-dependent nuclear export of unspliced and singly-spliced transcripts of human immunodeficiency virus type 1 (HIV-1) constitutes a critical yet poorly characterized post-transcriptional event essential for effective viral replication. In this study, we engineered a dual-fluorescent HIV-1-based cellular reporter system to elucidate the mechanisms underpinning Rev-dependent export. By generating multiple stably integrated inducible cellular clones, we ensured the expression of two distinct fluorescent proteins, mKO2, and ECFP, from unspliced (Rev dependent) and multiply spliced (Rev independent) HIV-1 transcripts, respectively. Utilizing flow cytometry, we performed quantitative analyses of dual-fluorescent cell populations. The developed tool enables precise assessment of the Rev-dependent export, and we validated it using known inhibitors of this pathway (leptomycin D), as well as targeted depletion of MATR3, an essential cofactor of Rev, and CRNKL1, a repressor of unspliced HIV-1 RNA export.IMPORTANCEThe developed dual-fluorescent reporter system represents a powerful and handy tool for the identification and characterization of novel molecular players involved in the Rev-dependent export pathway. This system not only holds promise for advancing our understanding of human immunodeficiency virus type 1 (HIV-1) biology but also serves as an invaluable platform for high-throughput drug screening aimed at targeting post-transcriptional HIV-1 RNA processes, particularly nuclear export. Consequently, this study offers significant implications for the development of novel therapeutic strategies to eradicate the virus.

Variation in Defensive Strategies of Brown Frogs against Conspecific and Heterospecific Alarm Cues

Abstract Chemical cues released upon injury play a crucial role in mediating antipredator responses in many aquatic species. Prey populations capable of exploiting information from different sources may enhance their fitness, although the factors determining this ability are not always clear. In this study, we investigated the antipredator responses to both conspecific and heterospecific injury cues (i.e., alarm cues) in three brown frog species: Rana dalmatina, Rana latastei, and Rana temporaria. We recorded two tadpole defensive behaviours: the proportion of time spent inactive and the distance covered. Responses to a native odonate predator were used as a positive control. Tadpoles of R. dalmatina showed a clear decrease in activity in response to both con- and heterospecific cues, similar to their reaction to predator cues. Tadpoles of R. latastei slightly decreased activity in response to alarm cues from both agile frog species but did not react to common frog cues. Finally, R. temporaria exhibited high sensitivity to conspecific cues and a weak response to heterospecific cues. The phylogenetic-relatedness hypothesis seems to explain the observations for both R. latastei and R. temporaria, while for R. dalmatina, the ecological coexistence hypothesis, given its overlapping distribution with the other two species, seems to better explain the data. However, since the invoked hypotheses are not mutually exclusive, further analysis of other populations of these species is necessary to confirm the generality of these findings and to better understand the role of environmental factors in shaping these antipredator responses.

Novel insights into sheep domestication in Southwest Asia based on genome-wide sequencing.

The origin of domestic sheep (Ovis aries) can be traced back to the Asian mouflon (Ovis gmelini), in the Near East around 10 000 years ago. Genetic divergence within mouflon populations can occur due to factors such as geographical isolation, social structures, and environmental pressures, leading to different affinities with domestic sheep. However, few studies have reported the extent to which mouflon sheep contribute to domestic sheep in different regions. Here, we implemented the demographic analyses of sheep populations across the globe based on the whole genome resequencing data of 410 samples, Y chromosome genetic variation of 417 rams, and 396 complete mitogenomes of O. aries. This revealed genetic differentiation within Iranian mouflons and a close genetic affinity between northern Iranian mouflons and worldwide domestic populations. The result illustrates that domestic sheep in our study may have derived from the same mouflon populations. Furthermore, analyses of paternal and maternal genetic diversity showed that five Y chromosome haplogroups and seven mitochondrial haplogroups were identified, of which the lineages mtF and mtG were newly found and defined. A phylogeographic interpretation of our data reveals a cline of north to south Iranian mouflons, which may be largely explained by increasing urial introgression.

Nanopore reads spanning the whole genome of arthropod-infecting large dsDNA viruses of the class Naldaviricetes enable assembly-free sequence analysis.

The nuclear arthropod-specific large DNA viruses comprise different phylogenetically related virus families (Baculoviridae, Nudiviridae, Hytrosaviridae and Nimaviridae) forming the class Naldaviricetes. One common characteristic of their large double-stranded circularly covalently closed DNA genomes is the size of up to hundreds of kilobase pairs, encoding up to hundreds of open reading frames. Until recently, analyzing such large viral dsDNA genomes was hampered by short read sequencing techniques, requiring bioinformatic assembly strategies to construct a consensus sequence as a descriptor of a population of haplotype sequences. The ideal aim for decoding large dsDNA genomes is an assembly-free method that allows the individual gnomes of a virus population to be sequenced in individual reads without fragmentation. Such full-length genome sequencing of single genome molecules is made possible by Nanopore sequencing, which is increasingly used to decode representatives of the Naldaviricetes. The present study discusses the impact of Nanopore sequencing on the characterization of viral NALDV populations. Full-length genome reads can be found in published sequence data from Bombyx mori nucleopolyhedrovirus (BmNPV; family Baculoviridae) and Oryctes rhinoceros nudivirus (OrNV; family Nudiviridae) isolates, providing insight into the future of deciphering populations of members of the order Lefavirales and class Naldaviricetes. Thirty years after the first sequencing of a baculovirus in 1994, a new era of sequencing of arthropod-infecting large dsDNA viruses has begun, which will allow assembly-free analysis of entire populations of large dsDNA viruses.

Improving population analysis using indirect count data: A case study of chimpanzees and elephants

AbstractEstimating spatiotemporal patterns of population density is a primary objective of wildlife monitoring programs. However, estimating density is challenging for species that are elusive and/or occur in habitats with limited visibility. In such situations, indirect measures (e.g., nests, dung) can serve as proxies for counts of individuals. Scientists have developed approaches to estimate population density using these “indirect count” data, although current methods do not adequately account for variation in sign production and spatial patterns of animal density. In this study, we describe a modified hierarchical distance sampling model that maximizes the information content of indirect count data using Bayesian inference. We apply our model to assess the status of chimpanzee and elephant populations using counts of nests and dung, respectively, which were collected along transects in 2007 and 2021 in western Uganda. Compared with conventional methods, our modeling framework produced more precise estimates of covariate effects on expected animal density by accounting for both long‐term and recent variations in animal abundance and enabled the estimation of the number of days that animal signs remained visible. We estimated a 0.98 probability that chimpanzee density in the region had declined by at least 10% and a 0.99 probability that elephant density had increased by 50% from 2007 to 2021. We recommend applying our modified hierarchical distance sampling model in the analysis of indirect count data to account for spatial variation in animal density, assess population change between survey periods, estimate the decay rate of animal signs, and obtain more precise density estimates than achievable with traditional methods.

A Population Analysis of 20 Exoplanets Observed from Optical to Near-infrared Wavelengths with the Hubble Space Telescope: Evidence for Widespread Stellar Contamination

We present a population study of 20 exoplanets, ranging from Neptune-like to inflated hot-Jupiter planets, observed during transit with the Space Telescope Imaging Spectrograph (STIS) and Wide Field Camera 3 (WFC3) instruments on board the Hubble Space Telescope (HST). To obtain spectral information from the near-ultraviolet to the near-infrared, we reanalyzed 16 WFC3 and over 50 STIS archival data sets with our dedicated HST pipeline. We also include 24 WFC3 data sets previously reduced with the same software. Across our target sample, we observe significant divergence among multiple observations conducted with the same STIS grating at various epochs, while we do not detect variations in the WFC3 data sets. These results are suggestive of stellar contamination, which we have investigated further using known Bayesian tools and other tailored metrics, facilitating a more objective assessment of stellar activity intensity within each system. Our findings reveal that stellar activity contaminates up to half of the studied exoplanet atmospheres, albeit at varying extents. Accounting for stellar activity can significantly alter planetary atmospheric parameters like molecular abundances (up to 6 orders of magnitude) and temperature (up to 145%), contrasting with the results of analyses that neglect activity. Our results emphasize the importance of considering the effects of stellar contamination in exoplanet transit studies; this issue is particularly true for data sets obtained with facilities that do not cover the optical and/or UV spectral range where the activity is expected to be more impactful but also more easily detectable. Our results also provide a catalog of potentially active stars for further investigation and monitoring.

