Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Within your rights: Dissociating wrongness and permissibility in moral judgement.

Are we ever morally permitted to do what is morally wrong? It seems intuitive that we are, but evidence for dissociations among judgement of permissibility and wrongness is relatively scarce. Across four experiments (N = 1438), we show that people judge that some behaviours can be morally wrong and permissible. The dissociations arise because these judgements track different morally relevant aspects of everyday moral encounters. Judgements of individual rights predicted permissibility but not wrongness, while character assessment predicted wrongness but not permissibility. These findings suggest a picture in which moral evaluation is granular enough to express reasoning about different types of normative considerations, notably the possibility that people can exercise their rights in morally problematic ways.

A computational modeling approach to investigating mind wandering-related adjustments to gaze behavior during scene viewing.

Research on gaze control has long shown that increased visual-cognitive processing demands in scene viewing are associated with longer fixation durations. More recently, though, longer durations have also been linked to mind wandering, a perceptually decoupled state of attention marked by decreased visual-cognitive processing. Toward better understanding the relationship between fixation durations and visual-cognitive processing, we ran simulations using an established random-walk model for saccade timing and programming and assessed which model parameters best predicted modulations in fixation durations associated with mind wandering compared to attentive viewing. Mind wandering-related fixation durations were best described as an increase in the variability of the fixation-generating process, leading to more variable-sometimes very long-durations. In contrast, past research showed that increased processing demands increased the mean duration of the fixation-generating process. The findings thus illustrate that mind wandering and processing demands modulate fixation durations through different mechanisms in scene viewing. This suggests that processing demands cannot be inferred from changes in fixation durations without understanding the underlying mechanism by which these changes were generated.

Purity is linked to cooperation but not necessarily through self-control.

Fitouchi et al. claim that seemingly victimless pleasures and nonproductive activities are moralized because they alter self-control. Their account predicts that: (1) victimless excesses are negatively moralized because they diminish self-control, and (2) restrained behaviors are positively moralized because they enhance self-control. Several examples run contrary to these predictions and call into question the general relationship between self-control and cooperation.

Rapport de cas Ossifying fibroma in the cervical vertebra of a dog.

The objective of this study was to describe the clinical signs, neurologic examination findings, diagnostic imaging results, and pathologic diagnosis of ossifying fibroma in the cervical vertebra of a dog. A 3-year-old spayed female Pembroke Welsh corgi dog exhibited severe cervical pain and left-sided postural reaction deficits. Magnetic resonance imaging (MRI) revealed a lobulated contrast enhancing mass associated with the C6 cervical vertebra. Due to the lack of response to pain medications, humane euthanasia was elected, and histopathologic evaluation of the mass revealed a fibro-osseous lesion most consistent with an ossifying fibroma. This neoplasm is most commonly associated with the mandible of young horses and has not been previously reported in vertebrae in veterinary medicine. Key clinical message: This case is the first report of a fibro-osseous lesion most consistent with an ossifying fibroma affecting a vertebra in veterinary medicine.

Fibrome ossifiant dans la vertèbre cervicale d'un chien. Décrire les signes cliniques, les résultats de l'examen neurologique, les résultats de l'imagerie diagnostique et le diagnostic pathologique du fibrome ossifiant dans la vertèbre cervicale d'un chien. Une chienne Pembroke Welsh corgi femelle stérilisée âgée de 3 ans présentait de fortes douleurs cervicales et des déficits de réaction posturale du côté gauche. L'imagerie par résonance magnétique (IRM) a révélé une masse lobulée augmentant le contraste associée à la vertèbre cervicale C6. En raison de l'absence de réponse aux analgésiques, l'euthanasie a été choisie et l'évaluation histopathologique de la masse a révélé une lésion fibro-osseuse plus compatible avec un fibrome ossifiant. Ce néoplasme est le plus souvent associé à la mandibule des jeunes chevaux et n'a jamais été signalé auparavant dans les vertèbres en médecine vétérinaire.Message clinique clé :Ce cas est le premier rapport d'une lésion fibro-osseuse plus compatible avec un fibrome ossifiant touchant une vertèbre en médecine vétérinaire.(Traduit par Dr Serge Messier).

