The detection of CMV in saliva can mark a systemic infection with CMV in renal transplant recipients

Human cytomegalovirus (CMV) is often transmitted through saliva. The salivary gland is a site of CMV replication and saliva can be used to diagnose congenital CMV infections. CMV replication is monitored in whole blood or plasma in renal transplant recipients (RTR) and associates with clinical disease. However, these assays may not detect replication in the salivary gland and there is little data linking detection in saliva with systemic infection and clinical sequelae. RTR (n = 82) were recruited \u3e 2 years after transplantation. An in-house quantitative PCR assay was used to detect CMV UL54 in saliva samples. CMV DNA was sought in plasma using a commercial assay. Vascular health was predicted using flow mediated dilatation (FMD) and plasma biomarkers. CMV-reactive antibodies were quantified by ELISA and circulating CMV-specific T-cells by an interferon-γ ELISpot assay. Vδ2− γδ T-cells were detected using multicolor flow cytometry reflecting population expansion after CMV infection. The presence of CMV DNA in saliva and plasma associated with plasma levels of antibodies reactive with CMV gB and with populations of circulating Vδ2− γδ T -cells (p \u3c 0.01). T-cells reactive to CMV immediate early (IE)-1 protein were generally lower in patients with CMV DNA in saliva or plasma, but the level of significance varied (p = 0.02–0.16). Additionally, CMV DNA in saliva or plasma associated weakly with impaired FMD (p = 0.06–0.09). The data suggest that CMV detected in saliva reflects systemic infections in adult RTR

Fostering Low-Income Homeownership: A Longitudinal Randomized Experiment on Individual Development Accounts

For low-income families, homeownership represents an important strategy to move out of poverty and offers long-term social and economic development opportunities. Individual Development Account (IDA) programs facilitate savings towards assets such as home purchase through matched savings, financial education and case management. Using longitudinal experiment data from the American Dream Demonstration, this study examines the influence of IDA participation on homeownership rates among low-income participants after 18 months (Wave 2) of program participation and after 48 months (Wave 3) at program completion. Involvement in specific home-search activities at Waves 2 and 3 was measured to determine whether these activities mediated the affect of IDA programs on homeownership. Results from this randomized experiment indicated that IDA participation significantly increased homeownership rates at 48 months. Furthermore, participation in the home search activity, clearing debt, at 18 months of program participation mediated the effect of the IDA program on homeownership at 48 months

Liver resection for hilar and peripheral cholangiocarcinomas: A study of 62 cases

Objective: To analyze a single center's 14-year experience with 62 consecutive patients with hilar (HCCA) and peripheral (PCCA) cholangiocarcinomas. Summary Background Data: Long-term survival after surgical treatment of HCCA and PCCA has been poor. Methods: From March 1981 until December 1994, 62 consecutive patients with HCCA (n = 28) and PCCA (n = 34) underwent surgical treatment. The operations were individualized and included local excision of the tumor and suprapancreatic bile duct, lymph node dissection, vascular reconstruction, and subtotal hepatectomy. Clinical and pathologic risk factors were examined for prognostic influence. Results: Patients were followed for a median of 25 months (12-102 months). Postoperative morbidity and mortality (at 30 days) were 32% and 14%, respectively, for HCCA and 24% and 6% for PCCA. The survival rates for HCCA and PCCA were 79% (±8%) and 67% (±8%) at 1 year; 39% (±10%) and 40% (±9%) at 3 years; and 8% (±7%) and 35% (±10%) at 5 years, respectively. The median survival was 24 (±4) months for HCCA and 19 (±8) months for PCCA. The disease-free survival rates for HCCA and PCCA were 85% (±10%) and 77% (±9%) at 1 year; 18% (±11%) and 41% (±12%) at 3 years; and 18% (±11%) and 41% (±12%) at 5 years, respectively. Nearly 80% of these patients had TNM stage IV tumors. With HCCA, no risk factors were associated with patient survival. For PCCA, multiple tumors (relative risk [RR] = 3.5; 95% confidence interval [CI] = 1.2-10.5) and incomplete resection (RR = 8.3; 95% CI = 2.3- 29.6) were independently associated with a worse prognosis. For HCCA, there was a trend for lower disease-free survival in females (p = 0.056; log rank test). For PCCA, tumor size >5 cm was the only factor associated with disease recurrence (p = 0.024; log rank test). Conclusions: Even though rare, 5-year survival by resection can be achieved in both HCCA and PCCA, but new adjuvant treatments are clearly needed

Joint Modeling and Registration of Cell Populations in Cohorts of High-Dimensional Flow Cytometric Data

In systems biomedicine, an experimenter encounters different potential sources of variation in data such as individual samples, multiple experimental conditions, and multi-variable network-level responses. In multiparametric cytometry, which is often used for analyzing patient samples, such issues are critical. While computational methods can identify cell populations in individual samples, without the ability to automatically match them across samples, it is difficult to compare and characterize the populations in typical experiments, such as those responding to various stimulations or distinctive of particular patients or time-points, especially when there are many samples. Joint Clustering and Matching (JCM) is a multi-level framework for simultaneous modeling and registration of populations across a cohort. JCM models every population with a robust multivariate probability distribution. Simultaneously, JCM fits a random-effects model to construct an overall batch template -- used for registering populations across samples, and classifying new samples. By tackling systems-level variation, JCM supports practical biomedical applications involving large cohorts

Clinical intestinal transplantation: New perspectives and immunologic considerations

Background: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high- dose treatment has inhibited the widespread use of these procedures. We have examined our 1990-1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. Study Design: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. Results: With a mean followup of 32 ± 26 months (range, 1-86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. Conclusions: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol

Establishing two principal dimensions of cognitive variation in Logopenic Progressive Aphasia

Logopenic Progressive Aphasia (LPA) is a neurodegenerative syndrome characterised by sentence repetition and naming difficulties arising from left-lateralised temporoparietal atrophy. Clinical descriptions of LPA largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits, even on tasks with minimal language demands. Although non-linguistic cognitive deficits in LPA are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose individual-level variation in cognitive performance in 43 well-characterised LPA patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify LPA. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralised temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, LPA patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralised temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in LPA, suggesting the presence of a genuine co-occurring cognitive impairment that is independent of language function and disease severity.This work was supported in part by funding to Forefront, a collaborative research group specialized to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council (NHMRC) of Australia program grant (APP1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE110001021). Siddharth Ramanan is supported by a Faculty of Science Ph.D. Research Scholarship from The University of Sydney. Olivier Piguet is supported by an NHMRC Senior Research Fellowship (APP1103258). Muireann Irish is supported by an ARC Future Fellowship (FT160100096) and an ARC Discovery Project (DP180101548). Matthew A. Lambon Ralph is supported by a UKRI-MRC Programme Grant (MR/R023883/1) and an ERC Advanced grant (GAP: 670428 - BRAIN2MIND_NEUROCOMP)

Variants of HCMV UL18 sequenced directly from clinical specimens associate with antibody and T-cell responses to HCMV

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host’s burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2− γδ T-cells—populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden

Sequencing of the viral UL111a gene directly from clinical specimens reveals variants of HCMV-encoded IL-10 that are associated with altered immune responses to HCMV

Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ~80% of adults worldwide. Acute infections are often asymptomatic in healthy individuals but generate diverse syndromes in neonates, renal transplant recipients (RTR), and people with HIV (PWH). The HCMV gene UL111a encodes a homolog of human interleukin-10 (IL-10) that interacts with the human IL-10 receptor. Deep sequencing technologies were used to sequence UL111a directly from 59 clinical samples from Indonesian PWH and Australian RTR, healthy adults, and neonates. Overall, 93% of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous variation. Carriage of these variants differed between neonates and adults, Australians and Indonesians, and between saliva and blood leukocytes. The variant alleles of N41D and S71Y occurred together in Australian RTR and were associated with higher T-cell responses to HCMV pp65. The variant P122S was associated with lower levels of antibodies reactive with a lysate of HCMV-infected fibroblasts. L174F was associated with increased levels of antibodies reactive with HCMV lysate, immediate-early 1 (IE-1), and glycoprotein B (gB) in Australian RTR and Indonesians PWH, suggesting a higher viral burden. We conclude that variants of UL111a are common in all populations and may influence systemic responses to HCMV

Lessons from the Pivot: Higher Education\u27s Response to the Pandemic

This text includes chapters from instructional designers, university faculty and staff, and undergraduate and graduate students, and the text has been divided into three sections to reflect these varied perspectives. Each section begins with research-based perspectives, but also contains more personal narratives at the end. While the context of most of the chapters is the United States, there are also chapters with a Canadian context. It is also important to note that, as of the first half of 2021, the pandemic rages on, and mentions of COVID-19 in the following chapters will be reflective of the state of affairs in North America in the spring and fall of 2020.https://scholar.umw.edu/education_books/1000/thumbnail.jp