Person: Milner, Danny
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Milner
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Danny
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Milner, Danny
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Publication Green Herring Syndrome: Bacterial Infection in Patients With Mucormycosis Cavitary Lung Disease(Oxford University Press, 2014) Peixoto, Driele; Hammond, Sarah; Issa, Nicolas; Madan, Rachna; Gill, Ritu; Milner, Danny; Colson, Yolonda; Koo, Sophia; Baden, Lindsey; Marty, FranciscoMucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease.Publication Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection(American Society of Microbiology, 2015) Hochman, Sarah E.; Madaline, Theresa F.; Wassmer, Samuel C.; Mbale, Emmie; Choi, Namjong; Seydel, Karl B.; Whitten, Richard O.; Varughese, Julie; Grau, Georges E. R.; Kamiza, Steve; Molyneux, Malcolm E.; Taylor, Terrie E.; Lee, Sunhee; Milner, Danny; Kim, KamiABSTRACT Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV+) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV+ and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV+ children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV+ children exacerbates the pathological features associated with CM. Importance There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV+) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV+ than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV+ children. Our findings raise the possibility that HIV+ children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.Publication Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location(Nature Publishing Group, 2016) Mima, Kosuke; Cao, Yin; Chan, Andrew; Qian, Zhi Rong; Nowak, Jonathan; Masugi, Yohei; Shi, Yan; Song, Mingyang; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Kosumi, Keisuke; Hanyuda, Akiko; Liu, Li; Kostic, Aleksandar; Giannakis, Marios; Bullman, Susan; Brennan, Caitlin; Milner, Danny; Baba, Hideo; Garraway, Levi; Meyerhardt, Jeffrey; Garrett, Wendy; Huttenhower, Curtis; Meyerson, Matthew; Giovannucci, Edward; Fuchs, Charles; Nakashima, Reiko; Ogino, ShujiObjectives: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum. Methods: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses’ Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum. Results: The proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5% 4/157) to cecal cancers (11% 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments. Conclusions: The proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm.Publication Inferring Developmental Stage Composition from Gene Expression in Human Malaria(Public Library of Science, 2013) Joice, Regina Carol; Narasimhan, Vagheesh; Montgomery, Jacqui; Sidhu, Amar Bir; Oh, Keunyoung; Meyer, Evan; Pierre-Louis, Willythssa; Seydel, Karl; Milner, Danny; Williamson, Kim; Wiegand, Roger; Ndiaye, Daouda; Daily, Johanna; Wirth, Dyann; Taylor, Terrie; Huttenhower, Curtis; Marti, MatthiasIn the current era of malaria eradication, reducing transmission is critical. Assessment of transmissibility requires tools that can accurately identify the various developmental stages of the malaria parasite, particularly those required for transmission (sexual stages). Here, we present a method for estimating relative amounts of Plasmodium falciparum asexual and sexual stages from gene expression measurements. These are modeled using constrained linear regression to characterize stage-specific expression profiles within mixed-stage populations. The resulting profiles were analyzed functionally by gene set enrichment analysis (GSEA), confirming differentially active pathways such as increased mitochondrial activity and lipid metabolism during sexual development. We validated model predictions both from microarrays and from quantitative RT-PCR (qRT-PCR) measurements, based on the expression of a small set of key transcriptional markers. This sufficient marker set was identified by backward selection from the whole genome as available from expression arrays, targeting one sentinel marker per stage. The model as learned can be applied to any new microarray or qRT-PCR transcriptional measurement. We illustrate its use in vitro in inferring changes in stage distribution following stress and drug treatment and in vivo in identifying immature and mature sexual stage carriers within patient cohorts. We believe this approach will be a valuable resource for staging lab and field samples alike and will have wide applicability in epidemiological studies of malaria transmission.Publication HIV-2 Encephalitis: Case Report and Literature Review(Mary Ann Liebert, 2012) Wood, Brian R.; Klein, Joshua; Lyons, Jennifer L; Milner, Danny; Phillips, Richard Edmund; Schutten, Martin; Folkerth, Rebecca D.; Ciarlini, Pedro; Henrich, Timothy J.; Johnson, JenniferWe report the case of a 59-year-old man who moved from Cape Verde to Massachusetts at the age of 29. He had multiple sexual contacts with female partners in Cape Verde and with West African women in Massachusetts, as well as multiple past indeterminate HIV-1 antibody tests. He presented to our facility with 2–3 months of inappropriate behaviors, memory impairment, weight loss, and night sweats, at which time he was found to have an abnormal enhancing lesion of the corpus collosum on brain magnetic resonance imaging (MRI). Laboratory testing revealed a CD4 count of \(63 cells/mm^3\), positive HIV-2 Western blot, serum HIV-2 RNA polymerase chain reaction (PCR) of 1160 copies per milliliter and cerebrospinal fluid (CSF) HIV-2 RNA PCR of 2730 copies per milliliter. Brain biopsy demonstrated syncytial giant cells centered around small blood vessels and accompanied by microglia, which correlated with prior pathologic descriptions of HIV-2 encephalitis and with well-described findings of HIV-1 encephalitis. Based on genotype resistance assay results, treatment guidelines, and prior studies validating success with lopinavir-ritonavir, he was treated with tenofovir-emtricitabine and lopinavir-ritonavir, which has led to virologic suppression along with steady neurologic and radiologic improvement, although he continues to have deficits.Publication The Role of Animal Models for Research on Severe Malaria(Public Library of Science, 2012) Craig, Alister G.; Grau, Georges E.; Janse, Chris; Kazura, James W.; Milner, Danny; Barnwell, John W.; Turner, Gareth; Langhorne, JeanIn light of the recent controversies over the role of animal models for research into the development of new treatments for severe malaria, particularly cerebral disease, a group of scientists came together to discuss the relative merits of a range of animal models and their overlap with the complex clinical syndromes of human disease. While it was not possible to fully resolve differences over the utility of the Plasmodium berghei ANKA model of experimental cerebral malaria, the meeting did bring the two research communities closer together to identify further work to provide information needed to validate the model and revitalise the development of other animal models displaying features of human pathology. The driving force behind this was the desire to ensure better translation of experimental findings into effective treatments for severe malaria.Publication Maternal–Fetal Microtransfusions and HIV-1 Mother-to-Child Transmission in Malawi(Public Library of Science, 2006) Kwiek, Jesse J.; Mwapasa, Victor; Milner, Danny; Alker, Alisa P.; Miller, William C.; Tadesse, Eyob; Molyneux, Malcolm E.; Rogerson, Stephen J.; Meshnick, Steven R.Background: Between 25% and 35% of infants born to HIV-infected mothers become HIV-1 infected. One potential route of mother-to-child transmission (MTCT) could be through a breakdown in the placental barrier (i.e., maternal–fetal microtransfusions). Methods and Findings: Placental alkaline phosphatase (PLAP) is a 130-kD maternal enzyme that cannot cross the intact placental barrier. We measured PLAP activity in umbilical vein serum as an indicator of maternal–fetal microtransfusion, and related this to the risk of HIV-1 MTCT. A case-cohort study was conducted of 149 women randomly selected from a cohort of HIV-1-infected pregnant Malawians; these women served as a reference group for 36 cases of in utero MTCT and 43 cases of intrapartum (IP) MTCT. Cord PLAP activity was measured with an immunocatalytic assay. Infant HIV status was determined by real-time PCR. The association between cord PLAP activity and HIV-1 MTCT was measured with logistic regression using generalized estimating equations. Among vaginal deliveries, PLAP was associated with IP MTCT (risk ratio, 2.25 per \(log_{10}\) ng/ml PLAP; 95% confidence interval, 0.95–5.32) but not in utero MTCT. In a multivariable model adjusted for HIV-1 RNA load, chorioamnionitis, and self-reported fever, the risk of IP MTCT almost tripled for every \(log_{10}\) increase in cord PLAP activity (risk ratio, 2.87; 95% confidence interval, 1.05–7.83). Conclusion: These results suggest that during vaginal deliveries, placental microtransfusions are a risk factor for IP HIV-1 MTCT. Future studies are needed to identify factors that increase the risk for microtransfusions in order to prevent IP HIV-1 MTCT.Publication Peritoneal Tuberculosis in a Pregnant Woman from