Effects of the delay of surgery in localized rectal cancer.

63 Background: The treatment landscape for localized rectal cancer has evolved significantly in recent years, with long-course neoadjuvant chemoradiation (CRT) and total neoadjuvant therapy (TNT) emerging as the primary options. However, the optimal timing of surgery remains an important clinical question, particularly in resource-limited settings where surgical delays can occur. Data from previous studies have shown conflicting results. This retrospective study aimed to assess the impact of delaying surgery beyond the longer interval used in previous studies, focusing on its effects on Pathologic Complete Response (pCR), DFS, and OS. Methods: We conducted a retrospective cohort study using electronic medical records from three centers in Brazil between the years 2013-2024. The study included 236 patients with localized rectal cancer treated with neoadjuvant CRT and/or chemotherapy. Patients were divided into two pre-specified groups based on the interval between the end of neoadjuvant therapy and surgery: ≤11 weeks and &gt;11 weeks. The primary endpoint was DFS. Secondary endpoints were pCR rates, and OS. Descriptive statistics were used for population analysis, while the Kaplan-Meier method estimated DFS and OS, with comparisons made using the log-rank test. A Cox proportional-hazards model was used to estimate hazard ratios and 95% confidence intervals. Results: The median age of the study population was 62 years, with males comprising 56.4% of the sample. The majority of the sample consisted of stage III patients, making up 72.2%, followed by stage II patients at 25.8%, and stage I patients at 1.9%. Most patients (77.8%) had surgery more than 11 weeks after completing neoadjuvant therapy, with a median time to surgery of 16 weeks. The pCR rates did not significantly differ between the two groups (29% for ≤11 weeks vs. 21.5% for &gt;11 weeks; p = 0.271). After a median follow-up of 30 months, the median DFS was not reached, and there was no significant difference between the groups (HR: 0.86; 95% CI: 0.48-1.5; p = 0.63). Similarly, the median OS was not reached, and no difference was observed between the groups (HR: 0.85; 95% CI: 0.47-1.54; p = 0.88). Conclusions: Delaying surgery beyond 11 weeks did not result in greater tumor downstaging in patients with localized rectal cancer. Furthermore, DFS and OS were not significantly impacted by extended intervals between neoadjuvant therapy and surgery.

CO2-rich protoplanetary discs as a probe of dust radial drift and trapping

Context. Mid-infrared spectra indicate considerable chemical diversity in the inner regions of protoplanetary discs, with some being H2O-dominated and others CO2-dominated. Sublimating ices from radially drifting dust grains are often invoked to explain some of this diversity, particularly with regards to H2O-rich discs. Aims. We model the contribution made by radially drifting dust grains to the chemical diversity of the inner regions of protoplanetary discs. These grains transport ices – including those of H2O and CO2 – inwards to snow lines, thus redistributing the molecular content of the disc. As radial drift can be impeded by dust trapping in pressure maxima, we also explore the difference between smooth discs and those with dust traps due to gas gaps, quantifying the effects of gap location and formation time. Methods. We used a 1D protoplanetary disc evolution code to model the chemical evolution of the inner disc resulting from gas viscous evolution and dust radial drift. We post-processed these models to produce synthetic spectra, which we analyse with 0D LTE slab models to understand how this evolution may be expressed observationally. Results. Discs evolve through an initial H2O-rich phase as a result of sublimating ices, followed by a CO2 -rich phase as H2O vapour is advected onto the star and CO2 is advected into the inner disc from its snow line. The introduction of traps hastens the transition between the phases, temporarily raising the CO2/H2O ratio. However, whether or not this evolution can be traced in observations depends on the contribution of dust grains to the optical depth. If the dust grains become coupled to the gas after crossing the H2O snow line – for example if bare grains fragment more easily than icy grains – then the dust that delivers the H2O adds to the continuum optical depth and obscures the H2O, preventing any evolution in its visible column density. However, the CO2/H2O visible column density ratio is only weakly sensitive to assumptions about the dust continuum obscuration, making it a more suitable tracer of the impact of transport on chemistry than either individual column density. This can be investigated with spectra that show weak features that probe deep enough into the disc. The least effective gaps are those that open close to the star on timescales competitive with dust growth and drift as they block too much CO2; gaps opened later or further out lead to higher CO2/H2O. This leads to a potential correlation between CO2/H2O and gap location that occurs on million-year timescales for fiducial parameters. Conclusions. Radial drift, especially when combined with dust trapping, produces CO2 -rich discs on timescales longer than the viscous timescale at the H2O snow line (while creating H2O-rich discs at earlier times). Population analyses of the relationship between observed inner disc spectra and large-scale disc structure are needed to test the predicted role of traps.

