Evolution and Ecology of Parasite Avoidance.

Parasite avoidance is a host defense that reduces the contact rate with parasites. We investigate avoidance as a primary driver of variation among individuals in the risk of parasitism and the evolution of host-parasite interactions. To bridge mechanistic and taxonomic divides, we define and categorize avoidance by its function and position in the sequence of host defenses. We also examine the role of avoidance in limiting epidemics and evaluate evidence for the processes that drive its evolution. Throughout, we highlight important directions to advance our conceptual and theoretical understanding of the role of avoidance in host-parasite interactions. We emphasize the need to test assumptions and quantify the effect of avoidance independent of other defenses. Importantly, many open questions may be most tractable in host systems that have not been the focus of traditional behavioral avoidance research, such as plants and invertebrates.

Complications after interval postpartum intrauterine device insertion.

BACKGROUND: In the United States, up to 57% of women report resumption of sexual activity by the 6 week postpartum visit. Effective contraception should be addressed and provided at that time, to avoid unintended pregnancies and optimize interpregnancy intervals. Long-acting reversible contraceptives are the most effective forms of reversible contraception and are increasingly popular during the postpartum period. However, timing of postpartum intrauterine device (IUD) placement varies among providers and many delay insertion due to concerns for uterine perforation or expulsion of the IUD. OBJECTIVE: This study aimed to evaluate uterine perforation and expulsion rates with IUD insertion at 4-8 weeks postpartum vs 9-36 weeks postpartum. STUDY DESIGN: We performed a retrospective cohort study using the Kaiser Permanente Southern California electronic medical record from 2010 to 2016. We calculated the proportion of perforations and expulsions with IUD insertion at 4-8 weeks vs 9-36 weeks postpartum. Our primary outcome was the perforation rate. Secondarily, we evaluated the expulsion rate. For our minimum sample size calculation, to detect a difference of 0.5% in the perforation rate, with a baseline perforation rate of 0.5% for the 9-36 week postpartum IUD placement group, 80% power, and 5% alpha error rate, we would need at least 4221 participants per group, 8442 in total. RESULTS: A total of 24,959 patients met inclusion criteria (n=13,180 in the 4-8 week group, n=11,777 in the 9-36 week group). Of 430 patients with a confirmed complication, 157 uterine perforations and 273 IUD expulsions were identified. Perforation rates were significantly higher with placement at 4-8 weeks than at 9-36 weeks (0.78% vs 0.46%; P=.001). After adjusting for race and ethnicity, breastfeeding, IUD type, provider type, parity, most recent delivery, and body mass index, the odds of perforation remained higher with placement at 4-8 weeks than at 9-36 weeks (adjusted odds ratio, 1.92; 95% confidence interval, 1.28-2.89). Our Kaplan-Meier survival curve showed that the risk of uterine perforation remained elevated until approximately 22-23 weeks postpartum. Expulsion rates were similar between the 2 groups (1.02 vs 1.17; P=.52). CONCLUSION: Uterine perforation after interval postpartum IUD insertion is greater at 4-8 weeks than at 9-36 weeks, although perforation rates remain low at <1%. Expulsion rates did not differ between the groups. Because overall rates of uterine perforation are low, women can safely be offered IUDs at any interval beyond 4 weeks with minimal concern for perforation.

Bidirectional interactions between host social behaviour and parasites arise through ecological and evolutionary processes.

An animal's social behaviour both influences and changes in response to its parasites. Here we consider these bidirectional links between host social behaviours and parasite infection, both those that occur from ecological vs evolutionary processes. First, we review how social behaviours of individuals and groups influence ecological patterns of parasite transmission. We then discuss how parasite infection, in turn, can alter host social interactions by changing the behaviour of both infected and uninfected individuals. Together, these ecological feedbacks between social behaviour and parasite infection can result in important epidemiological consequences. Next, we consider the ways in which host social behaviours evolve in response to parasites, highlighting constraints that arise from the need for hosts to maintain benefits of sociality while minimizing fitness costs of parasites. Finally, we consider how host social behaviours shape the population genetic structure of parasites and the evolution of key parasite traits, such as virulence. Overall, these bidirectional relationships between host social behaviours and parasites are an important yet often underappreciated component of population-level disease dynamics and host-parasite coevolution.

A need to consider the evolutionary genetics of host-symbiont mutualisms.

Despite the ubiquity and importance of mutualistic interactions, we know little about the evolutionary genetics underlying their long-term persistence. As in antagonistic interactions, mutualistic symbioses are characterized by substantial levels of phenotypic and genetic diversity. In contrast to antagonistic interactions, however, we, by and large, do not understand how this variation arises, how it is maintained, nor its implications for future evolutionary change. Currently, we rely on phenotypic models to address the persistence of mutualistic symbioses, but the success of an interaction almost certainly depends heavily on genetic interactions. In this review, we argue that evolutionary genetic models could provide a framework for understanding the causes and consequences of diversity and why selection may favour processes that maintain variation in mutualistic interactions.

The evolution of parasite host range in heterogeneous host populations.

Theory on the evolution of niche width argues that resource heterogeneity selects for niche breadth. For parasites, this theory predicts that parasite populations will evolve, or maintain, broader host ranges when selected in genetically diverse host populations relative to homogeneous host populations. To test this prediction, we selected the bacterial parasite Serratia marcescens to kill Caenorhabditis elegans in populations that were genetically heterogeneous (50% mix of two experimental genotypes) or homogeneous (100% of either genotype). After 20 rounds of selection, we compared the host range of selected parasites by measuring parasite fitness (i.e. virulence, the selected fitness trait) on the two focal host genotypes and on a novel host genotype. As predicted, heterogeneous host populations selected for parasites with a broader host range: these parasite populations gained or maintained virulence on all host genotypes. This result contrasted with selection in homogeneous populations of one host genotype. Here, host range contracted, with parasite populations gaining virulence on the focal host genotype and losing virulence on the novel host genotype. This pattern was not, however, repeated with selection in homogeneous populations of the second host genotype: these parasite populations did not gain virulence on the focal host genotype, nor did they lose virulence on the novel host genotype. Our results indicate that host heterogeneity can maintain broader host ranges in parasite populations. Individual host genotypes, however, vary in the degree to which they select for specialization in parasite populations.

Host heterogeneity mitigates virulence evolution.

Parasites often infect genetically diverse host populations, and the evolutionary trajectories of parasite populations may be shaped by levels of host heterogeneity. Mixed genotype host populations, compared to homogeneous host populations, can reduce parasite prevalence and potentially reduce rates of parasite adaptation due to trade-offs associated with adapting to specific host genotypes. Here, we used experimental evolution to select for increased virulence in populations of the bacterial parasite Serratia marcescens exposed to either heterogeneous or homogeneous populations of Caenorhabditis elegans. We found that parasites exposed to heterogeneous host populations evolved significantly less virulence than parasites exposed to homogeneous host populations over several hundred bacterial generations. Thus, host heterogeneity impeded parasite adaptation to host populations. While we detected trade-offs in virulence evolution, parasite adaptation to two specific host genotypes also resulted in modestly increased virulence against the reciprocal host genotypes. These results suggest that parasite adaptation to heterogeneous host populations may be impeded by both trade-offs and a reduction in the efficacy of selection as different host genotypes exert different selective pressures on a parasite population.

Antimicrobial Polymers: The Potential Replacement of Existing Antibiotics?

Antimicrobial resistance is now considered a major global challenge; compromising medical advancements and our ability to treat infectious disease. Increased antimicrobial resistance has resulted in increased morbidity and mortality due to infectious diseases worldwide. The lack of discovery of novel compounds from natural products or new classes of antimicrobials, encouraged us to recycle discontinued antimicrobials that were previously removed from routine use due to their toxicity, e.g., colistin. Since the discovery of new classes of compounds is extremely expensive and has very little success, one strategy to overcome this issue could be the application of synthetic compounds that possess antimicrobial activities. Polymers with innate antimicrobial properties or that have the ability to be conjugated with other antimicrobial compounds create the possibility for replacement of antimicrobials either for the direct application as medicine or implanted on medical devices to control infection. Here, we provide the latest update on research related to antimicrobial polymers in the context of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens. We summarise polymer subgroups: compounds containing natural peptides, halogens, phosphor and sulfo derivatives and phenol and benzoic derivatives, organometalic polymers, metal nanoparticles incorporated into polymeric carriers, dendrimers and polymer-based guanidine. We intend to enhance understanding in the field and promote further work on the development of polymer based antimicrobial compounds.

Periodic, Parasite-Mediated Selection For and Against Sex.

Asexual lineages should rapidly replace sexual populations. Why sex then? The Red Queen hypothesis proposes that parasite-mediated selection against common host genotypes could counteract the per capita birth rate advantage of asexuals. Under the Red Queen hypothesis, fluctuations in parasite-mediated selection can drive fluctuations in the asexual population, leading to the coexistence of sexual and asexual reproduction. Does shifting selection by parasites drive fluctuations in the fitness and frequency of asexuals in nature? Combining long-term field data with mesocosm experiments, we detected a shift in the direction of parasite selection in the snail Potamopyrgus antipodarum and its coevolving parasite, Microphallus sp. In the early 2000s, asexuals were more infected than sexuals. A decade later, the asexuals had declined in frequency and were less infected than sexuals. Over time, the mean infection prevalence of asexuals equaled that of sexuals but varied far more. This variation in asexual infection prevalence suggests the potential for parasite-mediated fluctuations in asexual fitness. Accordingly, we detected fitness consequences of the shift in parasite selection: when they were less infected than sexuals, asexuals increased in frequency in the field and in paired mesocosms that isolated the effect of parasites. The match between field and experiment argues that coevolving parasites drive temporal change in the relative fitness and frequency of asexuals, potentially promoting the coexistence of reproductive modes in P. antipodarum.

Bloody-minded parasites and sex: the effects of fluctuating virulence.

Asexual lineages can grow at a faster rate than sexual lineages. Why then is sexual reproduction so widespread? Much empirical evidence supports the Red Queen hypothesis. Under this hypothesis, coevolving parasites favour sexual reproduction by adapting to infect common asexual clones and driving them down in frequency. One limitation, however, seems to challenge the generality of the Red Queen: in theoretical models, parasites must be very virulent to maintain sex. Moreover, experiments show virulence to be unstable, readily shifting in response to environmental conditions. Does variation in virulence further limit the ability of coevolving parasites to maintain sex? To address this question, we simulated temporal variation in virulence and evaluated the outcome of competition between sexual and asexual females. We found that variation in virulence did not limit the ability of coevolving parasites to maintain sex. In fact, relatively high variation in virulence promoted parasite-mediated maintenance of sex. With sufficient variation, sexual females persisted even when mean virulence fell well below the threshold virulence required to maintain sex under constant conditions. We conclude that natural variation in virulence does not limit the relevance of the Red Queen hypothesis for natural populations; on the contrary, it could expand the range of conditions over which coevolving parasites can maintain sex.

A Model for Evolutionary Ecology of Disease: The Case for Caenorhabditis Nematodes and Their Natural Parasites.

Many of the outstanding questions in disease ecology and evolution call for combining observation of natural host-parasite populations with experimental dissection of interactions in the field and the laboratory. The "rewilding" of model systems holds great promise for this endeavor. Here, we highlight the potential for development of the nematode Caenorhabditis elegans and its close relatives as a model for the study of disease ecology and evolution. This powerful laboratory model was disassociated from its natural habitat in the 1960s. Today, studies are uncovering that lost natural history, with several natural parasites described since 2008. Studies of these natural Caenorhabditis-parasite interactions can reap the benefits of the vast array of experimental and genetic tools developed for this laboratory model. In this review, we introduce the natural parasites of C. elegans characterized thus far and discuss resources available to study them, including experimental (co)evolution, cryopreservation, behavioral assays, and genomic tools. Throughout, we present avenues of research that are interesting and feasible to address with caenorhabditid nematodes and their natural parasites, ranging from the maintenance of outcrossing to the community dynamics of host-associated microbes. In combining natural relevance with the experimental power of a laboratory supermodel, these fledgling host-parasite systems can take on fundamental questions in evolutionary ecology of disease.

Canthal cutdown for emergent treatment of orbital compartment syndrome.

