Deterministic reprogramming of neutrophils within tumors.

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.

Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy.

Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN+ extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell-cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN+ CAFs, FOLR2+ macrophages and PLVAP+ endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial-mesenchymal transition (EMT), tumor cell proliferation and recruitment of Treg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN+ CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.

Mitigation of Osteoclast-Mediated Arthritic Bone Remodeling By Short Chain Fatty Acids.

OBJECTIVE: The objective for this study was to evaluate the effects of short chain fatty acids (SCFAs) on arthritic bone remodeling. METHODS: We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA-supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum-level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by transcriptional analysis. RESULTS: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to robust osteoclast differentiation driven by an expansion of osteoclast progenitor cells (OCPs), accompanied by impaired osteoblast development. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow-derived OCPs from diseased mice expressed a higher level of SCFA receptors than those of control mice and that the progenitor cells in the bone marrow of SCFA-treated mice presented a modified transcriptomic landscape, suggesting a direct impact of SCFAs on bone marrow progenitors in the context of osteoporosis. CONCLUSION: We demonstrated how gut microbiota-derived SCFAs can regulate distal pathology (ie, osteoporosis) and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut-bone axis in these disorders.

Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration.

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.

c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome.

Macrophages are an essential part of tissue development and physiology. Perivascular macrophages have been described in tissues and appear to play a role in development and disease processes, although it remains unclear what the key features of these cells are. Here, we identify a subpopulation of perivascular macrophages in several organs, characterized by their dependence on the transcription factor c-MAF and displaying nonconventional macrophage markers including LYVE1, folate receptor 2, and CD38. Conditional deletion of c-MAF in macrophage lineages caused ablation of perivascular macrophages in the brain and altered muscularis macrophages program in the intestine. In the white adipose tissue (WAT), c-MAF­deficient perivascular macrophages displayed an altered gene expression profile, which was linked to an increased vascular branching. Upon feeding high-fat diet (HFD), mice with c-MAF­deficient macrophages showed improved metabolic parameters compared with wild-type mice, including less weight gain, greater glucose tolerance, and reduced inflammatory cell profile in WAT. These results define c-MAF as a central regulator of the perivascular macrophage transcriptional program in vivo and reveal an important role for this tissue-resident macrophage population in the regulation of metabolic syndrome.

Characteristics of Methamphetamine-associated Cardiomyopathy and the Impact of Methamphetamine Use on Cardiac Dysfunction.

Methamphetamine-associated cardiomyopathy (MACM) in an increasingly prevalent disease yet presenting clinical characteristics have not been well studied. We studied consecutive patients with MACM presenting between June 2018 and March 2020 who were interviewed for drug use and medical history. We retrospectively identified an age- and gender-matched cohort of Non-MACM (NMACM) patients and compared clinical characteristics. 140 patients (70 MACM and 70 NMACM) were studied. MACM patients were young (49.6 ± 10 years) and predominantly male (94%). Compared to NMACM, MACM patients were more likely to be Caucasian (21% vs 6%, p = 0.007) and homeless (47% vs 7%, p = 0.001). MACM was characterized by lower left ventricular ejection fraction (EF) (p <0.001) and greater LV end diastolic volume (LVEDV) (p = 0.024). Right ventricular (RV) dilation was present more often (p = s0.001) and was more often severe (p = 0.03). Among MACM cases, half of the cohort developed MACM within 5 years of starting MA (18% within 1 year). There was no apparent relationship between frequency or amount of MA used weekly with time until heart failure onset. Drug use patterns were not clearly related to the degree of LV structural change however there were more consistent, significant associations with RV and right atrial (RA) size parameters. In conclusion, patients with MACM have more severe myocardial impairment with lower EF, greater LVEDV and RV dilation. Drug use patterns do not clearly impact degree of LV structural changes by echocardiography however may be related to RV and RA size.

Microbial-derived antigens and metabolites in spondyloarthritis.

Spondyloarthritis (SpA) is a group of chronic, immune-mediated, inflammatory diseases affecting the bone, synovium, and enthesis. Microbiome, the community of microorganisms that has co-evolved with human hosts, plays a pivotal role in human health and disease. This invisible "essential organ" supplies the host with a myriad of chemicals and molecules. In turn, microbial metabolites can serve as messengers for microbes to communicate with each other and in the cross-talk with host cells. Gut dysbiosis in SpA is associated with altered microbial metabolites, and an accumulated body of research has contributed to the understanding that changes in intestinal microbiota can modulate disease pathogenesis. We review the novel findings from human and animal studies to provide an overview of the contribution of individual microbial metabolites and antigens to SpA.