What's inside is all that counts? The contours of everyday thinking about self-control.

Does self-control require willpower? The question cuts to the heart of a debate about whether self-control is identical with some psychological process internal to the agents or not. Noticeably absent from these debates is systematic evidence about the folk-psychological category of self-control. Here, we present the results of two behavioral studies (N = 296) that indicate the structure of everyday use of the concept. In Study 1, participants rated the degree to which different strategies to respond to motivational conflict exemplify self-control. Participants distinguished between intra-psychic and externally-scaffolded strategies and judged that the former exemplified self-control more than the latter. In Study 2, participants provided various solutions to manage motivational conflict and rated their proposals on effectiveness. Participants produced substantially more intra-psychic strategies, rated them as more effective, and advised them at a higher rate than externally-scaffolded strategies. Taken together, these results suggest that while people recognize a plurality of strategies as genuine instances of self-control, purely internal exercises of self-control are considered more prototypical than their externally-scaffolded counterparts. This implies a hierarchical structure for the folk psychological category of self-control. The concept encompasses a variety of regulatory strategies and organizes these strategies along a hierarchical continuum, with purely intra-psychic strategies at the center and scaffolded strategies in the periphery. Supplementary Information: The online version contains supplementary material available at 10.1007/s13164-021-00573-2.

Secreted phosphoprotein 24 kD (Spp24) inhibits the growth of human osteosarcoma through the BMP-2/Smad signaling pathway.

Autocrine stimulation of tumor cells is an important mechanism for the growth of skeletal tumors. In tumors that are sensitive, growth factor inhibitors can dramatically reduce tumor growth. In this study, our aim was to investigate the effects of Secreted phosphoprotein 24 kD (Spp24) on the growth of osteosarcoma (OS) cells in the presence and absence of exogenous BMP-2 both in vitro and in vivo. Our study demonstrated that Spp24 inhibited proliferation and promoted apoptosis of OS cells as confirmed by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay and immunohistochemical staining. We found that BMP-2 increased the mobility and invasiveness of tumor cells in vitro whereas Spp24 inhibited both of these processes alone and in the presence of exogenous BMP-2. Phosphorylation of Smad1/5/8 and Smad8 gene expression was enhanced by treatment with BMP-2 but inhibited by treatment with Spp24. Subcutaneous and intratibial tumor models in nude mice demonstrated that BMP-2 promoted OS growth in vivo, while Spp24 significantly inhibited tumor growth. We conclude that the BMP-2/Smad signaling pathway is involved in the pathogenesis of OS growth and that Spp24 inhibits the growth of human OS induced by BMP-2 both in vitro and in vivo. Interruption of Smad signaling and increased apoptosis appear to be the primary mechanisms involved. These results confirm the potential of Spp24 as a therapeutic agent for the treatment of OS and other skeletal tumors.

Moralization and self-control strategy selection.

To manage conflicts between temptation and commitment, people use self-control. The process model of self-control outlines different strategies for managing the onset and experience of temptation. However, little is known about the decision-making factors underlying strategy selection. Across three experiments (N = 317), we tested whether the moral valence of a commitment predicts how people advise attentional self-control strategies. In Experiments 1 and 2, people rated attentional focus strategies as significantly more effective for people tempted to break moral relative to immoral commitments, even when controlling for perceived temptation and trait self-control. Experiment 3 showed that as people perceived commitments to have more positive moral valence, they judged attentional focus strategies to be significantly more effective relative to attentional distraction strategies. Moreover, this effect was partly mediated by perceived differences in motivation. These results indicate that moralization informs decision-making processes related to self-control strategy selection.

A Rapid Review of "Low-Threshold" Psychiatric Medication Prescribing: Considerations for Street Medicine and Beyond.

OBJECTIVE: No widely accepted clinical guidelines, and scant directly applicable pragmatic research, are available to guide the prescription of psychiatric medications in "low-threshold" outpatient settings, such as street outreach, urgent care, and crisis care, as well as walk-in, shelter, and bridge and transition clinics. Providers frequently prescribe medications in these settings without patients' having firm psychiatric diagnoses and without medical records to guide clinical decision making. Persons who receive medications in these settings often seek help voluntarily and intermittently for mental illness symptoms. However, because of structural and individual factors, such patients may not engage in longitudinal outpatient psychiatric care. The authors reviewed the literature on psychiatric medication prescribing in low-threshold settings and offer clinical considerations for such prescribing. METHODS: The authors conducted a rapid literature review (N=2,215 abstracts), which was augmented with up-to-date clinical prescribing literature, the authors' collective clinical experience, and DSM-5 section II diagnostic criteria to provide considerations for prescribing medications in low-threshold settings. RESULTS: For individuals for whom diagnostic uncertainty is prominent, a symptom-based diagnostic and treatment approach may be best suited to weigh the risks and benefits of medication use in low-threshold settings. Practical considerations for treating patients with clinical presentations of psychosis and trauma, as well as mood, anxiety, and substance use disorders, in low-threshold settings are discussed. CONCLUSIONS: An urgent need exists to invest in pragmatic research and guideline development to delineate best-practice prescribing in low-threshold settings.

Mental control and attributions of blame for negligent wrongdoing.

Third-personal judgments of blame are typically sensitive to what an agent knows and desires. However, when people act negligently, they do not know what they are doing and do not desire the outcomes of their negligence. How, then, do people attribute blame for negligent wrongdoing? We propose that people attribute blame for negligent wrongdoing based on perceived mental control, or the degree to which an agent guides their thoughts and attention over time. To acquire information about others' mental control, people self-project their own perceived mental control to anchor third-personal judgments about mental control and concomitant responsibility for negligent wrongdoing. In four experiments (N = 841), we tested whether perceptions of mental control drive third-personal judgments of blame for negligent wrongdoing. Study 1 showed that the ease with which people can counterfactually imagine an individual being non-negligent mediated the relationship between judgments of control and blame. Studies 2a and 2b indicated that perceived mental control has a strong effect on judgments of blame for negligent wrongdoing and that first-personal judgments of mental control are moderately correlated with third-personal judgments of blame for negligent wrongdoing. Finally, we used an autobiographical memory manipulation in Study 3 to make personal episodes of forgetfulness salient. Participants for whom past personal episodes of forgetfulness were made salient judged negligent wrongdoers less harshly compared with a control group for whom past episodes of negligence were not salient. Collectively, these findings suggest that first-personal judgments of mental control drive third-personal judgments of blame for negligent wrongdoing and indicate a novel role for counterfactual thinking in the attribution of responsibility. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neural differences between internal and external episodic counterfactual thoughts.

Episodic counterfactual thoughts (eCFT) consist of imagining alternative outcomes to past experiences. A common sub-class of eCFT-upward eCFT-involves imagining how past negative experiences could have been better, either because one could have done something differently (internal) or because something about the circumstances could have been different (external). Although previous neuroimaging research has shown that the brain's default mode network (DMN) supports upward eCFT, it is unclear how it is differentially recruited during internal versus external upward eCFT. We collected functional magnetic resonance imaging data while participants remembered negative autobiographical memories, generated either internal or external upward eCFT for the memory, and then rated the plausibility, perceived control and difficulty of eCFT generation. Both internal and external eCFT engaged midline regions of cingulate cortex, a central node of the DMN. Most activity differentiating eCFT, however, occurred outside the DMN. External eCFT engaged cuneus, angular gyrus and precuneus, whereas internal eCFT engaged posterior cingulate and precentral gyrus. Angular gyrus and precuneus were additionally sensitive to perceived plausibility of external eCFT, while postcentral gyrus and insula activity scaled with perceived plausibility of internal eCFT. These results highlight the key brain regions that might be involved in cases of maladaptive mental simulations. This article is part of the theme issue 'Thinking about possibilities: mechanisms, ontogeny, functions and phylogeny'.

Matched Molecular Profiling of Cell-Free DNA and Tumor Tissue in Patients With Advanced Clear Cell Renal Cell Carcinoma.

PURPOSE: The clinical utility of cell-free DNA (cfDNA) as a biomarker for advanced clear cell renal cell carcinoma (ccRCC) remains unclear. We evaluated the validity of cfDNA-based genomic profiling in a large cohort of patients with ccRCC with matched next-generation sequencing (NGS) from primary tumor tissues. MATERIALS AND METHODS: We performed paired NGS of tumor DNA and plasma cfDNA using the MSK-IMPACT platform in 110 patients with metastatic ccRCC. Tissues were profiled for variants and copy number alterations with germline comparison. Manual cross-genotyping between cfDNA and tumor tissue was performed. Deep sequencing with a higher sensitivity platform, MSK-ACCESS, was performed on a subset of cfDNA samples. Clinical data and radiographic tumor volumes were assessed to correlate cfDNA yield with treatment response and disease burden. RESULTS: Tumor tissue MSK-IMPACT testing identified 582 genomic alterations (GAs) across the cohort. Using standard thresholds for de novo variant calling in cfDNA, only 24 GAs were found by MSK-IMPACT in cfDNA in 7 of 110 patients (6%). With manual cross-genotyping, 210 GAs were detectable below thresholds in 74 patients (67%). Intrapatient concordance with tumor tissue was limited, including VHL (31.6%), PBRM1 (24.1%), and TP53 (52.9%). cfDNA profiling did not identify 3p loss because of low tumor fractions. Tumor volume was associated with cfDNA allele frequency, and VHL concordance was superior for patients with greater disease burden. CONCLUSION: cfDNA-based NGS profiling yielded low detection rates in this metastatic ccRCC cohort. Concordance with tumor profiling was low, even for truncal mutations such as VHL, and some findings in peripheral blood may represent clonal hematopoiesis. Routine cfDNA panel testing is not supported, and its application in biomarker efforts must account for these limitations.

Association Between High-Need Education-Based Funding and School Suspension Rates for Autistic Students in New Zealand.

Importance: Autistic students often experience poor educational outcomes that have implications for later life, including unemployment, interactions with the criminal justice system, increased risk for substance abuse, and low socioeconomic status. Improving educational outcomes is critical for ensuring that autistic young people can reach their potential. Objective: To quantify differences in suspension rates between autistic and nonautistic students and to assess whether high-need education-based funding for autistic students is associated with reduced rates of school suspension. Design, Setting, and Participants: This national cohort study used linked health and education data from New Zealand's Integrated Data Infrastructure. Data were obtained for students aged 5 to 16 years from January 1 to December 31, 2018, and analyzed July 7, 2021, to January 1, 2022. A novel case identification method was used to identify autistic students. Exposures: High-need education-based funding (Ongoing Resourcing Scheme [ORS]) obtained before 2019. Main Outcomes and Measures: Rates of suspension from school. Crude and adjusted analyses of the association between suspension rates and autism among the full population with adjustment made for sociodemographic characteristics (sex, age, ethnicity, deprivation, and urban or rural profile of residence) were conducted using complete-case, 2-level random intercept logistic multivariable regressions. To assess the association between ORS funding and suspension, analysis was restricted to autistic students. Results: Of the 736 911 students in the study population, 9741 (1.3%) were identified as autistic (median [SD] age, 10 [3.2] years; 7710 [79.1%] boys), and 727 170 (98.7%) as nonautistic (median [SD] age, 10 [3.4] years; 369 777 [50.9%] boys). School suspension was experienced by 504 autistic students (5.2%) and 13 845 nonautistic students (1.9%). After adjustment for demographic characteristics, autistic students had significantly higher odds of suspension than their nonautistic peers (adjusted odds ratio, 2.81; 95% CI, 2.55-3.11). Of the 9741 autistic students, 2895 (29.7%) received high-need education-based (ORS) funding. Suspensions were experienced by 57 autistic students (2.0%) with high-need funding and 447 autistic students (6.5%) without high-need funding. After adjustment for demographic characteristics, co-occurring conditions, and level of disability support need, autistic students with high-need funding had significantly lower odds of suspension than autistic students without high-need funding (adjusted odds ratio, 0.29; 95% CI, 0.21-0.40). Conclusions and Relevance: In this cohort study, the findings of disparities in suspension rates between autistic and nonautistic students underscore the challenges faced in providing inclusive education for all young people, regardless of disability status. This study found that high-need funding was associated with reduced suspension rates among autistic students, suggesting that if appropriate supports are afforded to autistic students, a more inclusive education can be provided.

