Training Robust T1-Weighted Magnetic Resonance Imaging Liver Segmentation Models Using Ensembles of Datasets with Different Contrast Protocols and Liver Disease Etiologies.

Image segmentation of the liver is an important step in several treatments for liver cancer. However, manual segmentation at a large scale is not practical, leading to increasing reliance on deep learning models to automatically segment the liver. This manuscript develops a deep learning model to segment the liver on T1w MR images. We sought to determine the best architecture by training, validating, and testing three different deep learning architectures using a total of 819 T1w MR images gathered from six different datasets, both publicly and internally available. Our experiments compared each architecture's testing performance when trained on data from the same dataset via 5-fold cross validation to its testing performance when trained on all other datasets. Models trained using nnUNet achieved mean Dice-Sorensen similarity coefficients > 90% when tested on each of the six datasets individually. The performance of these models suggests that an nnUNet liver segmentation model trained on a large and diverse collection of T1w MR images would be robust to potential changes in contrast protocol and disease etiology.

CD112 Supports Lymphatic Migration of Human Dermal Dendritic Cells.

Dendritic cell (DC) migration from peripheral tissues via afferent lymphatic vessels to draining lymph nodes (dLNs) is important for the organism's immune regulation and immune protection. Several lymphatic endothelial cell (LEC)-expressed adhesion molecules have thus far been found to support transmigration and movement within the lymphatic vasculature. In this study, we investigated the contribution of CD112, an adhesion molecule that we recently found to be highly expressed in murine LECs, to this process. Performing in vitro assays in the murine system, we found that transmigration of bone marrow-derived dendritic cells (BM-DCs) across or adhesion to murine LEC monolayers was reduced when CD112 was absent on LECs, DCs, or both cell types, suggesting the involvement of homophilic CD112-CD112 interactions. While CD112 was highly expressed in murine dermal LECs, CD112 levels were low in endogenous murine dermal DCs and BM-DCs. This might explain why we observed no defect in the in vivo lymphatic migration of adoptively transferred BM-DCs or endogenous DCs from the skin to dLNs. Compared to murine DCs, human monocyte-derived DCs expressed higher CD112 levels, and their migration across human CD112-expressing LECs was significantly reduced upon CD112 blockade. CD112 expression was also readily detected in endogenous human dermal DCs and LECs by flow cytometry and immunofluorescence. Upon incubating human skin punch biopsies in the presence of CD112-blocking antibodies, DC emigration from the tissue into the culture medium was significantly reduced, indicating impaired lymphatic migration. Overall, our data reveal a contribution of CD112 to human DC migration.

In Silico Analysis of Genes Associated with the Pathogenesis of Odontogenic Keratocyst.

Odontogenic keratocyst (OK) is a benign intraosseous cystic lesion characterized by a parakeratinized stratified squamous epithelial lining with palisade basal cells. It represents 10-12% of odontogenic cysts. The changes in its classification as a tumor or cyst have increased interest in its pathogenesis. OBJECTIVE: Identify key genes in the pathogenesis of sporadic OK through in silico analysis. MATERIALS AND METHODS: The GSE38494 technical sheet on OK was analyzed using GEOR2. Their functional and canonical signaling pathways were enriched in the NIH-DAVID bioinformatic platform. The protein-protein interaction network was constructed by STRING and analyzed with Cytoscape-MCODE software v 3.8.2 (score > 4). Post-enrichment analysis was performed by Cytoscape-ClueGO. RESULTS: A total of 768 differentially expressed genes (DEG) with a fold change (FC) greater than 2 and 469 DEG with an FC less than 2 were identified. In the post-enrichment analysis of upregulated genes, significance was observed in criteria related to the organization of the extracellular matrix, collagen fibers, and endodermal differentiation, while the downregulated genes were related to defensive response mechanisms against viruses and interferon-gamma activation. CONCLUSIONS: Our in silico analysis showed a significant relationship with mechanisms of extracellular matrix organization, interferon-gamma activation, and response to viral infections, which must be validated through molecular assays.

Heterogeneity in intrahepatic macrophage populations and druggable target expression in patients with steatotic liver disease-related fibrosis.

Background & Aims: Clinical trials for reducing fibrosis in steatotic liver disease (SLD) have targeted macrophages with variable results. We evaluated intrahepatic macrophages in patients with SLD to determine if activity scores or fibrosis stages influenced phenotypes and expression of druggable targets, such as CCR2 and galectin-3. Methods: Liver biopsies from controls or patients with minimal or advanced fibrosis were subject to gene expression analysis using nCounter to determine differences in macrophage-related genes (n = 30). To investigate variability among individual patients, we compared additional biopsies by staining them with multiplex antibody panels (CD68/CD14/CD16/CD163/Mac387 or CD163/CCR2/galectin-3/Mac387) followed by spectral imaging and spatial analysis. Algorithms that utilize deep learning/artificial intelligence were applied to create cell cluster plots, phenotype profile maps, and to determine levels of protein expression (n = 34). Results: Several genes known to be pro-fibrotic (e.g. CD206, TREM2, CD163, and ARG1) showed either no significant differences or significantly decreased with advanced fibrosis. Although marked variability in gene expression was observed in individual patients with cirrhosis, several druggable targets and their ligands (e.g. CCR2, CCR5, CCL2, CCL5, and LGALS3) were significantly increased when compared to patients with minimal fibrosis. Antibody panels identified populations that were significantly increased (e.g. Mac387+), decreased (e.g. CD14+), or enriched (e.g. interactions of Mac387) in patients that had progression of disease or advanced fibrosis. Despite heterogeneity in patients with SLD, several macrophage phenotypes and druggable targets showed a positive correlation with increasing NAFLD activity scores and fibrosis stages. Conclusions: Patients with SLD have markedly varied macrophage- and druggable target-related gene and protein expression in their livers. Several patients had relatively high expression, while others were like controls. Overall, patients with more advanced disease had significantly higher expression of CCR2 and galectin-3 at both the gene and protein levels. Impact and implications: Appreciating individual differences within the hepatic microenvironment of patients with SLD may be paramount to developing effective treatments. These results may explain why such a small percentage of patients have responded to macrophage-targeting therapies and provide additional support for precision medicine-guided treatment of chronic liver diseases.

Disease activity is associated with changes in the innate immune function in patients with systemic lupus erythematosus.

OBJECTIVE: To address the relationship between systemic lupus erythematosus (SLE) disease activity and the functional parameters of the innate immunity. METHODS: We evaluated a cohort of 26 adult SLE patients and 10 sex and age-paired healthy donors. When the patients had a disease flare (baseline) and when they achieve clinical response (follow-up), we assessed the systemic lupus erythematosus disease activity index 2 K (SLEDAI 2 K) and the following parameters with flow cytometry and confocal microscopy: monocyte subsets, their expression of TLR2, phagocytic monocytes and neutrophils using the pHrodo Red E. coli BioParticles, the respiratory burst with 123-dihydrorhodamine in neutrophils, and the spontaneous and lipopolysaccharide (LPS)-induced production of neutrophil extracellular traps (NETs). We used the Wilcoxon test to compare the paired medians with interquartile range (IQR) and the Mann-Whitney U test for independent medians. To assess the effect of prednisone and SLEDAI 2 K on the mentioned parameters, we applied a generalized mixed linear model. RESULTS: Twenty-three patients (88.4%) were women. The SLEDAI 2 K was higher at baseline 8 (6-14) in comparison to that at follow-up (6 (4-8), P = 0.028). At baseline, SLE patients had a decreased percentage of intermediate monocytes, a higher expression of TLR2 in total monocytes, increased phagocytosis in monocytes and neutrophils, a decreased respiratory burst intensity, and an increased production of NETs. In the mix model, the SLEDAI 2 K was the main factor influencing these functional innate immune parameters. CONCLUSION: Disease activity regulates the innate immune function in SLE which may contribute to the clinical features and infection predisposition. Key points • This is the first cohort study addressing the effect of disease activity and prednisone use on the innate immune function of lupus patients. • Our results show that the disease activity is a key regulator of the respiratory burst, phagocytosis, and the production of neutrophil extracellular traps. • Also, we observed a differential proportion of monocyte subsets according to SLE disease activity. • We consider that our manuscript contributes to the evidence addressing the intrinsic immune abnormalities of patients with SLE regardless of the use of immunosuppressants and set the bases for new research work considering the disease activity as an element to decide the prescription and duration of antibiotic prophylaxis in SLE patients, which is of interest to all rheumatologists.

