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Background Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. Method Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. Discussion The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. Trial Registration ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017.

To gain insight into female-to-male HIV sexual transmission and how male circumcision protects against this mode of transmission, we visualized HIV-1 interactions with foreskin and penile tissues in ex vivo tissue culture and in vivo rhesus macaque models utilizing epifluorescent microscopy. 12 foreskin and 14 cadaveric penile specimens were cultured with R5-tropic photoactivatable (PA)-GFP HIV-1 for 4 or 24 hours. Tissue cryosections were immunofluorescently imaged for epithelial and immune cell markers. Images were analyzed for total virions, proportion of penetrators, depth of virion penetration, as well as immune cell counts and depths in the tissue. We visualized individual PA virions breaching penile epithelial surfaces in the explant and macaque model. Using kernel density estimated probabilities of localizing a virion or immune cell at certain tissue depths revealed that interactions between virions and cells were more likely to occur in the inner foreskin or glans penis (from local or cadaveric donors, respectively). Using statistical models to account for repeated measures and zero-inflated datasets, we found no difference in total virions visualized at 4 hours between inner and outer foreskins from local donors. At 24 hours, there were more virions in inner as compared to outer foreskin (0.0495 +/- 0.0154 and 0.0171 +/- 0.0038 virions/image, p = 0.001). In the cadaveric specimens, we observed more virions in inner foreskin (0.0507 +/- 0.0079 virions/image) than glans tissue (0.0167 +/- 0.0033 virions/image, p<0.001), but a greater proportion was seen penetrating uncircumcised glans tissue (0.0458 +/- 0.0188 vs. 0.0151 +/- 0.0100 virions/image, p = 0.099) and to significantly greater mean depths (29.162 +/- 3.908 vs. 12.466 +/- 2.985 μm). Our in vivo macaque model confirmed that virions can breach penile squamous epithelia in a living model. In summary, these results suggest that the inner foreskin and glans epithelia may be important sites for HIV transmission in uncircumcised men.

OBJECTIVE:--The aim of this study was to determine the effects of fenofibrate (160 mg/day) on fasting and postprandial lipoproteins, oxidized fatty acids, and inflammatory mediators in subjects with hypertriglyceridemia and the metabolic syndrome. RESEARCH DESIGN AND METHODS--Fifty-nine subjects with fasting hypertriglyceridemia (>=1.7 and <6.9 mmol/l) and two or more of the Adult Treatment Panel III criteria for the metabolic syndrome were randomly assigned to fenofibrate (160 mg/day) or placebo in a double-blind, controlled clinical trial. RESULTS:--Fenofibrate treatment lowered fasting triglycerides (-46.1%, P < 0.0001) and postprandial (area under the curve) triglycerides (-45.4%, P < 0.0001) due to significant reductions in postprandial levels of large (-40.8%, P < 0.0001) and medium (-49.5%, P < 0.0001) VLDL particles. The number of fasting total LDL particles was reduced in fenofibrate-treated subjects (-19.0%, P = 0.0033) primarily due to reductions in small LDL particles (-40.3%, P < 0.0001); these treatment differences persisted postprandially. Fasting and postprandial oxidized fatty acids were reduced in fenofibrate-treated subjects compared with placebo-administered subjects (-15.3%, P = 0.0013, and 31.0%, P < 0.0001, respectively), and fenofibrate therapy lowered fasting and postprandial soluble vascular cell adhesion molecule-1 (VCAM-1) (-10.9%, P = 0.0005, and -12.0%, P = 0.0001, respectively) as well as fasting and postprandial soluble intercellular adhesion molecule-1 (ICAM-1) (-14.8%, P < 0.0001, and -15.3%, P < 0.0001, respectively). Reductions in VCAM-1 and ICAM-1 were correlated with reductions in fasting and postprandial large VLDL particles (P < 0.0001) as well as postprandial oxidized fatty acids (P < 0.0005). CONCLUSIONS:--Triglyceride-lowering therapy with fenofibrate reduced fasting and postprandial free fatty acid oxidation and inflammatory responses, and these antiatherosclerotic effects were most highly correlated with reductions in large VLDL particles.

Context:Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown.Objective:To define differential gene expression and signaling pathways in leiomyoma cell populations.Design:Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b−. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2′-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma.Setting:Research laboratory.Patients:Eight African American women.Interventions:NoneMain Outcomes Measures:Gene expression patterns, cell proliferation, and differentiation.Results:A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b− intermediary cells, which then terminally differentiate to CD34−/CD49b− cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b− vs CD34−/CD49b− cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34−/CD49b− cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation.Conclusions:IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.Microarray and functional studies of three leiomyoma cell populations, including stem cells, implicated the IGF2 pathway in paracrine signaling and as important for cell proliferation.

The Yale Pharyngeal Residue Severity Rating Scale was developed, standardized, and validated to provide reliable, anatomically defined, and image-based assessment of post-swallow pharyngeal residue severity as observed during fiberoptic endoscopic evaluation of swallowing (FEES). It is a five-point ordinal rating scale based on residue location (vallecula and pyriform sinus) and amount (none, trace, mild, moderate, and severe). Two expert judges reviewed a total of 261 FEES evaluations and selected a no residue exemplar and three exemplars each of trace, mild, moderate, and severe vallecula and pyriform sinus residue. Hard-copy color images of the no residue, 12 vallecula, and 12 pyriform sinus exemplars were randomized by residue location for hierarchical categorization by 20 raters with a mean of 8.3 years of experience (range 2–27 years) performing and interpreting FEES. Severity ratings for all images were performed by the same 20 raters, 2 weeks apart, and with the order of image presentations randomized. Intra-rater test–retest reliability, inter-rater reliability, and construct validity were determined by pooled multi-category multi-rater kappa statistics. Residue ratings were excellent for intra-rater reliability for vallecula (kappa = 0.957 ± 0.014) and pyriform sinus (kappa = 0.854 ± 0.021); very good to excellent for inter-rater reliability for vallecula (kappa = 0.868 ± 0.011) and pyriform sinus (kappa = 0.751 ± 0.011); and excellent for validity for vallecula (kappa = 0.951 ± 0.014) and pyriform sinus (kappa = 0.908 ± 0.017). Clinical uses include accurate classification of vallecula and pyriform sinus residue severity patterns as none, trace, mild, moderate, or severe for diagnostic purposes, determination of functional therapeutic change, and precise dissemination of shared information. Scientific uses include tracking outcome measures, demonstrating efficacy of interventions to reduce pharyngeal residue, investigating morbidity and mortality in relation to pharyngeal residue severity, and improving training and accuracy of FEES interpretation by students and clinicians. The Yale Pharyngeal Residue Severity Rating Scale is a reliable, validated, anatomically defined, and image-based tool to determine residue location and severity based on FEES.

Background Literature has shown a significant relationship between radiation dose to the larynx and swallowing disorders. We prospectively studied the dose-volume relationship for larynx substructures and aspiration. Methods Forty nine patients with stage III/IV head-and-neck (H&N) squamous cell carcinoma were prospectively enrolled in this IRB-approved, federally funded study. All patients received IMRT-based chemoradiation therapy (CRT) and were scheduled for videofluorography (VFG) prior to CRT and at 3, 6, 9, 12, and 24 months post-CRT. Twelve laryngeal substructures were contoured in each patient: thyroid cartilage, cricoid cartilage, total epiglottis, suprahyoid epiglottis, infrahyoid epiglottis, total larynx, supraglottic larynx, subglottic larynx, glottic larynx, arytenoids, aryepiglottic (AE) folds, and glossoepiglottic fold. After exclusions, 29 patients were included in the final analysis. Incidence of aspiration at 1 year following CRT was correlated with dose-volume data to laryngeal substructures using logistic regression. Results The median age was 54 years with 79% being non-smokers. Tumor sites included oropharynx (22), unknown primary (6), and hypopharynx (1). One year following CRT, 10/29 (34%) showed aspiration on VFG. Dose to the AE folds showed the highest correlation with aspiration at 12 months and was significant on multivariate analysis ( p  = 0.025). A mean dose cutpoint of 6500 cGy or higher to the AE folds was associated with an increased risk of aspiration at 1 year [positive likelihood ratio (+LR) 2.81, positive predictive value (PPV) 60%, negative predictive value (NPV) 92.9%, relative risk (RR) 8.4]. Conclusions In this analysis, mean dose to the AE folds was associated with an increased risk of aspiration at 1 year. However, these are hypothesis-generating data that require further research and validation in a larger patient subset.

Cancer has surpassed heart disease as the leading cause of death among Hispanics in the U.S., yet data on cancer prevalence and risk factors in Hispanics in regard to ancestry remain scarce. This study sought to describe (a) the prevalence of cancer among Hispanics from four major U.S. metropolitan areas, (b) cancer prevalence across Hispanic ancestry, and (c) identify correlates of self-reported cancer prevalence. Participants were 16,415 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), who self-identified as Cuban, Dominican, Mexican, Puerto Rican, Central or South American. All data were collected at a single time point during the HCHS/SOL baseline clinic visit. The overall self-reported prevalence rate of cancer for the population was 4%. The rates varied by Hispanic ancestry group, with individuals of Cuban and Puerto Rican ancestry reporting the highest cancer prevalence. For the entire population, older age (OR = 1.47, p < .001, 95% CI, 1.26-1.71) and having health insurance (OR = 1.93, p < .001, 95% CI, 1.42-2.62) were all significantly associated with greater prevalence, whereas male sex was associated with lower prevalence (OR = 0.56, p < .01, 95% CI, .40-.79). Associations between study covariates and cancer prevalence also varied by Hispanic ancestry. Findings underscore the importance of sociodemographic factors and health insurance in relation to cancer prevalence for Hispanics and highlight variations in cancer prevalence across Hispanic ancestry groups. Characterizing differences in cancer prevalence rates and their correlates is critical to the development and implementation of effective prevention strategies across distinct Hispanic ancestry groups.

To create a standardized method for evaluating the video recordings of patients self-instilling eye drops and to determine the level of agreement of eye drop instillation efficacy, safety and efficiency ratings by three masked graders. Prospective cross-sectional study. 78 patients with open-angle glaucoma or ocular hypertension who had at least 6 months of experience with the use of eye drop medications. Participants were video recorded while self-instilling artificial tears sequentially to both eyes. Three masked observers graded these video recordings on three criteria: efficacy (the determination of whether an eye drop was instilled on the ocular surface), safety (assessment of whether the tip of the medication bottle made contact with the ocular surface or eyelids), and efficiency (the number of eye drops expressed from the bottle). After grading the video recordings based on efficacy, safety, and efficiency, kappa statistics were used to estimate inter-rater agreement. The mean kappa level of agreement for efficacy, safety, and efficiency was 0.64 (95% confidence interval (CI), 0.42-0.87), 0.73 (95% CI, 0.58-0.88), and 0.62 (95% CI, 0.42-0.81), respectively. We demonstrated good inter-rater reproducibility of the masked analysis of video recordings of patients self-instilling eye drops based on three criteria: efficiency, safety, and efficacy.

Aromatase inhibitors (AIs) are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC). Messenger RNA (mRNA) levels of 5 estrogen-related genes-AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR-were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy-defined as the combined complete response, partial response, and stable disease rates for at least 6 months-was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36%) and identical sensitivity (96%) to the current clinical practice (ERα/PR-IHC). In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection.

As the U.S. population ages, there is increasing need for data on the effects of aging in healthy elderly individuals over age 80. This investigation compared the swallowing ability of 8 healthy younger men between the ages of 21 and 29 and 8 healthy older men between the ages of 80 and 94 during two swallows each of 1 ml and 10 ml liquid. Videofluoroscopic studies of these swallows were analyzed to confirm the absence of swallowing disorders. Biomechanical analysis of each swallow was completed, from which data on temporal, range of motion, and coordination characteristics of the oropharyngeal swallow were taken. Position of the larynx at rest, length of neck, and pattern of hyoid bone movement were also compared between the two groups. None of the younger or older men exhibited any swallowing disorders. The C2 to C4 distance of older men was significantly shorter than that of younger men, and laryngeal position at rest was lower than in younger men but not significantly so. Older men had a significantly longer pharyngeal delay than younger men and significantly faster onset of posterior pharyngeal wall movement in relation to first cricopharyngeal opening. The older men exhibited significantly reduced maximum vertical and anterior hyoid movement as compared to the younger men even when accounting for the difference in C2 to C4 distance in older men. These data support the hypothesis of reduced muscular reserve in the swallows of older men as compared to younger men. Older men also exhibited less width of cricopharyngeal opening than younger men at 10 ml volume, indicating less upper esophageal sphincter flexibility in the swallows of older men. The potential for exercise to improve reserve is discussed. Significant changes in extent of hyoid elevation and duration of cricopharyngeal opening were seen as liquid bolus volume increased.