Variations in Care for Breastfed Infants Admitted to US Children's Hospitals: A Multicenter Survey of Inpatient Providers.

BACKGROUND: Studies have revealed an association between hospitalization of breastfed infants and weaning posthospitalization. It is unknown what steps inpatient providers at children's hospitals are currently taking to support breastfeeding mothers of hospitalized infants, their comfort providing breastfeeding counseling, and what training they receive. METHODS: We conducted a multicenter survey study of pediatric providers who care for infants hospitalized at 3 urban, tertiary-care children's hospitals over a 12-month period. A convenience sample of nurses, residents, and attending physicians agreed to participate. Participants completed a 24-question questionnaire addressing provider practices, comfort with breastfeeding counseling, and previous breastfeeding education. Data were summarized as medians (interquartile ranges) and frequencies (percentages). Kruskal-Wallis and χ2 tests were used to compare between provider types. RESULTS: A total of 361 out of 1097 (33%) eligible providers completed the survey: 133 (21%) nurses, 166 (45%) residents, and 62 (63%) attending physicians. Provider practices varied by provider type. We observed a general trend that providers do not routinely review breastfeeding techniques, directly observe feeds, or use standardized breastfeeding assessment tools. Residents and attending physicians were more likely than nurses to feel comfortable with breastfeeding counseling (P = .02). Residents were more likely than nurses and attending physicians to have received breastfeeding education in the last 3 years (P < .001). CONCLUSIONS: Practices, comfort, and previous education varied by provider type. There was a general pattern that providers do not routinely perform certain practices. Further studies are needed to determine if inpatient provider practices affect weaning posthospitalization and if inpatient quality improvement initiatives will help mothers continue breastfeeding posthospitalization.

Corynebacteria as a cause of pulmonary infection: a case series and literature review.

BACKGROUND: In most cases of community-acquired pneumonia (CAP), an etiologic agent is not determined; the most common report from the microbiological evaluation of sputum cites "normal respiratory flora." Non-diphtheria Corynebacterium spp., a component of this flora, is commonly viewed as a contaminant, but it may be the cause of pneumonia and the frequency with which it causes CAP may be underestimated. CASE PRESENTATIONS: This report present 3 cases of CAP in which Corynebacterium spp. was clearly the predominant isolate; identification was confirmed by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. Two cases were caused by C. propinquum and one by C. striatum. Two patients had a tracheostomy and one was on hemodialysis. Patients who received an appropriate antibiotic responded well. CONCLUSION: When identified as the predominant isolate in sputum from a patient with CAP, Corynebacterium spp. should be considered as a potential cause of the infection. In cases with patients who have compromised airway clearance or who are immunocompromised, microaspiration may be responsible. While some Corynebacterium spp. are suspectible to antibiotics usually prescribed for CAP, others are susceptible only to vancomycin or aminoglycosides. Vancomycin is thus the appropriate empiric antibiotic, pending speciation and susceptibility test results. The number of reported cases with result of antibiotic susceptibility testing, however, remains limited, and further investigation is needed. Non-diphtheria Corynebacterium spp. represent a noteworthy clinical cause of pneumonia. Identification by Gram stain and as a predominant organism on culture demands careful consideration for management.

Unintended adverse consequences of electronic health record introduction to a mature universal HIV screening program.

Early HIV detection and treatment decreases morbidity and mortality and reduces high-risk behaviors. Many Emergency Departments (EDs) have HIV screening programs as recommended by the Centers for Disease Control and Prevention. Recent federal legislation includes incentives for electronic health record (EHR) adoption. Our objective was to analyze the impact of conversion to EHR on a mature ED-based HIV screening program. A retrospective pre- and post-EHR implementation cohort study was conducted in a large urban, academic ED. Medical records were reviewed for HIV screening rates from August 2008 through October 2013. On 1 November 2010, a comprehensive EHR system was implemented throughout the hospital. Before EHR implementation, labs were requested by providers by paper orders with HIV-1/2 automatically pre-selected on every form. This universal ordering protocol was not duplicated in the new EHR; rather it required a provider to manually enter the order. Using a chi-squared test, we compared HIV testing in the 6 months before and after EHR implementation; 55,054 patients presented before, and 50,576 after EHR implementation. Age, sex, race, acuity of presenting condition, and HIV seropositivity rates were similar pre- and post-EHR, and there were no major patient or provider changes during this period. Average HIV testing rate was 37.7% of all ED patients pre-, and 22.3% post-EHR, a 41% decline (p < 0.0001), leading to 167 missed new diagnoses after EHR. The rate of HIV screening in the ED decreased after EHR implementation, and could have been improved with more thoughtful inclusion of existing human processes in its design.