This article evaluates the use of a "canthal cutdown" technique in orbital compartment syndrome in a cadaveric model. Twelve cadaver orbits were used to simulate orbital compartment syndrome using a blood analog solution. Two pressure probes, in different orbital locations, were used to monitor orbital pressure. Pressure was monitored during successive procedures: canthotomy, cantholysis, and canthal cutdown. Orbits were then re-injected with solution, simulating an active orbital hemorrhage, and pressure measurements were recorded over a 10-minute duration. No statistically significant difference was found between the two orbital pressure monitoring devices at each measurement point (p = 0.99). Significant pressure reductions, for both probes, were observed after canthal cutdown compared to initial measurement after injection of 20 mL blood analog (p < 0.001 and p = 0.005). When comparing the orbital pressure following canthotomy and inferior cantholysis versus canthal cutdown, the cutdown procedure provided an additional 74% in orbital pressure reduction (p =0.01). After re-injection of 10 mL of solution and 10 minutes of egress, pressure returned to baseline (probe 1: baseline 7 mm Hg vs. post-cutdown at 10 minutes 7 mm Hg; p = 0.83; and probe 2: 5 mm Hg vs. 5 mm Hg; p = 0.83). The canthal cutdown technique provides further reduction in orbital pressure versus canthotomy and cantholysis alone. The technique may be effective for treatment of static orbital compartment syndrome and temporizing treatment of compartment syndrome from active orbital hemorrhages.

Fine-Scale Spatial Covariation between Infection Prevalence and Susceptibility in a Natural Population.

The prevalence of infection varies dramatically on a fine spatial scale. Many evolutionary hypotheses are founded on the assumption that this variation is due to host genetics, such that sites with a high frequency of alleles conferring susceptibility are associated with higher infection prevalence. This assumption is largely untested and may be compromised at finer spatial scales where gene flow between sites is high. We put this assumption to the test in a natural snail-trematode interaction in which host susceptibility is known to have a strong genetic basis. A decade of field sampling revealed substantial spatial variation in infection prevalence between 13 sites around a small lake. Laboratory assays replicated over 3 years demonstrate striking variation in host susceptibility among sites in spite of high levels of gene flow between sites. We find that mean susceptibility can explain more than one-third of the observed variation in mean infection prevalence among sites. We estimate that variation in susceptibility and exposure together can explain the majority of variation in prevalence. Overall, our findings in this natural host-parasite system argue that spatial variation in infection prevalence covaries strongly with variation in the distribution of genetically based susceptibility, even at a fine spatial scale.

Tenofovir Alafenamide.

OBJECTIVE: To review the pharmacology, efficacy, safety, and place in therapy for tenofovir alafenamide (TAF). DATA SOURCES: A search using PubMed was conducted (2004 to May 2016) using the following keywords: tenofovir alafenamide, TAF, and GS-7340. Articles were evaluated for content, and bibliographies were reviewed. Data available exclusively as abstracts from major infectious diseases and HIV conferences were also evaluated for inclusion. STUDY SELECTION AND DATA EXTRACTION: Studies included were in vitro investigations; phase I, II, and III clinical trials; and pharmacokinetic and pharmacodynamic evaluations. DATA SYNTHESIS: Similar to tenofovir disoproxil fumarate (TDF), TAF is a prodrug of tenofovir but results in significantly higher intracellular tenofovir concentrations and lower serum levels. As a result, TAF is expected to have efficacy similar to that of TDF while reducing tenofovir-associated nephrotoxicity and bone mineral density losses. Clinical trials evaluating the safety and efficacy of TAF-containing antiretroviral regimens have confirmed these expectations, consistently demonstrating similar virological suppression compared with TDF-containing regimens as well as significant improvements in markers of kidney function and bone health. Three combination products containing TAF were approved by the United States Food and Drug Administration for the management of HIV-1 infection. The first of these was a single tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF which is now a recommended regimen in clinical practice guidelines for initial treatment in antiretroviral-naïve patients. CONCLUSIONS: TAF is a novel nucleotide reverse transcriptase inhibitor for the treatment of HIV-1 infection that has efficacy similar to that of TDF and improved safety compared with TDF.

Complex health conditions and mental health training: How prepared is the frontline service provider?

How prepared are frontline service providers for dealing with mental illness in patients with multiple, complex health conditions? The aims of this study were two-fold, to gain insight into the kinds of training and education desired by frontline service providers in a healthcare setting and to compile a list of key questions for health service managers and education leaders to address based on our findings. Over 100 care providers responded to a survey. Over half of the respondents indicated no mental health training, and the majority desired increased training and support. Suggested approaches ranged from regular workshops (eg, case presentations) to systems-level strategies (eg, partnering with mental health organizations). This study provides a critical first look into what frontline service providers identify as being essential to their skill set in working with a complex population and raises important questions for healthcare managers and educators to consider in addressing this gap.