Fixation, flexibility, and creativity: The dynamics of mind wandering.

The mind-wandering literature is long on results and short on theory. One notable exception is the Dynamic Framework, a theoretical framework that characterizes mind wandering as thoughts that are relatively unconstrained from deliberate and automatic sources, or "freely moving." Critically, this framework makes numerous testable predictions, including (a) a positive association between freely moving thought and ADHD, (b) negative associations between freely moving thought and depression, anxiety, and OCD, and (c) a positive association between freely moving thought and divergent thinking ability. In Study 1, to test these predictions, we measured participants' reports of freely moving thoughts during a cognitive task and assessed divergent thinking and various psychopathological symptoms. Results failed to support any of the Dynamic Framework's predictions. In Study 2, we assessed the predicted relations between freely moving thought and divergent-thinking performance by manipulating thought constraint during a creative-incubation interval that preceded a divergent-thinking task. Here, we found some evidence (albeit very weak) to support the Dynamic Framework's prediction. Finally, in Study 3, we examined the possibility that indexing freely moving thought during a divergent-thinking task would yield the predicted associations but failed to find support for these associations. These results, most of which are at odds with the predictions of the Dynamic Framework, suggest either the need to revise the framework and/or that current methods are inadequate to properly test these predictions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Phase II Study of Neoadjuvant Nivolumab in Patients with Locally Advanced Clear Cell Renal Cell Carcinoma Undergoing Nephrectomy.

Immune checkpoint inhibitor therapy improves survival in patients with metastatic renal cell carcinoma (RCC) but has not been studied well preoperatively in patients with localized disease undergoing nephrectomy. We conducted a single-center study to evaluate the safety and feasibility of neoadjuvant nivolumab in patients undergoing nephrectomy for localized RCC. Eligible patients had a >20% risk of recurrence, as estimated by a preoperative nomogram. Patients received nivolumab every 2 wk for four treatments prior to surgery. The primary endpoints were feasibility, defined as completing at least three treatments without significant surgical delay, and safety, defined as the rate of surgical complications. Treatment effects were assessed by radiomics and immunohistochemistry. A total of 18 patients (11 men; median age 60 yr) with clear cell RCC were enrolled. All received at least one dose of nivolumab and proceeded to nephrectomy without delay; 16/18 patients completed all four doses. Two patients discontinued nivolumab for immune-related adverse events, and four had surgical complications as per the Clavien-Dindo classification. Integrated pathology plus radiomic analysis demonstrated an association between post-treatment immune infiltration and low entropy apparent diffusion coefficient on magnetic resonance imaging. Nivolumab prior to nephrectomy was safe and feasible, without significant surgical delays and with an expected rate of immune-related adverse events. PATIENT SUMMARY: We evaluated the outcomes for patients with localized kidney cancer who received immunotherapy prior to surgery to remove their kidney tumor. In a small group of patients who had cancer confined to the kidney, this approach appeared safe and feasible.

Thought dynamics under task demands: Evaluating the influence of task difficulty on unconstrained thought.