A single-cell RNA sequencing dataset of peripheral blood cells in long COVID patients on herbal therapy

Following the coronavirus disease 2019 (COVID-19) pandemic, the rise of long COVID, characterized by persistent respiratory and cognitive dysfunctions, has become a significant health concern. This leads to an increased role of complementary and alternative medicine in addressing this condition. However, our comprehension of the effectiveness and safety of herbal medicines for long COVID remains limited. Here, we present a single-cell RNA sequencing (scRNA-seq) dataset of peripheral whole blood cells derived from participants in a clinical study involving three commercially available herbal medicines, targeting fatigue and brain fog in long COVID. The dataset comprises 181,205 quality control (QC)-passed cells, along with clinical metadata, enabling a comparative analysis of immune cell populations before and after treatment. To ensure the technical validity of our dataset, we implemented rigorous quality checks throughout stages of the study, including sample preparation, sequencing, and bioinformatic data analysis levels. This transcriptomic data may serve as a resource to deepen our insights into the role of herbal medicines in management of long COVID.

Clinical effectiveness and cost-effectiveness of first-line early combination of dipeptidyl peptidase 4 inhibitors and metformin in patients with type 2 diabetes in Taiwan: A modelling study.

Early dipeptidyl peptidase-4 inhibitors and metformin (DPP4i-Met) combination has been shown to extend the time to treatment failure and provide better glycaemic control for newly diagnosed type 2 diabetes (T2D) patients; however, the long-term clinical and economic outcomes of early DPP4i-Met combination remain unknown. We seek to assess the comparative long-term clinical and cost-effectiveness of DPP4i-Met versus Met for treatment-naïve T2D patients with inadequately controlled HbA1c (i.e., ≥8.5%). The IQVIA CORE Diabetes Model was used to simulate the quality-adjusted life years (QALYs) and healthcare costs over a lifetime from Taiwan's National Health Insurance Administration's perspective, with both QALYs and costs discounted at 3% annually. Model inputs were taken from the analyses of Taiwanese or Asian populations. Primary outcomes included the number needed to treat (NNT) to prevent one case of a clinical event and the incremental cost-effectiveness ratios (ICERs). Costs are presented in 2023 US dollars. Over 40 years of projection, Met-DPP4i-treated patients had fewer complications than those using Met alone (e.g., lowering the incidence of stroke by 2.21% [2.68, 1.74]). The NNT using DPP4i-Met versus Met alone to prevent one case of stroke, microalbuminuria, neuropathy and background retinopathy was 45, 135, 65 and 182, respectively. Such long-term benefits in reducing costly complications offset the higher treatment cost of DDP4i-Met versus Met ($5796 vs. $5484/person). As a result, using DPP4i-Met versus Met yielded 0.086 QALYs gained and savings of $489 for overall treatment-naïve T2D patients and 0.064 QALYs gained and savings of $714 for young-onset T2D patients. Early DPP4i-Met provides long-term clinical and economic benefits compared to Met alone for newly diagnosed T2D patients, including those with young-onset T2D.

Dissecting macrophage heterogeneity and kaempferol in lung adenocarcinoma: a single-cell transcriptomic approach and network pharmacology.

Lung adenocarcinoma (LUAD) is a leading form of non-small cell lung cancer characterized by a complex tumor microenvironment (TME) that influences disease progression and therapeutic response. Tumor-associated macrophages (TAMs) within the TME promote tumorigenesis and evasion of immune surveillance, though their heterogeneity poses challenges in understanding their roles and therapeutic targeting. Additionally, traditional Chinese medicine (TCM) offers potential anti-cancer agents that could modulate the immune landscape. We conducted single-cell RNA sequencing (scRNA-seq) on LUAD samples, performing an in-depth analysis of macrophage populations and their expression signatures. Network pharmacology was used to identify TCM components with potential TAM-modulatory effects, focusing on Astragalus membranaceus. Pseudotime trajectory analysis, immunofluorescence staining, and in vitro assays examined the functional roles of TAMs and the effects of selected compounds on macrophage polarization. Our scRNA-seq analysis identified notable heterogeneity among macrophages, revealing predominant M2-like phenotypes within TAMs. Network pharmacology highlighted active TCM ingredients, including quercetin, isorhamnetin, and kaempferol, targeting genes related to macrophage function. Survival analysis implicated AHSA1, CYP1B1, SPP1, and STAT1 as prognostically significant factors. Further experiments demonstrated kaempferol's efficacy in inhibiting M2 polarization, underlining a selective influence on TAM functionality. This study delineates the diverse macrophage landscape in LUAD and suggests a pivotal role for STAT1 in TAM-mediated immunosuppression. Kaempferol, identified from TCM, emerges as an influential agent capable of altering TAM polarization, potentially enhancing anti-tumoral immunity. These findings underscore the translational potential of integrating TCM-derived compounds into immunotherapeutic strategies for LUAD.

P-2304. Prevalence and clinical features of cefepime heteroresistance among bloodstream isolates of Pseudomonas aeruginosa in patients with hematologic malignancy

Abstract Background Cefepime (FEP) is a primary choice for the empiric treatment of febrile neutropenia in hematologic malignancy (HM) patients who are at high risk for Pseudomonas aeruginosa (PA) infection. However, heteroresistance (hR) of Gram-negative pathogens has been associated with treatment failure, and the prevalence and impact of FEP hR across PA isolates in HM patients is unknown. We assessed FEP hR prevalence and associated microbiologic and clinical factors across PA bloodstream infections (BSI) in our institution’s HM patients. Figure 1: Clinical and microbiologic progression of two patients who developed breakthrough bacteremia on FEP therapy as seen by (A) standard clinical antimicrobial susceptibility assessment and (B) population analysis profile. * indicates hR per PAP-AUC. Methods We retrospectively analyzed clinical data and isolates from 23 HM patients diagnosed with FEP susceptible PA BSIs at our institution from 2011-2023. Broth microdilution (BMD) minimum inhibitory concentration (MIC) and population analysis profile-area under the curve (PAP-AUC) were performed on index isolates and any subsequent BSI isolates while on FEP treatment. hR was defined as &amp;lt; 6log drop in growth at FEP PA MIC breakpoint (16 µg/mL) or PAP-AUC &amp;gt; 79, the 99% confidence interval predicted cut-off for PA14. Correlations between clinical data and susceptibility phenotype were assessed by Fischer-exact analyses and t-tests. Table 1: Clinical and microbiologic characteristics of FEP hR and non-hR P. aeruginosa bloodstream isolates in HM patients Results Twenty-three index isolates had confirmed susceptible MICs ≤ 8 µg/mL (Table 1) per BMD. Ten of 23 (43%) isolates met criteria for hR. FEP MICs for hR isolates were significantly higher than susceptible isolates (P=0.0008, Table 1). There was no difference between prior FEP exposures among hR and non-hR isolates, but prior piperacillin-tazobactam (PTZ) exposure correlated with FEP hR (Table 1, P=0.04). Despite equal morbidity and severity presentation amongst cohorts, there was a trend towards increased 30-day mortality amongst patients with FEP hR PA BSI (P=0.06) treated with FEP. Two patients with FEP hR BSIs developed breakthrough bacteremia on FEP with FEP-R isolates (Figure 1); both died in the setting of recurrent PA BSIs. Conclusion FEP hR is prevalent in HM patients with PA BSIs, particularly isolates with MICs ≥ 4µg/mL. Our study showed numerically higher mortality in HM patients with BSIs due to FEP hR isolates treated with FEP, and prior PTZ exposure may increase risk of BSI with an FEP hR isolate. Further studies are needed to determine prevalence and clinical impact of FEP hR in this vulnerable population. Disclosures William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties James S. Lewis, PharmD, FIDSA, Entasis: Advisor/Consultant|La Jolla pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant

The genetics of neurodegenerative diseases is the genetics of age-related damage clearance failure.

In this perspective we draw together the data from the genome wide association studies for Alzheimer's disease, Parkinson's disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer's disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relate to failures to remove age related damage. We discuss these issues in the context of copathologies in elderly individuals and the prediction of disease through polygenic risk score analysis at different ages. Finally, we discuss what analytic approaches are needed now that we have adequately sized case control analyses in white populations.

313. Genomic Features Associated with Non-susceptibility to Cefiderocol in Pseudomonas aeruginosa and Cross-resistance to Novel β-lactam/β-lactamase Inhibitors in the Prospective Observational Pseudomonas (POP) study

Abstract Background Cefiderocol (FDC) is a last-line agent used to treat carbapenem-resistant P. aeruginosa (CR-PA). We evaluated the prevalence of FDC heteroresistance (hR) and non-susceptibility (NS) in the POP cohort and associations with genes previously related to FDC resistance.Figure 1.Proportion of isolates harboring genomic feature by geographic region (US vs non-US). Methods 972 genomes from the multicenter, global POP study were screened for mutations in genes implicated in decreased FDC susceptibility: ampC, pirR, pirS, pirA, piuA/D, ftsI, cpxS and exogenous β-lactamases. A representative population was selected to encompass all variants as well as controls obtained by phylogenetically mapping each mutant isolate with a closest non-mutant isolate (n=187). All strains were assessed by broth microdilution (BMD) and population analysis profile (PAP). FDC NS was defined as minimum inhibitory concentration (MIC) ≥ 8 μg/m. hR was determined by PAP area under the curve &amp;gt; 80, per the 99% confidence interval for PAO1. Chi-squared test was used to assess correlation of ceftolozane-tazobactam (C/T), ceftazidime-avibactam (CZA), and imipenem-relebactam (IMR) categorization and FDC hR/NS as well as gene correlations with FDC hR/NS and geographic region of the isolate. Association between FDC phenotype and MIC category of novel β-lactam/β-lactamase inhibitor combinations. Results Over 20% of isolates displayed a NS or hR FDC phenotype (n=39: 28 hR, 11 MIC ≥ 8 μg/mL), equally distributed among US and non-US isolates (Fig 1, P =0.36). Isolates with increased C/T, CZA, and IMR MICs were more likely to be FDC NS or hR (Tbl 1). IMR susceptibility was low across FDC NS, hR and susceptible cohorts. The combination of mutations in both ampC and the PirRS system demonstrated higher risk for FDC NS or hR (Tbl 2, P = 0.0003), but isolated mutations in either ampC or PirRS did not increase risk for FDC NS or hR. VEB and NDM β-lactamases were present in non-US isolates and their presence correlated with FDC NS or hR (Tbl 2, P = 0.0003, 0.0017). Mutations in the PirRS system showed a geographic predisposition in US isolates (Fig 1, P= 0.0047), while exogenous β-lactamases were associated with international isolates (P &amp;lt; 0.0001). Genotypic determinants associated with FDC susceptibility phenotype. Conclusion NS and hR to FDC is prevalent globally among CR-PA and is associated with reduced C/T, CZA, and IMR susceptibility. NS and hR isolates were associated with mutations in ampC, pirRS, and the exogenous β-lactamases VEB, NDM. Further studies are needed to define clinical significance of FDC hR. Disclosures Cesar A. Arias, MD, MSc, PhD, UpToDate, Inc.: Royalties Vincent Tam, Pharm. D., AbbVie Inc: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties