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.

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.

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.

Li0.5La0.5TiO3 as an Ionic Conducting Additive Enhancing the High-Voltage Performance of LiNi0.8Mn0.1Co0.1O2 Cathodes in Lithium-Ion Batteries.

Although high-voltage (e.g., >4.3 VvsLi) operation can increase specific capacity and energy of Ni-rich NMC cathodes, it accelerates the oxidative decomposition of electrolytes and surface degradation of NMC cathodes, leading to rapid capacity fading. This work presents a novel approach that employs Li0.5La0.5TiO3 (LLTO) solid-electrolyte as a Li-ion conductor and surface passivation agent to stabilize the cathode/electrolyte interphase (CEI) layer of the LiNi0.8Mn0.1Co0.1O2 (NMC811) cathode and enhance its high-voltage performances. The LLTO particles improve Li-ion transportation across the CEI layer, as evidenced by its reduced impedance in Nyquist plots. Furthermore, passivation of CEI by LLTO mitigates parasitic reactions (e.g., transition metal dissolution) that occur on the graphite solid electrolyte interphase layer during extended cycles of pouch-cells. As a result, pouch-cells with the 1 or 5 wt % LLTO-blended NMC811 cathodes can deliver 19-23% increase in specific capacity and improved cycle life (1000 cycles) at high voltages (up to 4.4 V), comparing to bare NMC811 cathodes. Post-mortem characterization of pouch-cells quantitatively identified the degradation sources of NMC811 cathode at high-voltages, which highlighted the improvement mechanisms of LLTO blended-cathodes.

Characterisation of the bovine C-type lectin receptor Mincle and potential evidence for an endogenous ligand.

Innate immune receptors that form complexes with secondary receptors, activating multiple signalling pathways, modulate cellular activation and play essential roles in regulating homeostasis and immunity. We have previously identified a variety of bovine C-type lectin-like receptors that possess similar functionality than their human orthologues. Mincle (CLEC4E), a heavily glycosylated monomer, is involved in the recognition of the mycobacterial component Cord factor (trehalose 6,6'-dimycolate). Here we characterise the bovine homologue of Mincle (boMincle), and demonstrate that the receptor is structurally and functionally similar to the human orthologue (huMincle), although there are some notable differences. In the absence of cross-reacting antibodies, boMincle-specific antibodies were created and used to demonstrate that, like the human receptor, boMincle is predominantly expressed by myeloid cells. BoMincle surface expression increases during the maturation of monocytes to macrophages. However, boMincle mRNA transcripts were also detected in granulocytes, B cells, and T cells. Finally, we show that boMincle binds to isolated bovine CD4+ T cells in a specific manner, indicating the potential to recognise endogenous ligands. This suggests that the receptor might also play a role in homeostasis in cattle.

Real-World Treatment Patterns and Effectiveness of Targeted and Immune Checkpoint Inhibitor-Based Systemic Therapy in BRAF Mutation-Positive NSCLC.

Introduction: BRAF mutations (present in 2%-3% of NSCLC) are a known oncogenic driver and emerging therapeutic target. There is a scarcity of real-world data describing the clinical characteristics, treatment patterns, and effectiveness of targeted BRAF-inhibiting and immune checkpoint inhibitor (ICI)-based systemic therapies, yet this is required for appropriate treatment decisions that optimize patient outcome. Methods: Demographic, clinical, treatment, and outcome data of patients with BRAF mutation-positive NSCLC diagnosed between 2018 and 2022 were identified from the Glans-Look Lung Cancer Research database and included in this analysis. Results: A total of 53 BRAF mutation-positive patients were identified (V600E, n = 35; non-V600E, n = 18). Furthermore, 46 patients (87%) were diagnosed with metastatic disease, of whom 61% were treated with systemic anticancer therapy, which significantly improved overall survival (34.1 versus 2.2 mo, p = 0.01). ICI-based regimens were found to have effectiveness in the first-line setting for both V600E and non-V600E cohorts (objective response rate: 38%-43%; real-world calculations of median progression-free survival: 10.5-10.8 mo, respectively). Dual-targeted BRAF/MEK inhibition was also found to have effectiveness in the first-line setting for V600E patients (objective response rate: 33%, real-world calculations of median progression-free survival: 15.2 mo). Conclusions: This study of real-world patients with BRAF mutations confirms the importance of effective systemic therapies. Both dual-targeted BRAF/MEK inhibition and ICI-based regimens have evidence of benefit in this population revealing that real-world populations can experience similar clinical response and outcome to clinical trial cohorts on these treatment regimens. Future studies to clarify the role of co-mutations on response to both dual-targeted BRAF/MEK inhibition and ICI-based regimens may be important to treatment selection and optimization of patient outcome.