Early-Life Resource Scarcity in Mice Does Not Alter Adult Corticosterone or Preovulatory Luteinizing Hormone Surge Responses to Acute Psychosocial Stress.

Early-life stressors can affect reproductive development and change responses to adult stress. We tested if resource scarcity in the form of limited bedding and nesting (LBN) from postnatal days (PND) 4 to 11 delayed sexual maturation in male and female mice and/or altered the response to an acute, layered, psychosocial stress (ALPS) in adulthood. Contrary to the hypotheses, age and mass at puberty were unaffected by the present application of LBN. Under basal conditions and after ALPS, corticosterone concentrations in males, diestrous females, and proestrous females reared in standard (STD) or LBN environments were similar. ALPS disrupts the luteinizing hormone (LH) surge in most mice when applied on the morning of proestrus; this effect was not changed by resource scarcity. In this study, the paucity of effects in the offspring may relate to a milder response of CBA dams to the paradigm. While LBN dams exited the nest more often and their offspring were smaller than STD-reared offspring on PND11, dam corticosterone concentrations were similar on PND11. To test if ALPS disrupts the LH surge by blunting the increase in excitatory GABAergic input to gonadotropin-releasing hormone (GnRH) neurons on the afternoon of proestrus, we conducted whole-cell voltage-clamp recordings. The frequency of GABAergic postsynaptic currents in GnRH neurons was not altered by LBN, ALPS, or their interaction. It remains possible that ALPS acts at afferents of GnRH neurons, changes response of GnRH neurons to input, and/or alters pituitary responsiveness to GnRH and that a more pronounced resource scarcity would affect the parameters studied.

Genetic variation in parasite avoidance, yet no evidence for constitutive fitness costs.

Behavioral avoidance of parasites is a widespread strategy among animal hosts and in human public health. Avoidance has repercussions for both individual and population-level infection risk. Although most cases of parasite avoidance are viewed as adaptive, there is little evidence that the basic assumptions of evolution by natural selection are met. This study addresses this gap by testing whether there is a heritable variation in parasite avoidance behavior. We quantified behavioral avoidance of the bacterial parasite Serratia marcescens for 12 strains of the nematode host Caenorhabditis elegans. We found that these strains varied in their magnitude of avoidance, and we estimated the broad-sense heritability of this behavior to be in the range of 11%-26%. We then asked whether avoidance carries a constitutive fitness cost. We did not find evidence of one. Rather, strains with higher avoidance had higher fitness, measured as population growth rate. Together, these results direct future theoretical and empirical work to identify the forces maintaining genetic variation in parasite avoidance.

Do biological control agents adapt to local pest genotypes? A multiyear test across geographic scales.

Parasite local adaptation has been a major focus of (co)evolutionary research on host-parasite interactions. Studies of wild host-parasite systems frequently find that parasites paired with local, sympatric host genotypes perform better than parasites paired with allopatric host genotypes. In contrast, there are few such tests in biological control systems to establish whether biological control parasites commonly perform better on sympatric pest genotypes. This knowledge gap prevents the optimal design of biological control programs: strong local adaptation could argue for the use of sympatric parasites to achieve consistent pest control. To address this gap, we tested for local adaptation of the biological control bacterium Pasteuria penetrans to the root-knot nematode Meloidogyne arenaria, a global threat to a wide range of crops. We measured the probability and intensity of P. penetrans infection on sympatric and allopatric M. arenaria over the course of 4 years. Our design accounted for variation in adaptation across scales by conducting tests within and across fields, and we isolated the signature of parasite adaptation by comparing parasites collected over the course of the growing season. Our results are largely inconsistent with local adaptation of P. penetrans to M. arenaria: in 3 of 4 years, parasites performed similarly well in sympatric and allopatric combinations. In 1 year, however, infection probability was 28% higher for parasites paired with hosts from their sympatric plot, relative to parasites paired with hosts from other plots within the same field. These mixed results argue for population genetic data to characterize the scale of gene flow and genetic divergence in this system. Overall, our findings do not provide strong support for using P. penetrans from local fields to enhance biological control of Meloidogyne.