Cellular and Molecular Mechanisms of Liver Fibrosis in Patients with NAFLD.

The expression of immune- and cancer-related genes was measured in liver biopsies from 107 NAFLD patients. The strongest difference in overall gene expression was between liver fibrosis stages F3 and F4, with 162 cirrhosis-associated genes identified. Strong correlations with fibrosis progression from F1 to F4 were observed for 91 genes, including CCL21, CCL2, CXCL6, and CCL19. In addition, the expression of 21 genes was associated with fast progression to F3/F4 in an independent group of eight NAFLD patients. These included the four chemokines, SPP1, HAMP, CXCL2, and IL-8. A six-gene signature including SOX9, THY-1, and CD3D had the highest performance detecting the progressors among F1/F2 NAFLD patients. We also characterized immune cell changes using multiplex immunofluorescence platforms. Fibrotic areas were strongly enriched in CD3+ T cells compared to CD68+ macrophages. While the number of CD68+ macrophages increased with fibrosis severity, the increase in CD3+ T-cell density was more substantial and progressive from F1 to F4. The strongest correlation with fibrosis progression was observed for CD3+CD45R0+ memory T cells, while the most significant increase in density between F1/F2 and F3/F4 was for CD3+CD45RO+FOXP3+CD8- and CD3+CD45RO-FOXP3+CD8- regulatory T cells. A specific increase in the density of CD68+CD11b+ Kupffer cells with liver fibrosis progression was also observed.

Patients with fibrosis from non-alcoholic steatohepatitis have heterogeneous intrahepatic macrophages and therapeutic targets.

Background and Aims: In clinical trials for reducing fibrosis in NASH patients, therapeutics that target macrophages have had variable results. We evaluated intrahepatic macrophages in patients with non-alcoholic steatohepatitis to determine if fibrosis influenced phenotypes and expression of CCR2 and Galectin-3. Approach & Results: We used nCounter to analyze liver biopsies from well-matched patients with minimal (n=12) or advanced (n=12) fibrosis to determine which macrophage-related genes would be significantly different. Known therapy targets (e.g., CCR2 and Galectin-3) were significantly increased in patients with cirrhosis.However, several genes (e.g., CD68, CD16, and CD14) did not show significant differences, and CD163, a marker of pro-fibrotic macrophages was significantly decreased with cirrhosis. Next, we analyzed patients with minimal (n=6) or advanced fibrosis (n=5) using approaches that preserved hepatic architecture by multiplex-staining with anti-CD68, Mac387, CD163, CD14, and CD16. Spectral data were analyzed using deep learning/artificial intelligence to determine percentages and spatial relationships. This approach showed patients with advanced fibrosis had increased CD68+, CD16+, Mac387+, CD163+, and CD16+CD163+ populations. Interaction of CD68+ and Mac387+ populations was significantly increased in patients with cirrhosis and enrichment of these same phenotypes in individuals with minimal fibrosis correlated with poor outcomes. Evaluation of a final set of patients (n=4) also showed heterogenous expression of CD163, CCR2, Galectin-3, and Mac387, and significant differences were not dependent on fibrosis stage or NAFLD activity. Conclusions: Approaches that leave hepatic architecture intact, like multispectral imaging, may be paramount to developing effective treatments for NASH. In addition, understanding individual differences in patients may be required for optimal responses to macrophage-targeting therapies.

Spatial molecular and cellular determinants of STAT3 activation in liver fibrosis progression in non-alcoholic fatty liver disease.

Background & Aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Individuals with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in individuals with NASH. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice. Methods: Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and transcriptomic changes in fibrotic NAFLD livers.Results: pSTAT3 scores in non-hepatocyte areas progressively increased with fibrosis severity (r = 0.53, p <0.001). Correlation analyses between pSTAT3 scores and expression of 1,540 immune- and cancer-associated genes revealed a large effect of STAT3 activation on gene expression changes in non-hepatocyte areas and confirmed a major role for STAT3 activation in fibrogenesis. Digital spatial transcriptomic profiling was also performed on 13 regions selected in hepatocyte and non-hepatocyte areas from four NAFLD liver biopsies with advanced fibrosis, using a customized panel of markers including pSTAT3, PanCK+CK8/18, and CD45. The regions were further segmented based on positive or negative pSTAT3 staining. Cell deconvolution analysis revealed that activated STAT3 was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells. Regression of liver fibrosis upon STAT3 inhibition in mice with NASH resulted in a reduction of HPCs, demonstrating a direct role for STAT3 in HPC expansion. Conclusion: Increased understanding of the spatial dependence of STAT3 signaling in NASH and liver fibrosis progression could lead to novel targeted treatment approaches. Impact and implications: Advanced liver fibrosis is the main determinant of mortality in patients with NASH. This study showed using liver biopsies from 133 patients with NAFLD, that STAT3 activation in non-hepatocyte areas is strongly associated with fibrosis severity, inflammation, and progression to NASH. STAT3 activation was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells (SECs), as determined by innovative technologies interrogating the spatial distribution of pSTAT3. Finally, STAT3 inhibition in mice resulted in reduced liver fibrosis and depletion of HPCs, suggesting that STAT3 activation in HPCs contributes to their expansion and fibrogenesis in NAFLD.

Challenges accessing contraceptive care and interest in over-the-counter oral contraceptive pill use among Black, Indigenous, and people of color: An online cross-sectional survey.

OBJECTIVE: To examine challenges accessing contraception in the past year and their association with interest in using an over the counter (OTC) oral contraceptive pill (OCP) among Black, Indigenous, and people of color (BIPOC) in the United States. STUDY DESIGN: From May 2021 to March 2022, a collaborative research team conducted a cross-sectional online survey using convenience sampling to recruit people who identify as Asian American, Native Hawaiian, or Pacific Islander, Black or African American, Indigenous, or Latina/Latinx and used or wanted to use a contraceptive method in the past year. Respondents were recruited through reproductive justice and community-based organizations. RESULTS: Among 727 respondents, 45% reported experiencing at least one challenge accessing contraception in the past year of which 37% reported a logistical challenge, and 20% reported an interpersonal challenge. Sixty-seven percent of respondents said they were likely to use an OTC OCP. Respondents who reported experiencing at least one challenge accessing contraception in the past year were more likely to say they would use an OTC OCP. Fifty-seven percent of respondents who were not using a contraceptive method in the past year reported they were likely to use an OTC OCP. CONCLUSION: Among people in this study, interest in an OTC OCP is high, particularly among those who have faced challenges accessing contraception, and among those who are not currently using a contraceptive method. IMPLICATIONS: Availability of an OCP OTC has the potential to address challenges accessing contraceptive care among BIPOC in the United States, who are often impacted by structural inequities and racism. Findings from this study can inform future OTC implementation strategies to ensure OTC access addresses logistical and interpersonal challenges.

Profiling of syngeneic mouse HCC tumor models as a framework to understand anti-PD-1 sensitive tumor microenvironments.

BACKGROUND AND AIMS: The treatment of hepatocellular carcinoma (HCC) has been transformed by the use of immune checkpoint inhibitors. However, most patients with HCC do not benefit from treatment with immunotherapy. There is an urgent need to understand the mechanisms that underlie response or resistance to immunotherapy for patients with HCC. The use of syngeneic mouse models that closely recapitulate the heterogeneity of human HCC will provide opportunities to examine the complex interactions between cancer cells and nonmalignant cells in the tumor microenvironment. APPROACH AND RESULTS: We leverage a multifaceted approach that includes imaging mass cytometry and suspension cytometry by time of flight to profile the tumor microenvironments of the Hep53.4, Hepa 1-6, RIL-175, and TIBx (derivative of TIB-75) syngeneic mouse HCC models. The immune tumor microenvironments vary across these four models, and various immunosuppressive pathways exist at baseline in orthotopic liver tumors derived from these models. For instance, TIBx, which is resistant to anti-programmed cell death protein 1 therapy, contains a high proportion of "M2-like" tumor-associated macrophages with the potential to diminish antitumor immunity. Investigation of The Cancer Genome Atlas reveals that the baseline immunologic profiles of Hep53.4, RIL-175, and TIBx are broadly representative of human HCCs; however, Hepa 1-6 does not recapitulate the immune tumor microenvironment of the vast majority of human HCCs. CONCLUSIONS: There is a wide diversity in the immune tumor microenvironments in preclinical models and in human HCC, highlighting the need to use multiple syngeneic HCC models to improve the understanding of how to treat HCC through immune modulation.

Building Team-based Primary Care: Lessons From an Academic-Community Network Partnership.

BACKGROUND: Team-based care is fundamental to providing high-quality health care for patients. However, moving from a traditional, hierarchical way of providing care to team-based care is challenging and involves systematic and sustained process changes. OBJECTIVES: To describe the implementation and evaluation of a partnership between academics, clinic, and community to improve team-based care in primary care practices serving vulnerable populations utilizing a structured change package and implementation support. METHODS: The partners 1) created a six-strategy structured change package, 2) designed implementation support, and 3) evaluated implementation using an assessment scale at baseline and every 6 months. RESULTS: Practices improved in all care-team functions from May 2015 to August 2018, with the most improvement seen in population management, planned care and empanelment. CONCLUSIONS: Academic-community partnerships can use evidence-based practice supports to measurably improve team-based care in primary care practices serving vulnerable populations.

Conventional Ameloblastoma. A Case Report with Microarray and Bioinformatic Analysis.

Ameloblastoma is a rare benign epithelial odontogenic neoplasm, but with great clinical implications, as despite its benignity and slow growth, most cases are locally aggressive with a significant recurrence rate. Histological, cellular, or molecular analyses of its pathogenesis have confirmed the complexity of this neoplasm. We present the case of a 20-year-old patient with a suggestive clinical and radiographic diagnosis of ameloblastoma. An incisional biopsy was obtained confirming the diagnosis of conventional ameloblastoma. Left hemimandibulectomy and plate reconstruction were performed. Histopathological analysis of the surgical specimen confirmed the conventional ameloblastoma with a plexiform pattern and significant areas of cystic degeneration and amyloid-like-like deposits. Additionally, a microarray was carried out with bioinformatic analysis for the enrichment, protein interaction, and determination of eight hub genes (CRP, BCHE, APP, AKT1, AGT, ACTC1, ADAM10, and APOA2) related to their pathogenesis.

A novel trophic cascade between cougars and feral donkeys shapes desert wetlands.

Introduced large herbivores have partly filled ecological gaps formed in the late Pleistocene, when many of the Earth's megafauna were driven extinct. However, extant predators are generally considered incapable of exerting top-down influences on introduced megafauna, leading to unusually strong disturbance and herbivory relative to native herbivores. We report on the first documented predation of juvenile feral donkeys Equus africanus asinus by cougars Puma concolor in the Mojave and Sonoran Deserts of North America. We then investigated how cougar predation corresponds with differences in feral donkey behaviour and associated effects on desert wetlands. Focusing on a feral donkey population in the Death Valley National Park, we used camera traps and vegetation surveys to compare donkey activity patterns and impacts between wetlands with and without cougar predation. Donkeys were primarily diurnal at wetlands with cougar predation, thereby avoiding cougars. However, donkeys were active throughout the day and night at sites without predation. Donkeys were ~87% less active (measured as hours of activity a day) at wetlands with predation (p < 0.0001). Sites with predation had reduced donkey disturbance and herbivory, including ~46% fewer access trails, 43% less trampled bare ground and 192% more canopy cover (PERMANOVA, R2  = 0.22, p = 0.0003). Our study is the first to reveal a trophic cascade involving cougars, feral equids and vegetation. Cougar predation appears to rewire an ancient food web, with diverse implications for modern ecosystems. Our results suggest that protecting apex predators could have important implications for the ecological effects of introduced megafauna.