Diet can alter the cost of resistance to a natural parasite in Caenorhabditis elegans.

Resistance to parasites confers a fitness advantage, yet hosts show substantial variation in resistance in natural populations. Evolutionary theory indicates that resistant and susceptible genotypes can coexist if resistance is costly, but there is mixed evidence that resistant individuals have lower fitness in the absence of parasites. One explanation for this discrepancy is that the cost of resistance varies with environmental context. We tested this hypothesis using Caenorhabditis elegans and its natural microsporidian parasite, Nematocida ironsii. We used multiple metrics to compare the fitness of two near-isogenic host genotypes differing at regions associated with resistance to N. ironsii. To quantify the effect of the environment on the cost associated with these known resistance regions, we measured fitness on three microbial diets. We found that the cost of resistance varied with both diet and the measure of fitness. We detected no cost to resistance, irrespective of diet, when fitness was measured as fecundity. However, we detected a cost when fitness was measured in terms of population growth, and the magnitude of this cost varied with diet. These results provide a proof of concept that, by mediating the cost of resistance, environmental context may govern the rate and nature of resistance evolution in heterogeneous environments.

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.

A diverse parasite pool can improve effectiveness of biological control constrained by genotype-by-genotype interactions.

The outcomes of biological control programs can be highly variable, with natural enemies often failing to establish or spread in pest populations. This variability has posed a major obstacle in use of the bacterial parasite Pasteuria penetrans for biological control of Meloidogyne species, economically devastating plant-parasitic nematodes for which there are limited management options. A leading hypothesis for this variability in control is that infection is successful only for specific combinations of bacterial and nematode genotypes. Under this hypothesis, failure of biological control results from the use of P. penetrans genotypes that cannot infect local Meloidogyne genotypes. We tested this hypothesis using isofemale lines of M. arenaria derived from a single field population and multiple sources of P. penetrans from the same and nearby fields. In strong support of the hypothesis, susceptibility to infection depended on the specific combination of host line and parasite source, with lines of M. arenaria varying substantially in which P. penetrans source could infect them. In light of this result, we tested whether using a diverse pool of P. penetrans could increase infection and thereby control. We found that increasing the diversity of the P. penetrans inoculum from one to eight sources more than doubled the fraction of M. arenaria individuals susceptible to infection and reduced variation in susceptibility across host lines. Together, our results highlight genotype-by-genotype specificity as an important cause of variation in biological control and call for the maintenance of genetic diversity in natural enemy populations.

Local structure elucidation of tungsten-substituted vanadium dioxide (V[Formula: see text]W[Formula: see text]O[Formula: see text]).

Initially, vanadium dioxide seems to be an ideal first-order phase transition case study due to its deceptively simple structure and composition, but upon closer inspection there are nuances to the driving mechanism of the metal-insulator transition (MIT) that are still unexplained. In this study, a local structure analysis across a bulk powder tungsten-substitution series is utilized to tease out the nuances of this first-order phase transition. A comparison of the average structure to the local structure using synchrotron x-ray diffraction and total scattering pair-distribution function methods, respectively, is discussed as well as comparison to bright field transmission electron microscopy imaging through a similar temperature-series as the local structure characterization. Extended x-ray absorption fine structure fitting of thin film data across the substitution-series is also presented and compared to bulk. Machine learning technique, non-negative matrix factorization, is applied to analyze the total scattering data. The bulk MIT is probed through magnetic susceptibility as well as differential scanning calorimetry. The findings indicate the local transition temperature ([Formula: see text]) is less than the average [Formula: see text] supporting the Peierls-Mott MIT mechanism, and demonstrate that in bulk powder and thin-films, increasing tungsten-substitution instigates local V-oxidation through the phase pathway VO[Formula: see text] V[Formula: see text]O[Formula: see text] V[Formula: see text]O[Formula: see text].

Defining the Genes Required for Survival of Mycobacterium bovis in the Bovine Host Offers Novel Insights into the Genetic Basis of Survival of Pathogenic Mycobacteria.

Tuberculosis has severe impacts on both humans and animals. Understanding the genetic basis of survival of both Mycobacterium tuberculosis, the human-adapted species, and Mycobacterium bovis, the animal-adapted species, is crucial to deciphering the biology of both pathogens. There are several studies that identify the genes required for survival of M. tuberculosis in vivo using mouse models; however, there are currently no studies probing the genetic basis of survival of M. bovis in vivo. In this study, we utilize transposon insertion sequencing in M. bovis AF2122/97 to determine the genes required for survival in cattle. We identify genes encoding established mycobacterial virulence functions such as the ESX-1 secretion system, phthiocerol dimycocerosate (PDIM) synthesis, mycobactin synthesis, and cholesterol catabolism that are required in vivo. We show that, as in M. tuberculosis H37Rv, phoPR is required by M. bovis AF2122/97 in vivo despite the known defect in signaling through this system. Comparison to studies performed in species that are able to use carbohydrates as an energy source, such as M. bovis BCG and M. tuberculosis, suggests that there are differences in the requirement for genes involved in cholesterol import (mce4 operon) and oxidation (hsd). We report a good correlation with existing mycobacterial virulence functions but also find several novel virulence factors, including genes involved in protein mannosylation, aspartate metabolism, and glycerol-phosphate metabolism. These findings further extend our knowledge of the genetic basis of survival in vivo in bacteria that cause tuberculosis and provide insight for the development of novel diagnostics and therapeutics. IMPORTANCE This is the first report of the genetic requirements of an animal-adapted member of the Mycobacterium tuberculosis complex (MTBC) in a natural host. M. bovis has devastating impacts on cattle, and bovine tuberculosis is a considerable economic, animal welfare, and public health concern. The data highlight the importance of mycobacterial cholesterol catabolism and identify several new virulence factors. Additionally, the work informs the development of novel differential diagnostics and therapeutics for TB in both human and animal populations.

Contrasting parasite-mediated reductions in fitness within versus between patches of a nematode host.

Host and parasites interact across spatial scales, but parasite-mediated fitness effects are typically measured only at local scales. Recent work suggests that parasites can reduce host fitness during dispersal between patches, highlighting the potential for both within- and between-patch effects to contribute to the net fitness consequences of parasitism. Building on this work, we measured the contribution of the dispersal phase to parasite-mediated reductions in host fitness. We used the nematode Caenorhabditis elegans and its natural microsporidian parasite Nematocida parisii to quantify the fitness consequences of parasitism at the individual, population, and metapopulation level. Nematocida parisii reduced individual fecundity and population growth but had its greatest fitness impact at the dispersal stage: parasitism reduced the fitness of dispersing larvae by 62%-100%. These results indicate that the cost of parasitism in this system is greatly underestimated if the metapopulation level is not taken into account. We also found that the effects of N. parisii vary with host genotype, and the relative advantage of the most resistant genotype increases with inclusion of the dispersal stage. Taken together, our findings demonstrate that host-parasite interactions at the dispersal stage can magnify selection for parasite resistance.

Opioid-Free Anesthesia and Certified Registered Nurse Anesthetists: Barriers to Implementation.

While knowledge surrounding opioid-free anesthesia (OFA) has increased in current literature, there is an absence of research specific to nurse anesthesia practice. This study aimed to identify the number of surveyed Certified Registered Nurse Anesthetists (CRNAs) who incorporated OFA into practice and uncovered barriers to its implementation. This quantitative survey solicited data from 2,883 CRNAs across the United States. Of the participants, 81% administered OFA, and 88% felt that OFA techniques are beneficial in anesthesia practice. The results of the survey revealed that gender may be a barrier to the implementation of OFA. Female respondents were less likely to administer OFA often due to the facility culture. The level of education also influenced how CRNAs perceived their facility's culture as a barrier. Perceived access to a variety of multimodal anesthetics was also problematic. While most of those surveyed had administered OFA and acknowledged its benefit, barriers to wider implementation still exist.

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort.

The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014-2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

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.

Genetic diversity and disease: The past, present, and future of an old idea.

Why do infectious diseases erupt in some host populations and not others? This question has spawned independent fields of research in evolution, ecology, public health, agriculture, and conservation. In the search for environmental and genetic factors that predict variation in parasitism, one hypothesis stands out for its generality and longevity: genetically homogeneous host populations are more likely to experience severe parasitism than genetically diverse populations. In this perspective piece, I draw on overlapping ideas from evolutionary biology, agriculture, and conservation to capture the far-reaching implications of the link between genetic diversity and disease. I first summarize the development of this hypothesis and the results of experimental tests. Given the convincing support for the protective effect of genetic diversity, I then address the following questions: (1) Where has this idea been put to use, in a basic and applied sense, and how can we better use genetic diversity to limit disease spread? (2) What new hypotheses does the established disease-diversity relationship compel us to test? I conclude that monitoring, preserving, and augmenting genetic diversity is one of our most promising evolutionarily informed strategies for buffering wild, domesticated, and human populations against future outbreaks.

A Real-World Evaluation of Atezolizumab Plus Platinum-Etoposide Chemotherapy in Patients With Extensive-Stage SCLC in Canada.

INTRODUCTION: The real-world data evaluating treatment outcomes of atezolizumab plus carboplatin-etoposide chemotherapy (atezolizumab) for extensive-stage SCLC (ESCLC) are lacking. Our objective was to evaluate real-world outcomes of ESCLC treated with atezolizumab. METHODS: A retrospective analysis of provincial patients with ESCLC who started first-line (1L) systemic treatment was conducted. We primarily evaluated the progression-free survival (PFS) and overall survival (OS) outcomes in association with atezolizumab compared with platinum-etoposide chemotherapy (chemotherapy) while adjusting for relevant demographic and clinical factors. Adverse events (AEs) during 1L were evaluated. RESULTS: A total of 67 patients were identified. Of the 34 patients who received atezolizumab, 24% had Eastern Cooperative Oncology Group performance status greater than or equal to 2, approximately 50% were more than or equal to 65 years, 21% received cisplatin-etoposide chemotherapy before atezolizumab, and 12% had thoracic radiation (tRT).Within the atezolizumab versus chemotherapy group, the median PFS equals to 6.0 versus 4.3 months (p = 0.03) whereas OS = 12.8 versus 7.1 months (p = 0.01). Relative to chemotherapy, the hazard ratio (95% confidence interval) for PFS was 0.53 (0.28-1.02) and OS was 0.42 (0.20-0.88) with atezolizumab. tRT compared with no tRT receipt correlated with reduced death risk (hazard ratio [95% confidence interval] = 0.33 [0.13-0.88]).AE-related treatment withdrawal with atezolizumab was 32% and 15% with chemotherapy (p = 0.02). Within the tRT subgroup, 25% versus 20% in atezolizumab versus chemotherapy group, respectively, discontinued 1L owing to AE. CONCLUSIONS: This is the first real-world study revealing comparable survival with that in the IMpower133 trial. Treatment discontinuation from AEs was higher with atezolizumab among Canadian patients with ESCLC. Our data suggest safe use of tRT and chemoimmunotherapy, but its efficacy for ESCLC warrants further study.

Prenatal Androgen Treatment Does Not Alter the Firing Activity of Hypothalamic Arcuate Kisspeptin Neurons in Female Mice.

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome (PCOS), who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational days 16-18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in three-week (3wk)-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin, also known as KNDy neurons. We hypothesized PNA treatment changes firing rates of KNDy neurons in a similar age-dependent manner as GnRH neurons. We conducted targeted extracellular recordings (0.5-2 h) of Tac2-identified KNDy neurons from control and PNA mice at 3wks of age and in adulthood. About half of neurons were quiescent (<0.005 Hz). Long-term firing rates of active cells varied, suggestive of episodic activity, but were not different among groups. Short-term burst firing was also similar. We thus reject the hypothesis that PNA alters the firing rate of KNDy neurons. This does not preclude altered neurosecretory output of KNDy neurons, involvement of other neuronal populations, or in vivo networks as critical drivers of altered GnRH firing rates in PNA mice.

Retrospective Real-World Outcomes for Patients With ALK-Rearranged Lung Cancer Receiving ALK Receptor Tyrosine Kinase Inhibitors.

INTRODUCTION: This study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK-rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada. METHODS: Demographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK-rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis. RESULTS: A total of 92 patients with ALK-rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK-rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK-wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement (ALK-rearranged versus ALK-wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p = 0.04). CONCLUSIONS: Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer.

In Vitro Supplementation of Copper Modulates the Functional Th1/Th2 Phenotype of Peripheral Blood Mononuclear Cells in Cattle.

This study investigated the association of copper levels and monocyte plasticity between M1 (CD14+ CD16-) and M2 (CD14- CD16++) phenotypes. Five samples of female bovine PBMCs were incubated in 0, 4, 8 and 16 µM copper and stimulated (PPD-A, TLR- 2 ligand (Pam3CSK4), or media alone) before they were washed and stained for cell surface expression analysis by flow cytometry. M1 function was measured through nitric oxide production using a Griess assay. Flow cytometry analysis showed a significant reduction in viability with increased copper (p < 0.001). Increasing copper had a significant impact on CD14 expression (p = 0.026) and in cows older than 4 years copper levels positively affected CD14 expression (p = 0.001), whereas in animals of four years or younger, Cu did not affect the CD14 expression (p = 0.701 and 0.939, respectively). CD14 expression affected both CD16 expression and NO production. For CD16 expression, there was a further significant negative effect of copper levels in cows older than 4 years, NO was not affected by varying copper levels. In our small sample, monocytes in the presence of a higher copper environment showed a stronger M1 support for better cellular immunity which might contain intracellular infections more effectively. To test this, a randomised clinical trial will be required to determine whether copper supplementation could prevent progression to Johne's disease in MAP infected cows.