Haiti, United States(U.S. National Center for Infectious Diseases, 2013) Ard, Kevin; Chan, Brian; Milner, Danny; Farmer, Paul; Koenig, SerenaPublication A histological method for quantifying Plasmodium falciparum in the brain in fatal paediatric cerebral malaria(BioMed Central, 2013) Milner, Danny; Valim, Clarissa; Carr, Richard A; Chandak, Pankaj B; Fosiko, Nedson G; Whitten, Richard; Playforth, Krupa B; Seydel, Karl B; Kamiza, Steve; Molyneux, Malcolm E; Taylor, Terrie EBackground: The sequestration of Plasmodium falciparum-infected erythrocytes in brain microvasculature through cytoadherence to endothelium, is the hallmark of the definitive diagnosis of cerebral malaria and plays a critical role in malaria pathogenesis. The complex pathophysiology, which leads each patient to the final outcome of cerebral malaria, is multifaceted and thus, metrics to delineate specific patterns within cerebral malaria are needed to further parse patients. Methods: A method was developed for quantification utilizing counts of capillary contents (early-stage parasites, late-stage parasites and fibrin) from histological preparations of brain tissue after death, and compared it to the standard approach, in which the percentage of parasitized vessels in cross-section is determined. Results: Within the initial cohort of 50 patients, two different observers agreed closely on the percentage of vessels parasitized, pigmented parasites and pigment globules (ICC = 0.795-0.970). Correlations between observers for correct diagnostic classification were high (Kendall’s tau-b = 0.8779, Kappa = 0.8413). When these methods were applied prospectively to a second set of 50 autopsy samples, they revealed a heterogeneous distribution of sequestered parasites in the brain with pigmented parasites and pigment globules present in the cerebellum > cortex > brainstem. There was no difference in the distribution of early stages of parasites or in the percentage of vessels parasitized across the same sites. The second cohort of cases was also used to test a previously published classification and regression tree (CART) analysis; the quantitative data alone were able to accurately classify and distinguish cerebral malaria from non-cerebral malaria. Classification errors occurred within a subclassification of cerebral malaria (CM1 vs CM2). A repeat CART analysis for the second cohort generated slightly different classification rules with more accurate subclassification, although misclassification still occurred. Conclusions: The traditional measure of parasite sequestration in falciparum malaria, the percentage of vessels parasitized, is the most reliable and consistent for the general diagnosis of cerebral malaria. Methods that involve quantitative measures of different life cycle stages are useful for distinguishing patterns within the cerebral malaria population; these subclassifications may be important for studies of disease pathogenesis and ancillary treatment.Publication Discordance between clinical and immunological ART eligibility criteria for children in Malawi(BioMed Central, 2014) O’Hare, Bernadette; Milner, Danny; Newberry, Laura; Pelani, Isaac; Malisita, KenBackground: Since May 2014, all HIV positive children aged less than five years in Malawi are eligible for ART. For children older than five years they are eligible if they are in WHO stage III/IV, if stage I/II, if their CD4 < 500 cells/mm3. Our goal was to compare the WHO clinical classification criteria (WHO stage + CD4/age) to CD4 count (CD4/age) on all children. Prior to 2014, children aged 2–5 years in stage I and II were eligible for ART if their CD4 was < 750 cells/mm3. We were interested in the increase in numbers of children in this age group who now meet the eligibility criteria and their average CD4 count. Methods: Data including age, stage and CD4 count were used. We examined the effect of using two different criteria; WHO staging and checking CD4 count if stage I or II versus CD4 count on all, on the numbers of children eligibility for ART in a cohort of 969 children aged 0 to 14 years in Blantyre, Malawi. Results: Using WHO stage + CD4/age, 786 patients out of 969 would have been treated and 183 would not. Using CD4/age, 745 patients out of 969 would have been treated and 224 would not. Within the 224 patients not treated by CD4 classification, 41 were clinical stage III or IV. The most common staging condition in these 41 children was low weight for age (i.e. underweight). 41% of children age2-5 years have a CD4 count >750. Conclusion: Most children are correctly started on treatment using recent guidelines. 41% more children <5 years will be started on ART.