An enhanced IL17 and muted type I interferon nasal epithelial cell state characterizes severe COVID-19 with fungal coinfection.

Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation-in part driven by Candida colonization-and blunted interferon signaling represent a common feature of severe COVID-19 infection. IMPORTANCE: In this paper, we present an analysis suggesting that symptomatic and asymptomatic fungal coinfections can impact patient disease progression during COVID-19 hospitalization. By looking into the presence of other pathogens and their effect on the host immune response during COVID-19 hospitalizations, we aim to offer insight into an underestimated scenario, furthering our current knowledge of determinants of severity that could be considered for future diagnostic and intervention strategies.

Genetic and Functional Diversity Help Explain Pathogenic, Weakly Pathogenic, and Commensal Lifestyles in the Genus Xanthomonas.

The genus Xanthomonas has been primarily studied for pathogenic interactions with plants. However, besides host and tissue-specific pathogenic strains, this genus also comprises nonpathogenic strains isolated from a broad range of hosts, sometimes in association with pathogenic strains, and other environments, including rainwater. Based on their incapacity or limited capacity to cause symptoms on the host of isolation, nonpathogenic xanthomonads can be further characterized as commensal and weakly pathogenic. This study aimed to understand the diversity and evolution of nonpathogenic xanthomonads compared to their pathogenic counterparts based on their cooccurrence and phylogenetic relationship and to identify genomic traits that form the basis of a life history framework that groups xanthomonads by ecological strategies. We sequenced genomes of 83 strains spanning the genus phylogeny and identified eight novel species, indicating unexplored diversity. While some nonpathogenic species have experienced a recent loss of a type III secretion system, specifically the hrp2 cluster, we observed an apparent lack of association of the hrp2 cluster with lifestyles of diverse species. We performed association analysis on a large data set of 337 Xanthomonas strains to explain how xanthomonads may have established association with the plants across the continuum of lifestyles from commensals to weak pathogens to pathogens. Presence of distinct transcriptional regulators, distinct nutrient utilization and assimilation genes, transcriptional regulators, and chemotaxis genes may explain lifestyle-specific adaptations of xanthomonads.

EnvC Homolog Encoded by Xanthomonas citri subsp. citri Is Necessary for Cell Division and Virulence.

Peptidoglycan hydrolases are enzymes responsible for breaking the peptidoglycan present in the bacterial cell wall, facilitating cell growth, cell division and peptidoglycan turnover. Xanthomonas citri subsp. citri (X. citri), the causal agent of citrus canker, encodes an Escherichia coli M23 peptidase EnvC homolog. EnvC is a LytM factor essential for cleaving the septal peptidoglycan, thereby facilitating the separation of daughter cells. In this study, the investigation focused on EnvC contribution to the virulence and cell separation of X. citri. It was observed that disruption of the X. citri envC gene (ΔenvC) led to a reduction in virulence. Upon inoculation into leaves of Rangpur lime (Citrus limonia Osbeck), the X. citri ΔenvC exhibited a delayed onset of citrus canker symptoms compared with the wild-type X. citri. Mutant complementation restored the wild-type phenotype. Sub-cellular localization confirmed that X. citri EnvC is a periplasmic protein. Moreover, the X. citri ΔenvC mutant exhibited elongated cells, indicating a defect in cell division. These findings support the role of EnvC in the regulation of cell wall organization, cell division, and they clarify the role of this peptidase in X. citri virulence.

Preterm Birth Risk and Maternal Nativity, Ethnicity, and Race.