Real-World Analysis of Post-Progression Treatment Patterns and Outcomes for EGFR Mutation-Positive Patients Treated with First-Line Osimertinib.

Introduction: The use of osimertinib in the first-line (1L) setting is an effective treatment option for sensitizing EGFR-mutations (EGFRm+) and has significantly altered the standard of care practice for EGFRm+ disease in Canada. Unfortunately, acquired resistance to osimertinib is almost universal, and outcomes are disparate. Post-progression treatment patterns and the outcome of real-world Canadian EGFRm+ patients receiving 1L osimertinib were the focus of this retrospective review. Methods: The Glans-Look Lung Cancer Research database was used to identify and collect demographic, clinical, treatment, and outcome data on EGFRm+ patients who received 1L osimertinib in the Canadian province of Alberta between 2018 and 2022. Results: A total of 150 patients receiving 1L osimertinib were identified. In total, 86 developed progressive disease, with 56 (65%) continuing systemic therapy, 73% continuing osimertinib, and 27% switching to second-line (2L) systemic therapy. Patients were similar both in clinical characteristics at 1L osimertinib initiation and patterns of treatment failure at progression; those continuing 1L osimertinib post-progression had a longer time to progression (13.5 vs. 8.8 months, p = 0.05) and subsequent post-osimertinib initiation survival (34.7 vs. 22.8 months, p = 0.11). Conclusions: The continuation of osimertinib post-progression is an effective disease management strategy for select real-world EGFRm+ patients, providing continued clinical benefit, potentially due to different underlying disease pathogenesis.

Contrast-enhanced ultrasound of renal masses in the pre-transplant setting: literature review with case highlights.

With the rising incidence of chronic kidney disease worldwide, an increasing number of patients are expected to require renal transplantation, which remains the definitive treatment of end stage renal disease. Medical imaging, primarily ultrasonography and contrast-enhanced CT and/or MRI, plays a large role in pre-transplantation assessment, especially in the characterization of lesions within the native kidneys. However, patients with CKD/ESRD often have relative contraindications to CT- and MR-contrast agents, limiting their utilization within this patient population. Contrast-enhanced ultrasound (CEUS), which combines the high temporal and spatial resolution of ultrasonography with intravascular microbubble contrast agents, provides a promising alternative. This review aims to familiarize the reader with the literature regarding the use of CEUS in the evaluation of cystic and solid renal lesions and provide case examples of its use at our institution in the pre-transplant setting.

Treatment patterns and outcomes in KRASG12C-positive advanced NSCLC patients previously treated with immune checkpoint inhibitors: A Canada-wide real-world, multi-center, retrospective cohort study.

OBJECTIVES: KRAS mutations, particularly KRASG12C, are prevalent in non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have been a frontline treatment, but recently developed KRASG12C-selective inhibitors, such as sotorasib, present new therapeutic options. We conducted a multi-center retrospective cohort study to gain insights into real-world treatment patterns and outcomes in patients with KRASG12C-positive advanced NSCLC receiving systemic therapy post-ICI treatment. METHODS: From the CAnadian CAncers With Rare Molecular Alterations-Basket Real-world Observational Study (CARMA-BROS), a cohort of 102 patients with KRASG12C-positive advanced NSCLC across 9 Canadian centers diagnosed between 2015 and 2021 was analyzed. Clinico-demographic and treatment data were obtained from electronic health records. Survival outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: The patients (median age 66 years; 58 % female; 99 % current/former tobacco exposure; 59 % PD-L1 ≥ 50 %), exhibited heterogeneous treatment patterns post-ICI. Most patients received ICIs as a first-line therapy, with varying subsequent lines including chemotherapy and targeted therapy. In patients receiving systemic therapy post-ICI, median overall survival was 12.6 months, and real-world progression-free survival was 4.7 months. KRASG12C-selective targeted therapy post-ICI (n = 20) showed longer real-world progression-free survival compared to single-agent chemotherapy (aHR = 0.39, p = 0.012). CONCLUSION: This study contributes valuable real-world data on KRASG12C-positive advanced NSCLC post-ICI treatment. The absence of a standard treatment sequencing post-ICI underscores the need for further investigation and consensus-building in the evolving landscape of KRASG12C-targeted therapies.