As research on mind wandering has accelerated, the construct's defining features have expanded and researchers have begun to examine different dimensions of mind wandering. Recently, Christoff and colleagues have argued for the importance of investigating a hitherto neglected variety of mind wandering: "unconstrained thought," or, thought that is relatively unguided by executive-control processes. To date, with only a few studies investigating unconstrained thought, little is known about this intriguing type of mind wandering. Across 2 experiments, we examined, for the first time, whether changes in task demand influence rates of constrained versus unconstrained thoughts. In both experiments, participants completed either an easy (0-back) or hard (2-back) task and responded to intermittently presented thought probes that gauged thought constraint throughout the task. In Experiment 1, we found that participants completing the easy task engaged in unconstrained thoughts more frequently than those completing the difficult task. In Experiment 2, we replicated this result and further demonstrated manipulations of unconstrained thought while also measuring task-relatedness (a common dimension of mind wandering). Finally, exploratory analyses showed associations between constrained thought and age, verbal intelligence, and an assessment of flow ('deep effortless concentration'), thereby adding further evidence to indicate a dissociation between task-relatedness and constraint. We discuss the methodological and theoretical applications of our findings to the burgeoning field of research on unconstrained thought. All data, analysis, article, and experiment code can be found at https://osf.io/wr2vk/ (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Impact of Error-Consequence Severity on Cue Processing in Importance-Biased Prospective Memory.

Prospective memory (PM) enables people to remember to complete important tasks in the future. Failing to do so can result in consequences of varying severity. Here, we investigated how PM error-consequence severity impacts the neural processing of relevant cues for triggering PM and the ramification of that processing on the associated prospective task performance. Participants role-played a cafeteria worker serving lunches to fictitious students and had to remember to deliver an alternative lunch to students (as PM cues) who would otherwise experience a moderate or severe aversive reaction. Scalp-recorded, event-related potential (ERP) measures showed that the early-latency frontal positivity, reflecting the perception-based neural responses to previously learned stimuli, did not differ between the severe versus moderate PM cues. In contrast, the longer-latency parietal positivity, thought to reflect full PM cue recognition and post-retrieval processes, was elicited earlier by the severe than the moderate PM cues. This faster instantiation of the parietal positivity to the severe-consequence PM cues was then followed by faster and more accurate behavioral responses. These findings indicate how the relative importance of a PM can be neurally instantiated in the form of enhanced and faster PM-cue recognition and processing and culminate into better PM.

Remodeling of the maternal gut microbiome during pregnancy is shaped by parity.

BACKGROUND: The maternal microbiome has emerged as an important factor in gestational health and outcome and is associated with risk of preterm birth and offspring morbidity. Epidemiological evidence also points to successive pregnancies-referred to as maternal parity-as a risk factor for preterm birth, infant mortality, and impaired neonatal growth. Despite the fact that both the maternal microbiome and parity are linked to maternal-infant health, the impact of parity on the microbiome remains largely unexplored, in part due to the challenges of studying parity in humans. RESULTS: Using synchronized pregnancies and dense longitudinal monitoring of the microbiome in pigs, we describe a microbiome trajectory during pregnancy and determine the extent to which parity modulates this trajectory. We show that the microbiome changes reproducibly during gestation and that this remodeling occurs more rapidly as parity increases. At the time of parturition, parity was linked to the relative abundance of several bacterial species, including Treponema bryantii, Lactobacillus amylovorus, and Lactobacillus reuteri. Strain tracking carried out in 18 maternal-offspring "quadrads"-each consisting of one mother sow and three piglets-linked maternal parity to altered levels of Akkermansia muciniphila, Prevotella stercorea, and Campylobacter coli in the infant gut 10 days after birth. CONCLUSIONS: Collectively, these results identify parity as an important environmental factor that modulates the gut microbiome during pregnancy and highlight the utility of a swine model for investigating the microbiome in maternal-infant health. In addition, our data show that the impact of parity extends beyond the mother and is associated with alterations in the community of bacteria that colonize the offspring gut early in life. The bacterial species we identified as parity-associated in the mother and offspring have been shown to influence host metabolism in other systems, raising the possibility that such changes may influence host nutrient acquisition or utilization. These findings, taken together with our observation that even subtle differences in parity are associated with microbiome changes, underscore the importance of considering parity in the design and analysis of human microbiome studies during pregnancy and in infants. Video abstract.

High Response Rate and Durability Driven by HLA Genetic Diversity in Patients with Kidney Cancer Treated with Lenvatinib and Pembrolizumab.

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1-based combination therapy. IMPLICATIONS: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. EXPERIMENTAL DESIGN: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. RESULTS: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively. CONCLUSIONS: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.