Importance: Immigrant birthing people have lower rates of preterm birth compared with their US-born counterparts. This advantage and associated racial and ethnic disparities across the gestational age spectrum have not been examined nationally. Objective: To examine associations of maternal nativity, ethnicity, and race with preterm birth. Design, Setting, and Participants: This cohort study used birth certificates from the National Vital Statistics System to analyze in-hospital liveborn singleton births in the US between January 1, 2009, and December 31, 2018. Data were analyzed from January to June 2023. Exposure: Mutually exclusive nativity, ethnicity, and race subgroups were constructed using nativity (defined as US-born or non-US-born), ethnicity (defined as Hispanic or non-Hispanic), and race (defined as American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific Islander, White, or other [individuals who selected other race or more than 1 race]). Main Outcomes and Measures: The primary outcome of interest was preterm birth. Modified Poisson and multinomial logistic regression models quantified relative risk (RR) of preterm birth overall (<37 weeks' gestation) and by gestational category (late preterm: 34-36 weeks' gestation; moderately preterm: 29-33 weeks' gestation; and extremely preterm: <29 weeks' gestation) for each maternal nativity, ethnicity, and race subgroup compared with the largest group, US-born non-Hispanic White (hereafter, White) birthing people. The RR of preterm birth overall and by category was also measured within each racial and ethnic group by nativity. Models were adjusted for maternal demographic and medical covariates, birth year, and birth state. Results: A total of 34 468 901 singleton live births of birthing people were analyzed, with a mean (SD) age at delivery of 28 (6) years. All nativity, ethnicity, and race subgroups had an increased adjusted risk of preterm birth compared with US-born White birthing people except for non-US-born White (adjusted RR, 0.85; 95% CI, 0.84-0.86) and Hispanic (adjusted RR, 0.98; 95% CI, 0.97-0.98) birthing people. All racially and ethnically minoritized groups had increased adjusted risks of extremely preterm birth compared with US-born White birthing people. Non-US-born individuals had a decreased risk of preterm birth within each subgroup except non-Hispanic Native Hawaiian or Other Pacific Islander individuals, in which immigrants had significantly increased risk of overall (adjusted RR, 1.07; 95% CI, 1.01-1.14), moderately (adjusted RR, 1.10; 95% CI, 0.92-1.30), and late (adjusted RR, 1.11; 95% CI, 1.02-1.22) preterm birth than their US-born counterparts. Conclusions and Relevance: Results of this cohort study suggest heterogeneity of preterm birth across maternal nativity, ethnicity, and race and gestational age categories. Understanding these patterns could aid the design of targeted preterm birth interventions and policies, especially for birthing people typically underrepresented in research.

Child Health and the Neonatal-Perinatal Medicine Workforce: 2020-2040.

In 2022, 3.7 million children were born in the United States, of whom ∼600 000 received care from a neonatologist. The dramatic growth of the neonatal-perinatal medicine (NPM) workforce from 375 in 1975 to 5250 in 2022 has paralleled exploding clinical demand. As newborn medicine continues to push the limits of gestational viability and medical complexity, the NPM workforce must advance in numbers, clinical capability, scientific discovery, and leadership. This article, as part of an American Board of Pediatrics Foundation-sponsored supplement that is designed to project the future of the pediatric subspecialty workforce, features a discussion of the NPM workforce's history and current status, factors that have shaped its current profile, and some plausible scenarios of the workforce's needs and configuration in the future. In the article, we use an analytical model that forecasts the growth trajectory of the neonatologist workforce from 2020 through 2040. The model uses recent data on the number of neonatologists and clinical work equivalents per 100 000 children and projects future workforce supply under several theoretical scenarios created by modifying key baseline parameters. The predictions of this model confirm the need for a greater sustainable clinical capacity of the NPM workforce. Several future trends indicate that there may be geographic shortages of neonatologists, similar to expected shortages in other pediatric subspecialties. We do not address what an appropriate target for workforce size should be with the model or this article because the current and projected geographic variability in the NPM workforce and risk-appropriate care suggest that a uniform answer is unlikely.

Unexpected Diversity of Pseudomonads Associated with Bacterial Leaf Spot of Cucurbits in the Southeastern United States.

Bacterial leaf spot of cucurbits (BLS) is an emerging disease in the southeastern United States that is capable of causing widespread outbreaks under conducive conditions. Historically attributed solely to the bacterium Pseudomonas syringae pv. lachrymans, recent studies have identified additional P. syringae pathovars as causal agents of the disease. To further investigate the identity and diversity of P. syringae strains associated with BLS in the southeastern United States, 47 bacterial isolates were recovered from symptomatic cucurbits from Florida, Alabama, and Georgia. Strains were characterized using the LOPAT testing scheme, fluorescence, and pathogenicity to watermelon and squash seedlings. Thirty-eight fluorescent isolates underwent whole-genome sequencing and were further characterized with 16S rRNA, four gene multilocus sequence analysis (MLSA) phylogeny, and average nucleotide identity analysis. Thirty-four isolates were identified as members of the P. syringae species complex, including P. syringae sensu stricto (12), P. alliivorans (12), P. capsici (nine), and P. viridiflava (one). An additional four isolates were found to belong to the Pseudomonas genus outside of the syringae species complex, though they did not share 95% or greater average nucleotide identity to any validly published species and are believed to belong to three novel Pseudomonas species. These results reveal an unpredicted level of diversity of Pseudomonas strains associated with BLS in the region and show the benefits of whole-genome sequencing for strain identification. Identification of P. capsici, which is capable of causing disease at higher temperatures than P. syringae, as a causal agent of BLS may also affect management strategies in the future.

Transcriptome profiling of type VI secretion system core gene tssM mutant of Xanthomonas perforans highlights regulators controlling diverse functions ranging from virulence to metabolism.

IMPORTANCE: T6SS has received attention due to its significance in mediating interorganismal competition through contact-dependent release of effector molecules into prokaryotic and eukaryotic cells. Reverse-genetic studies have indicated the role of T6SS in virulence in a variety of plant pathogenic bacteria, including the one studied here, Xanthomonas. However, it is not clear whether such effect on virulence is merely due to a shift in the microbiome-mediated protection or if T6SS is involved in a complex virulence regulatory network. In this study, we conducted in vitro transcriptome profiling in minimal medium to decipher the signaling pathways regulated by tssM-i3* in X. perforans AL65. We show that TssM-i3* regulates the expression of a suite of genes associated with virulence and metabolism either directly or indirectly by altering the transcription of several regulators. These findings further expand our knowledge on the intricate molecular circuits regulated by T6SS in phytopathogenic bacteria.

IL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury.

The high mortality rates of acute lung injury and acute respiratory distress syndrome challenge the field to identify biomarkers and factors that can be exploited for therapeutic approaches. IL-22 is a cytokine that has antibacterial and reparative properties in the lung. However, it also can exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). This study showed the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2-/-) in the bleomycin model of acute lung injury/acute respiratory distress syndrome. Il22ra2-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared with wild-type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A+ γδ T cells to the lung. Interestingly, this inflammation was initiated in part by the noncanonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. This study further showed that IL-22 receptor alpha-1+ macrophages can be stimulated by IL-22 to produce a number of IL-17-inducing cytokines such as IL-1ß, IL-6, and transforming growth factor-ß1. Together, the results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.

Enhanced production of eicosanoids in plasma and activation of DNA damage pathways in PBMCs are correlated with the severity of ancestral COVID-19 infection.

Background: Many questions remain unanswered regarding the implication of lipid metabolites in severe SARS-CoV-2 infections. By re-analyzed sequencing data from the nasopharynx of a previously published cohort, we found that alox genes, involved in eicosanoid synthesis, were up-regulated in high WHO score patients, especially in goblet cells. Herein, we aimed to further understand the roles played by eicosanoids during severe SARS-CoV-2 infection. Methods and findings: We performed a total fatty acid panel on plasma and bulk RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) collected from 10 infected and 10 uninfected patients. Univariate comparison of lipid metabolites revealed that lipid metabolites were increased in SARS-CoV-2 patients including the lipid mediators Arachidonic Acid (AA) and Eicosapentaenoic Acid (EPA). AA, EPA and the fatty acids Docosahexaenoic acid (DHA) and Docosapentaenoic acid (DPA), were positively correlated to WHO disease severity score. Transcriptomic analysis demonstrated that COVID-19 patients can be segregated based on WHO scores. Ontology, KEGG and Reactome analysis identified pathways enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells, interleukin signaling and, cell cycling pathways. Conclusions: Our study offers an association between nasopharynx mucosa eicosanoid genes expression, specific serum inflammatory lipids and, subsequent DNA damage pathways activation in PBMCs to severity of COVID-19 infection.