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice.

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.

The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model.

The P522R variant of PLCG2, expressed by microglia, is associated with reduced risk of Alzheimer's disease (AD). Yet, the impact of this protective mutation on microglial responses to AD pathology remains unknown. Chimeric AD and wild-type mice were generated by transplanting PLCG2-P522R or isogenic wild-type human induced pluripotent stem cell microglia. At 7 months of age, single-cell and bulk RNA sequencing, and histological analyses were performed. The PLCG2-P522R variant induced a significant increase in microglial human leukocyte antigen (HLA) expression and the induction of antigen presentation, chemokine signaling, and T cell proliferation pathways. Examination of immune-intact AD mice further demonstrated that the PLCG2-P522R variant promotes the recruitment of CD8+ T cells to the brain. These data provide the first evidence that the PLCG2-P522R variant increases the capacity of microglia to recruit T cells and present antigens, promoting a microglial transcriptional state that has recently been shown to be reduced in AD patient brains.

Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics.

T cell migration via afferent lymphatics to draining lymph nodes (dLNs) depends on expression of CCR7 in T cells and CCL21 in the lymphatic vasculature. Once T cells have entered lymphatic capillaries, they slowly migrate into contracting collecting vessels. Here, lymph flow picks up, inducing T cell detachment and rapid transport to the dLNs. We find that the atypical chemokine receptor 4 (ACKR4), which binds and internalizes CCL19 and CCL21, is induced by lymph flow in endothelial cells lining lymphatic collectors, enabling them to scavenge these chemokines. In the absence of ACKR4, migration of T cells to dLNs in TPA-induced inflammation is significantly reduced. While entry into capillaries is not impaired, T cells accumulate in the ACKR4-deficient dermal collecting vessel segments. Overall, our findings identify an ACKR4-mediated mechanism by which lymphatic collectors facilitate the detachment of lymph-borne T cells in inflammation and their transition from crawling to free-flow toward the dLNs.

Impact of social distancing on early SARS-CoV-2 transmission in the United States.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral pathogen that quickly became a global pandemic in the winter of 2020-2021. In response, governments issued social distancing orders to minimize transmission by reducing community contacts. We tested the efficacy of this social distancing at the state level during the first 2 months of the pandemic in the United States. We utilized data on daily SARS-CoV-2 case numbers and human community mobility (anonymized, aggregated cell phone location data stratified into six categories used as an index of social distancing), the date of government-issued social distancing orders, demographics, urbanization and public transportation. We implemented cross-correlation to identify lag times between declines in mobility and SARS-CoV-2 cases. Incorporating state-specific lag times, we tested for associations between case counts and mobility metrics using Bayesian multilevel models. Decreased mobility around grocery stores/pharmacies, retail/recreation locations, transit stations and workplaces was correlated with decreases in SARS-CoV-2 cases with significant lag times of ≥21 days. Social distancing orders were associated with fewer cumulative SARS-CoV-2 cases when they were put in place earlier. Community mobility had already started declining prior to most social distancing orders, especially the more restrictive orders implemented later in the pandemic. Social distancing is an important tool that has been implemented throughout the pandemic to decrease SARS-CoV-2 transmission, although with significant social and economic impacts. Our results suggest that declines in cases were observed several weeks subsequent to implementation of social distancing measures, and that implementing social distancing earlier could potentially minimize the duration of time these policies need to be in effect. Our findings can inform ongoing management of this pandemic and other emerging infectious disease outbreaks by identifying areas where reductions in mobility are associated with reduced disease transmission, and the expected time frame between behavioural changes and measurable population outcomes.

