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Background: Social isolation is a global public health threat. Veterans are particularly at risk for social isolation due to high rates of comorbid physical and mental health problems. Yet, effective interventions are limited. Objectives: Our primary objective was to assess the feasibility and acceptability of CONNECTED, a novel, transdiagnostic intervention to reduce social isolation that includes individual and group components and is delivered by peers via telehealth. Secondary objectives were to identify appropriate outcome measures and explore preliminary intervention effects. Methods: This was a two-phase study. In Phase 1, to evaluate study feasibility, we surveyed 200 veterans to assess prevalence of social isolation and their interest in social connectedness interventions. In Phase 2, we employed a mixed-methods, pre-post study design in which we piloted CONNECTED with 19 veterans through 2 successive cohorts to further assess feasibility, to evaluate acceptability, and to explore preliminary effectiveness. Quantitative analyses involved descriptive and bivariate analyses as well as multivariate modeling. Qualitative interviews were analyzed using thematic analysis. Results: For Phase 1, 39% of veterans surveyed were socially isolated. Participants who were ≤ 55 years old, caregivers, and those who experienced unmet social needs were more likely to report social isolation. Over 61% expressed interest in VA programs to reduce social isolation. For Phase 2, the pilot intervention, recruitment rate was 88% and the enrollment rate was 86%. Retention rates for the two cohorts were 80% and 50%, respectively, and satisfaction rates among intervention completers were 100%. Results also showed statistically significant improvements in social isolation (+ 5.91, SD = 4.99; p =.0028), social support (+ 0.74, SD = 1.09; p =.03), anxiety (-3.92, SD = 3.73; p =.003), and depression (-3.83, SD = 3.13; p =.001). Results for the other measures were not statistically significant. Conclusion: CONNECTED is a feasible and acceptable intervention and is likely to be an effective tool to intervene on social isolation among veterans. [ABSTRACT FROM AUTHOR]

Traditional vaccine clinical development is an undertaking involving meticulous, multiple studies in multiple populations at risk of infection and disease over multiple years. SARS-CoV-2 and COVID-19 vaccine development is following this traditional development pathway, and accelerated Phase I-II-III clinical programs are being applied. This is not the first time vaccines have been manufactured and tested quickly to meet a public health crisis. Selected statistical concepts pertaining to vaccine efficacy and safety, relevant during the design and implementation of such clinical development programs, will be discussed. [ABSTRACT FROM AUTHOR]

Clinical safety and immunogenicity data in vaccines are commonly dichotomized into responder and nonresponder binary data. This article expands upon Fagerland, Lyndersen, and Laake to further study Newcombe's hybrid score and Fisher's conditional exact test using imbalanced randomization in vaccine clinical studies. The intent of this article is to study a potential statistical issue in clinical study design and analysis; hence, no reference to any particular product is made. [ABSTRACT FROM AUTHOR]

Objective: To evaluate care retention among Veterans with serious mental illness (SMI) who were lost to Veterans Health Administration (VHA) care for at least one year and subsequently returned to VHA care via the SMI Re-Engagement program, an outreach program for Veterans with SMI who are lost-to-care. Methods: For the 410 Veterans with SMI who returned to care via SMI Re-Engagement between April 4th, 2016 and January 31, 2018, we assessed VHA in-person and telehealth utilization (overall, primary care, mental health care) for two years following the date of return to care. Results: Care retention was common: 70.2% of Veterans had at least one encounter in each year of the two-year follow-up period and an additional 22.7% had at least one encounter during one of the two years. During the two-year follow-up period, 72.4% of Veterans had at least one primary care encounter and 70.7% of Veterans had at least one mental health care encounter. Adjusted binomial logistic regression analyses found a return-to-care encounter in primary care (OR = 2.70; 95% CI: 1.34, 5.42) predicted primary care retention, and a return-to-care encounter in mental health care (OR = 4.01; 95% CI: 2.38, 6.75) predicted mental health care retention. Conclusion: Most Veterans who return to care via the SMI Re-Engagement program remain in VHA care for the subsequent two years. [ABSTRACT FROM AUTHOR]

T regulatory cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and nonharmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require these cells to be near their targets of suppression; however, it is not known how Treg-to-target proximity is controlled. Here, we found that Tregs attract CD4+ and CD8+ T cells by producing chemokines. Specifically, Tregs produced both CCL3 and CCL4 in response to stimulation, and production of these chemokines was critical for migration of target T cells, as Tregs from Ccl3-/- mice, which are also deficient for CCL4 production, did not promote migration. Moreover, CCR5 expression by target T cells was required for migration of these cells to supernatants conditioned by Tregs. Tregs deficient for expression of CCL3 and CCL4 were impaired in their ability to suppress experimental autoimmune encephalomyelitis or islet allograft rejection in murine models. Moreover, Tregs from subjects with established type 1 diabetes were impaired in their ability to produce CCL3 and CCL4. Together, these results demonstrate a previously unappreciated facet of Treg function and suggest that chemokine secretion by Tregs is a fundamental aspect of their therapeutic effect in autoimmunity and transplantation. [ABSTRACT FROM AUTHOR]

Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1) were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot). Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues. [ABSTRACT FROM AUTHOR]

Chronic inflammation is known to promote metabolic dysregulation in obesity and type 2 diabetes. Although the precise origin of the unchecked inflammatory response in obesity is unclear, it is known that overproduction of proinflammatory cytokines by innate immune cells affects metabolism. For example, TNF-α contributes to the inability of cells to respond to insulin and to the increase in levels of insulin. Whether this hyperinsulinemia itself is part of a feedback loop that affects the progression of chronic adipose inflammation is unknown. In this article, we show that regulatory T cells (Tregs) express the insulin receptor, and that high levels of insulin impair the ability of Tregs to suppress inflammatory responses via effects on the AKT/mTOR signaling pathway. Insulin activated AKT signaling in Tregs, leading to inhibition of both IL-10 production and the ability of Tregs to suppress the production of TNF-α by macrophages in a contact-independent manner. The effect of insulin on Treg suppression was limited to IL-10 production and it did not alter the expression of other proteins associated with Treg function, including CTLA-4, CD39, and TGF-β. In a model of diet-induced obesity, Tregs from the visceral adipose tissue of hyperinsulinemic, obese mice showed a similar specific decrease in IL-10 production, as well as a parallel increase in production of IFN-γ. These data suggest that hyperinsulinemia may contribute to the development of obesity-associated inflammation via a previously unknown effect of insulin on the IL-10-mediated function of Tregs. [ABSTRACT FROM AUTHOR]

The 13-valent pneumococcal conjugate vaccine compared with the 7-valent pneumococcal conjugate vaccine (PCV7) significantly reduced nasopharyngeal colonization of single serotypes 1, 6A, 6C, 7F, 19A, and 19F, but not serotype 3 or other PCV7 serotypes; serotype 5 had too few events for analysis.Background. The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed to replace the 7-valent pneumococcal conjugate vaccine (PCV7) based on serological noninferiority criteria. To date no randomized PCV13 pediatric trial has included clinical endpoints.Methods. This randomized double-blind trial compared the impact of PCV13 versus PCV7 on nasopharyngeal (NP) colonization and immunogenicity. Healthy infants were randomized (1:1) to receive PCV7 or PCV13 at ages 2, 4, 6, and 12 months; NP swabs were collected at 2, 4, 6, 7, 12, 13, 18, and 24 months, and blood was drawn at 7 and 13 months. Rates of NP acquisition and prevalence, and serotype-specific immunoglobulin G (IgG) concentrations were assessed.Results. The per protocol analysis population included 881 PCV13 and 873 PCV7 recipients. PCV13 significantly reduced NP acquisition of the additional PCV13 serotypes 1, 6A, 7F, and 19A; the cross-reacting serotype 6C; and the common PCV7 serotype 19F. For serotype 3, and the other PCV7 serotypes, there were no significant differences between the vaccine groups. There were too few serotype 5 events to draw inference. The impact on prevalence at predefined time points was similar to that observed with NP acquisition. PCV13 elicited significantly higher IgG responses for PCV13 additional serotypes and serotype 19F, and similar or lower responses for 6/7 PCV7 serotypes.Conclusions. PCV13 resulted in lower acquisition and prevalence of NP colonization than PCV7 did for 4 additional PCV13 serotypes, and serotypes 6C and 19F. It was comparable with PCV7 for all other common serotypes. These findings predict vaccine effectiveness through both direct and indirect protection.Clinical Trials Registration. NCT00508742. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)2D3 to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25(OH)2D3 treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)2D3-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)2D3- treated mice showed defects in their production of the antimicrobial peptide REG3γ. Taken together, these studies show that 1,25(OH)2D3 suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade ll-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4- iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade ll-IV aGVHD in patients receiving CD4" iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4" iNKT-cell dose was associated with a relative risk of grade ll-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4∼ iNKT cells effectively suppressed T-cell proliferation and IFN-7 secretion in a contact-dependent manner. In conclusion, higher doses of CD4∼ iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) have a reduced capacity to activate the PI3K/Akt pathway downstream of the TCR, and the resulting low activity of Akt is necessary for their development and function. The molecular basis for the failure of Tregs to activate Akt efficiently, however, remains unknown. We show that PH-domain leucine-rich-repeat protein phosphatase (PHLPP), which dephosphorylates Akt, is upregulated in Tregs, thus suppressing Akt activation. Tregs expressed higher levels of PHLPP than those of conventional T cells, and knockdown of PHLPP1 restored TCR-mediated activation of Akt in Tregs. Consistent with their high Akt activity, the suppressive capacity of Tregs from PHLPP1-/- mice was significantly reduced. Moreover, the development of induced Tregs was impaired in PHLPP1-/- mice. The increased level of Akt's negative regulator, PHLPP, provides a novel mechanism used by T cells to control the Akt pathway and the first evidence, to our knowledge, for a molecular mechanism underlying the functionally essential reduction of Akt activity in Tregs. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are a small but powerful subset of regulatory T cells involved in the modulation of a variety of normal and pathological immune responses. In contrast to conventional or other types of regulatory T cells, they are activated by glycolipid and phospholipid ligands that are presented to them by the non-polymorphic, major histocompatibility complex class I-like molecule CD1d. The in-depth understanding of their function has resulted in successful, iNKT cell-centred experimental therapeutic interventions including prevention of graft- versus-host disease and anti-leukaemia effects. Extending these successes into the clinical arena will require better understanding of their contribution to the pathogenesis of human, including haematological, diseases. [ABSTRACT FROM AUTHOR]

Proteomics is the systematic study of the many and diverse properties of proteins in a parallel manner with the aim of providing detailed descriptions of the structure, function and control of biological systems in health and disease. Advances in methods and technologies have catalyzed an expansion of the scope of biological studies from the reductionist biochemical analysis of single proteins to proteome-wide measurements. Proteomics and other complementary analysis methods are essential components of the emerging 'systems biology' approach that seeks to comprehensively describe biological systems through integration of diverse types of data and, in the future, to ultimately allow computational simulations of complex biological systems. [ABSTRACT FROM AUTHOR]

Discusses the issues surrounding the large-scale application of complex-mixture proteomic analysis for drug target discovery. Identification of disease-specific biomarkers that could be used for diagnostics or prognostic test; Characterization of the frequency of a differential expression across a range of samples taken from many individuals with the disease.

A retrospective review of cases from 1988 through 1992 was performed examining high-risk breast cancer patients treated with modified radical mastectomy without postoperative radiation at a single institution. Locoregional recurrence, distant metastases, overall survival, and number of lymph nodes removed were examined. This was compared with recent Danish and Canadian studies. Thirty-three premenopausal node-positive breast cancer patients had a 9 per cent locoregional recurrence rate. In the Danish and Canadian studies the locoregional recurrence rates were 32 and 21 per cent. These were reduced to 9 per cent and 10 per cent respectively in the radiated arms. Our locoregional recurrence in nonradiated patients was similar to that in the radiated arms of the studies and improved when compared with recurrence in their non-radiated controls. The adequacy of the axillary lymph node dissection was examined. In the current study a median of 18 lymph nodes were recovered with only 3 per cent containing less than 12 nodes. In the Danish study a median of seven lymph nodes were removed. Similarly in the Canadian trial a median of 11 nodes were removed. With complete axillary dissection results equivalent to those of postoperative adjuvant radiation is achieved. Further randomized controlled studies with standard axillary dissections are needed before the recommendation of routine postoperative radiotherapy. [ABSTRACT FROM AUTHOR]

This article adds to the debate over whether easy access to the Internet is the only outcome of community computer network projects or if there are tangible impacts to these initiatives. Building from Putnam's links between quality of life, community involvement, and social capital, the authors provide evidence as to the quality-of-life implications of the community computer network known as the Blacksburg Electronic Village (BEV). The results of the longitudinal study indicate frequent and increasing use of the BEV and the Internet for local, social-capital-building activities. However, there is no trend toward an increase in community involvement or attachment except in a subset of the population that scores high on measures of preexisting community involvement. The results offer Putnam justification for his claims about the Internet's role in social capital formation. [ABSTRACT FROM AUTHOR]

Components of the pre-mRNA splicing machinery are localized in interchromatin granule clusters (IGCs) and perichromatin fibrils (PFs). Here we report the biochemical purification of IGCs. Approximately 75 enriched proteins were present in the IGC fraction. Protein identification employing a novel mass spectrometry strategy and peptide microsequencing identified 33 known proteins, many of which have been linked to pre-mRNA splicing, as well as numerous uncharacterized proteins. Thus far, three new protein constituents of the IGCs have been identified. One of these, a 137 kDa protein, has a striking sequence similarity over its entire length to UV-damaged DNA-binding protein, a protein associated with the hereditary disease xeroderma pigmentosum group E, and to the 160 kDa subunit of cleavage polyadenylation specificity factor. Overall, these results provide a key framework that will enable the biological functions associated with the IGCs to be elucidated. [ABSTRACT FROM AUTHOR]