County-Level Maternal Vulnerability and Preterm Birth in the US.

Importance: Appreciation for the effects of neighborhood conditions and community factors on perinatal health is increasing. However, community-level indices specific to maternal health and associations with preterm birth (PTB) have not been assessed. Objective: To examine the association of the Maternal Vulnerability Index (MVI), a novel county-level index designed to quantify maternal vulnerability to adverse health outcomes, with PTB. Design, Setting, and Participants: This retrospective cohort study used US Vital Statistics data from January 1 to December 31, 2018. Participants included 3 659 099 singleton births at 22 plus 0/7 to 44 plus 6/7 weeks of gestation born in the US. Analyses were conducted from December 1, 2021, through March 31, 2023. Exposure: The MVI, a composite measure of 43 area-level indicators, categorized into 6 themes reflecting physical, social, and health care landscapes. Overall MVI and theme were stratified by quintile (very low to very high) by maternal county of residence. Main Outcomes and Measures: The primary outcome was PTB (gestational age <37 weeks). Secondary outcomes were PTB categories: extreme (gestational age ≤28 weeks), very (gestational age 29-31 weeks), moderate (gestational age 32-33 weeks), and late (gestational age 34-36 weeks). Multivariable logistic regression quantified associations of MVI, overall and by theme, with PTB, overall and by PTB category. Results: Among 3 659 099 births, 298 847 (8.2%) were preterm (male, 51.1%; female, 48.9%). Maternal race and ethnicity included 0.8% American Indian or Alaska Native, 6.8% Asian or Pacific Islander, 23.6% Hispanic, 14.5% non-Hispanic Black, 52.1% non-Hispanic White, and 2.2% with more than 1 race. Compared with full-term births, MVI was higher for PTBs across all themes. Very high MVI was associated with increased PTB in unadjusted (odds ratio [OR], 1.50 [95% CI, 1.45-1.56]) and adjusted (OR, 1.07 [95% CI, 1.01-1.13]) analyses. In adjusted analyses of PTB categories, MVI had the largest association with extreme PTB (adjusted OR, 1.18 [95% CI, 1.07-1.29]). Higher MVI in the themes of physical health, mental health and substance abuse, and general health care remained associated with PTB overall in adjusted models. While the physical health and socioeconomic determinant themes were associated with extreme PTB, physical health, mental health and substance abuse, and general health care themes were associated with late PTB. Conclusions and Relevance: The findings of this cohort study suggest that MVI was associated with PTB even after adjustment for individual-level confounders. The MVI is a useful measure for county-level PTB risk that may have policy implications for counties working to lower preterm rates and improve perinatal outcomes.

High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet.

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.

Recommendations to improve recruitment and retention of underrepresented in medicine trainees in neonatal-perinatal medicine.

Physicians who identify as Black, Latinx, American Indian, Pacific Islander, and certain Asian subgroups represent racial and ethnic populations that are underrepresented in medicine (URM). While the proportion of URM pediatric trainees has remained unchanged, that of Neonatal-Perinatal Medicine (NPM) fellows has decreased. Informed by the medical literature and our lived experiences, we compiled and developed a list of recommendations to support NPM fellowship programs in the recruitment, retention, and promotion of URM trainees. We describe ten recommendations that address 1) creating a culture of inclusivity and psychological safety, 2) the critical appraisal of recruitment practices and climate, and 3) an inclusive and holistic fellowship application process. The first two themes lay the foundation, while the final theme spotlights our recommendations for URM recruitment. Each recommendation is a step towards improvement in recruitment and inclusion at a program.

Association of Primary Language with Provision of Mother's Milk Among Very-Low-Birthweight Infants in Massachusetts.

Background: Racial/ethnic inequities in mother's milk provision for hospitalized preterm infants persist. The extent to which primary language contributes to these racial/ethnic inequities is unknown. Objective: Examine associations of maternal race/ethnicity and primary language with (1) any/exclusive mother's milk at hospital discharge and (2) the time to cessation of mother's milk provision during the hospitalization. Methods: We examined 652 mother/very-low-birthweight (VLBW) infant dyads at 9 level 3 neonatal intensive care units in Massachusetts from January 2017 to December 2018. We abstracted maternal race/ethnicity and language from medical records, and examined English and non-English-speaking non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic mothers of any race. We examined associations of race/ethnicity and language with (1) any/exclusive mother's milk at discharge (yes/no) using mixed-effects logistic regression and (2) cessation of mother's milk during the hospitalization using cox proportional hazard models, adjusting for gestational age, birthweight, and accounting for clustering by plurality and hospital. Results: Fifty-three percent were English-speaking NHW, 22% English-speaking NHB, 4% non-English-speaking NHB, 14% English-speaking Hispanic, and 7% non-English-speaking Hispanic. Compared with English-speaking NHW, NHB mothers (English adjusted odds ratio [aOR] 0.28 [0.17, 0.44]; and non-English-speaking aOR 0.55 [0.19, 0.98]), and non-English-speaking Hispanic mothers (aOR 0.29 [0.21, 0.87]) had lower odds of any mother's milk at discharge. In time-to-event analyses, non-English-speaking Hispanic (adjusted hazard ratio [aHR] 4.37 [2.20, 6.02]) and English-speaking NHB mothers (aHR 3.91 [1.41, 7.61] had the earliest cessation of mother's milk provision. Conclusion: In Massachusetts, maternal primary language was associated with inequities in mother's milk provision for VLBW infants with a differential effect for NHB and Hispanic mothers.

Impact of COVID-19 on Infants followed after Discharge from the Neonatal Intensive Care Unit Using a Telemedicine Model.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) continues to have a profound impact on infant health care and health outcomes. In this study, we aimed to characterize the social impact of the first COVID-19 lockdown on families in a neonatal follow-up program (NFP). Given the ongoing increased use of telehealth across the medicine, we also evaluated for patient-level differences in virtual visit rates to identify patients at risk of follow-up challenges. STUDY DESIGN: To assess the impact of virtual health care utilization, we conducted a retrospective cohort study to describe challenges associated with telemedicine use in this vulnerable patient population during our telemedicine epoch (March 13, 2020-July 31, 2020). We also looked for patient-level factors associated with attending NFP visits as scheduled. Finally, we summarized caregiver responses to a COVID-19 Obstacles Assessment Survey and assessed for racial disparities in these responses. RESULTS: When comparing patients who completed their virtual visit to those who did not, we found no differences by infants' sex, birthweight, gestational age at birth, or caregiver self-reported race and ethnicity. However, infants whose visits did not occur were more often discharged with equipment or covered by public insurance. Nine percent of families reported food insecurity. CONCLUSION: During the initial COVID-19 lockdown, families with infants discharged from a neonatal intensive care unit (NICU) faced significant obstacles caring for their infants and attending scheduled follow-up visits. Infants in families with lower socioeconomic status or with increased medical complexity faced increased challenges in attending virtual follow-up visits during this epoch. Given the ongoing reliance on telemedicine in health care and the need to better prepare for future epidemics/pandemics, this study offers critical information that can assist neonatal teams in bolstering transitions to home and creating stronger safety nets for their patients after discharge. KEY POINTS: · Telemedicine works well for high-risk neonatal populations.. · Infant medical complexity may be a risk factor for challenges attending neonatal follow-up visits.. · NICUs should work to prevent food insecurity postdischarge..

Mycobacterium bovis bacille Calmette-Guerin-derived extracellular vesicles as an alternative to live BCG immunotherapy.

For over 40 years, the gold standard treatment for non-muscular invasive bladder cancer (NMIBC) has been repeated administration of Mycobacterium bovis bacille Calmette-Guerin (BCG). Upon administration, BCG initiates a cascade of immunological events that lead to the recruitment of immune cells to the bladder that eliminates NMIBC cells in a multi-mechanistic, yet incompletely defined manner. Despite its effectiveness, live BCG immunotherapy is often impacted by limited supply and availability and can cause rare but serious side effects. Bacterial extracellular vesicles (EV) are nanoparticles secreted by live bacteria. EVs are composed of multiple surface proteins, sugars, and lipid that can elicit cellular responses and host recognition similar to live bacteria. In this study, we sought to evaluate the cellular responses of epithelial bladder cancer cells (BCC) to BCG EVs and live BCG. We compared the effect of each treatment on BCC cytokine production, cellular viability and apoptosis. Our data suggest that BCG EVs are as effective as live BCG in eliciting cytokine responses and halting cancer cell growth by, in part, inducing apoptosis. These results indicate that BCG EVs warrant investigation as an alternative to live BCG for NMIBC immunotherapy.

Including measures of chronic kidney disease to improve cardiovascular risk prediction by SCORE2 and SCORE2-OP.

AIMS: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach. METHODS: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. RESULTS: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. CONCLUSION: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Natural language processing approach to model the secretion signal of type III effectors.

Type III effectors are proteins injected by Gram-negative bacteria into eukaryotic hosts. In many plant and animal pathogens, these effectors manipulate host cellular processes to the benefit of the bacteria. Type III effectors are secreted by a type III secretion system that must "classify" each bacterial protein into one of two categories, either the protein should be translocated or not. It was previously shown that type III effectors have a secretion signal within their N-terminus, however, despite numerous efforts, the exact biochemical identity of this secretion signal is generally unknown. Computational characterization of the secretion signal is important for the identification of novel effectors and for better understanding the molecular translocation mechanism. In this work we developed novel machine-learning algorithms for characterizing the secretion signal in both plant and animal pathogens. Specifically, we represented each protein as a vector in high-dimensional space using Facebook's protein language model. Classification algorithms were next used to separate effectors from non-effector proteins. We subsequently curated a benchmark dataset of hundreds of effectors and thousands of non-effector proteins. We showed that on this curated dataset, our novel approach yielded substantially better classification accuracy compared to previously developed methodologies. We have also tested the hypothesis that plant and animal pathogen effectors are characterized by different secretion signals. Finally, we integrated the novel approach in Effectidor, a web-server for predicting type III effector proteins, leading to a more accurate classification of effectors from non-effectors.

Plugging the Leaky Pipeline: The Role of Peer Mentorship for Increasing Diversity.

I arrived to my shift early, nervous about caring for critically ill patients as a first-year fellow. I sat in the workroom alone, paralyzed, not sure how to preround despite being months into fellowship. The senior fellow appeared minutes before sign-out; fresh, knowledgeable, and calm, despite her busy night and lack of sleep. She asked me how I was doing. With tears in my eyes, my emotions poured out. I explained that I felt lost, unsure of myself, my place, and my knowledge. For the first time, I confessed out loud, "I don't think I'm supposed to be here. I have no idea what I'm doing." I could trust her in a way I couldn't trust others. She was like me: othered by her identity, minoritized by society. Though different from my own, her identity allowed her to understand my own experiences. We were different from one another and we were also the same. Unlike the senior faculty, it was safe to talk to her. And, unlike my other cofellows, there was a kinship between us in our otherness. She looked at me, closed the door, and shared words of strength that I needed to hear. I belonged. I was more than enough. She shared that the pressure I was experiencing was common among systematically minoritized individuals; she too had felt it before. Sitting with her, I was finally seen, supported, and comforted. As a peer mentor from a minoritized background, she provided a sense of security and belonging that had not been provided in my training and was distinct from the support of senior faculty.

Racial and ethnic disparities in outcomes after NICU discharge: An equity-focused model.

Significant racial and ethnic disparities exist in birth outcomes and complications related to prematurity. However, little is known about racial and ethnic variations in health outcomes after premature infants are discharged from the neonatal intensive care unit (NICU). We propose a novel, equity-focused conceptual model to guide future evaluations of post-discharge outcomes that centers on a multi-dimensional, comprehensive view of health, which we call thriving. We then apply this model to existing literature on post-discharge inequities, revealing a need for rigorous analysis of drivers and strength-based, longitudinal outcomes.