Comprehensive Evaluation of the Impact of Sociodemographic Inequalities on Adverse Outcomes and Excess Mortality During the Coronavirus Disease 2019 (COVID-19) Pandemic in Mexico City.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic in Mexico City has been sharp, as several social inequalities at all levels coexist. Here we conducted an in-depth evaluation of the impact of individual and municipal-level social inequalities on the COVID-19 pandemic in Mexico City. METHODS: We analyzed suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases, from the Mexico City Epidemiological Surveillance System from 24 February 2020 to 31 March 2021. COVID-19 outcomes included rates of hospitalization, severe COVID-19, invasive mechanical ventilation, and mortality. We evaluated socioeconomic occupation as an individual risk, and social lag, which captures municipal-level social vulnerability, and urban population density as proxies of structural risk factors. Impact of reductions in vehicular mobility on COVID-19 rates and the influence of risk factors were also assessed. Finally, we assessed discrepancies in COVID-19 and non-COVID-19 excess mortality using death certificates from the general civil registry. RESULTS: We detected vulnerable groups who belonged to economically unfavored sectors and experienced increased risk of COVID-19 outcomes. Cases living in marginalized municipalities with high population density experienced greater risk for COVID-19 outcomes. Additionally, policies to reduce vehicular mobility had differential impacts modified by social lag and urban population density. Finally, we report an under-registry of COVID-19 deaths along with an excess mortality closely related to marginalized and densely populated communities in an ambulatory setting. This could be attributable to a negative impact of modified hospital admission criteria during the pandemic. CONCLUSIONS: Socioeconomic occupation and municipality-wide factors played a significant role in shaping the course of the COVID-19 pandemic in Mexico City.

Imaging leukocyte migration through afferent lymphatics.

Afferent lymphatics mediate the transport of antigen and leukocytes, especially of dendritic cells (DCs) and T cells, from peripheral tissues to draining lymph nodes (dLNs). As such they play important roles in the induction and regulation of adaptive immunity. Over the past 15 years, great advances in our understanding of leukocyte trafficking through afferent lymphatics have been made through time-lapse imaging studies performed in tissue explants and in vivo, allowing to visualize this process with cellular resolution. Intravital imaging has revealed that intralymphatic leukocytes continue to actively migrate once they have entered into lymphatic capillaries, as a consequence of the low flow conditions present in this compartment. In fact, leukocytes spend considerable time migrating, patrolling and interacting with the lymphatic endothelium or with other intralymphatic leukocytes within lymphatic capillaries. Cells typically only start to detach once they arrive in downstream-located collecting vessels, where vessel contractions contribute to enhanced lymph flow. In this review, we will introduce the biology of afferent lymphatic vessels and report on the presumed significance of DC and T cell migration via this route. We will specifically highlight how time-lapse imaging has contributed to the current model of lymphatic trafficking and the emerging notion that - besides transport - lymphatic capillaries exert additional roles in immune modulation.

Pathogen surveillance and epidemiology in endangered Peninsular bighorn sheep (Ovis canadensis nelsoni).

Peninsular bighorn sheep (Ovis canadensis nelsoni) are found exclusively in Southern California and Baja Mexico. They are federally endangered due to multiple threats, including introduced infectious disease. From 1981 - 2017, we conducted surveillance for 16 pathogens and estimated population sizes, adult survival, and lamb survival. We used mixed effects regression models to assess disease patterns at the individual and population levels. Pathogen infection/exposure prevalence varied both spatially and temporally. Our findings indicate that the primary predictor of individual pathogen infection/exposure was the region in which an animal was captured, implying that transmission is driven by local ecological or behavioral factors. Higher Mycoplasma ovipneumoniae seropositivity was associated with lower lamb survival, consistent with lambs having high rates of pneumonia-associated mortality, which may be slowing population recovery. There was no association between M. ovipneumoniae and adult survival. Adult survival was positively associated with population size and parainfluenza-3 virus seroprevalence in the same year, and orf virus seroprevalence in the previous year. Peninsular bighorn sheep are recovering from small population sizes in a habitat of environmental extremes, compounded by infectious disease. Our research can help inform future pathogen surveillance and population monitoring for the long-term conservation of this population.