A Proof-of-Concept Simulation of the Accelerated Longitudinal Planned Missing Design for Latent Panel Modeling

Longitudinal planned missing, represented in the literature by the time-lag model (McArdle&Woodcock, 1997) and the cohort sequential design (Nesselroade&Baltes, 1979), has been thus far restricted to growth modeling and often does not fully utilize the benefits of the planned missingness by estimating a full-longitudinal model. The accelerated longitudinal design may serve as a more flexible and powerful alternative. This study presents a test of the accelerated longitudinal design in a simulated latent panel modeling framework to examine the method's appropriateness for contexts untestable using traditional longitudinal planned missing designs. Three-, four-, and five-cohort models are tested, using a continuum of sample sizes and cohort effect sizes. Results indicate that factor loadings, factor variances, and stabilities across time are replicated well, while characteristics and relationships of the means (i.e., manifest intercepts, latent means, and especially cohort differences) show low efficiency relative to the full sample case. In general, the technique is recommended when no cohort effects are expected, though more expansive research into other possible modeling situations should follow

Proportional Consistency of Apportionment Methods

We analyze a little-known property of apportionment methods that captures how allocations scale with the size of the house: specifically, if, for a fixed population distribution, the house size and allocation can be scaled down within the set of integers, then the apportionment should be correspondingly scaled down. Balinski and Young (2001) include this property among the minimal requirements for a "reasonable" apportionment method. We argue that this property is better understood as a consistency requirement since quota-based apportionments that are "less proportional" meet this requirement while others that are "more proportional" do not. We also show that the family of quotatone methods based on stationary divisors (including the quota method) do not satisfy this property

Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus

Abstract Introduction Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo. Methods Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry. Results After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01). Conclusions Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists

Walk A Hound, Lose A Pound, & Stay Fit for Seniors

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionBackground: Obesity rates in older adults are linked with the national problem of limited physical activity (PA), resulting in chronic illness. Obesity-related illness and functional loss require innovative interventions. Older adult dog walkers maintained physical functioning over a 3 year period (Thorpe 2006). Dog walking may improve long-term PA by improving readiness and physical function. Purpose: The study aimed to test the association between dog walking and physical functioning. Methods: A three-group, repeated measures design tested efficacy of a 12-week (5 days/week) shelter dog walking program for community-dwelling adults over age 65. Three retirement facilities were assigned to the shelter dog walking (DW), human walking companion (HWC), or no-treatment control (C) group. DW group members selected a dog matching their walking capability & walked on a paved road at the animal shelter. HWC group members walked with a friend or spouse on a paved road at their residence. Both groups were accompanied by study staff. Pretest, mid-trial & posttest findings included 6-minute walk, weight, physical activity during the previous week, physical activity stage of change, mood & social support. Findings: Fifty-four adults participated {DW n=12, HWC n=23 & C n=19}. Fourteen males & 40 females, ranged in age from 67-97 years (Mean=85). The 6-minute walk compared pre and post for the DW group increased 28% (p=0.012), the HWC had a 4% increase (p=0.32) and the C group a 6% increase (p=0.18). Conclusions: DW group participants expressed affinity for the shelter dogs. The DW group's walking ability improved significantly. They stated that their balance & walking confidence improved. They stated that they liked the program because it “gets me out,” “is helping me to feel more confident,” & “is fun.” Dog walking may be beneficial to improve or maintain functioning in older adults. Walking speed is an important indicator of balance

IFN-α-Induced Upregulation of CCR5 Leads to Expanded HIV Tropism In Vivo

Chronic immune activation and inflammation (e.g., as manifest by production of type I interferons) are major determinants of disease progression in primate lentivirus infections. To investigate the impact of such activation on intrathymic T-cell production, we studied infection of the human thymus implants of SCID-hu Thy/Liv mice with X4 and R5 HIV. X4 HIV was observed to infect CD3−CD4+CD8−CXCR4+CCR5− intrathymic T-cell progenitors (ITTP) and to abrogate thymopoiesis. R5 HIV, by contrast, first established a nonpathogenic infection of thymic macrophages and then, after many weeks, began to replicate in ITTP. We demonstrate here that the tropism of R5 HIV is expanded and pathogenicity enhanced by upregulation of CCR5 on these key T-cell progenitors. Such CCR5 induction was mediated by interferon-α (IFN-α) in both thymic organ cultures and in SCID-hu mice, and antibody neutralization of IFN-α in R5 HIV-infected SCID-hu mice inhibited both CCR5 upregulation and infection of the T-cell progenitors. These observations suggest a mechanism by which IFN-α production may paradoxically expand the tropism of R5 HIV and, in so doing, accelerate disease progression

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans