Suitability of Goal Attainment Scaling in Older Adult Populations with Neurodegenerative Disease Experiencing Cognitive Impairment: A Systematic Review and Meta-Analysis.

INTRODUCTION: Identifying responsive outcome measures for assessing functional change related to cognition, communication, and quality of life for individuals with neurodegenerative disease is important for intervention design and clinical care. Goal Attainment Scaling (GAS) has been used as an outcome measure to formally develop and systematically measure incremental progress toward functional, patient-centered goals in clinical settings. Evidence suggests that GAS is reliable and feasible for use in older adult populations and in adult populations with cognitive impairment, but no review has assessed the suitability of GAS in older adults with neurodegenerative disease experiencing dementia or cognitive impairment, based on responsiveness. This study conducted a systematic review to evaluate the suitability of GAS as an outcome measure for older adult populations with neurodegenerative disease experiencing dementia or cognitive impairment, based on responsiveness. METHODS: The review was registered with PROSPERO and performed by searching ten electronic scientific databases (PubMed, Medline OVID, CINAHL, Cochrane, Embase, Web of Science, PsycINFO, Scopus, OTSeeker, REHABDATA) and four registries (Clinicaltrials.gov, Grey Literature Report, Mednar, OpenGrey). A summary measure of responsiveness (post-intervention minus pre-intervention mean GAS T-score) was compared across eligible studies using a random-effects meta-analysis. Risk of bias in included studies was assessed using the NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. RESULTS: 882 eligible articles were identified and screened by two independent reviewers. Ten studies met inclusion criteria for the final analysis. Of the ten included reports, 3 focus on all-cause dementia, 3 on multiple sclerosis, 1 on Parkinson's disease, 1 on mild cognitive impairment, 1 on Alzheimer's disease, and 1 on primary progressive aphasia. Responsiveness analyses showed pre- and post-intervention GAS goals were significantly different from zero (Z = 7.48, p < 0.001), with post-intervention GAS scores being higher than pre-intervention GAS scores. Three included studies showed a high risk of bias, 3 showed a moderate risk of bias, and 4 showed a low risk of bias. Overall risk of bias of included studies was rated as moderate. CONCLUSION: GAS showed an improvement in goal attainment across different dementia patient populations and intervention types. The overall moderate risk of bias suggests that while bias is present across included studies (e.g., small sample size, unblinded assessors), the observed effect likely represents the true effect. This suggests that GAS is responsive to functional change and may be suitable for use in older adult populations with neurodegenerative disease experiencing dementia or cognitive impairment.

Communication Bridge™-2 (CB2): an NIH Stage 2 randomized control trial of a speech-language intervention for communication impairments in individuals with mild to moderate primary progressive aphasia.

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.

Association Between the Size and 3D CT-Based Radiomic Features of Breast Cancer Hepatic Metastasis.

PURPOSE: To evaluate the effect of the anatomic size on 3D radiomic imaging features of the breast cancer hepatic metastases. MATERIALS AND METHODS: CT scans of 81 liver metastases from 54 patients with breast cancer were evaluated. Ten most common 3D radiomic features from the histogram and gray level co-occurrence matrix (GLCM) categories were calculated for the hepatic metastases (HM) and compared to normal liver (NL). The effect of size was evaluated by using linear mixed-effects regression models. The effect of size on different radiomic features was analyzed for both liver lesions and background liver. RESULTS: Three-dimensional radiomic features from GLCM demonstrate an important size dependence. The texture-feature size dependence was found to be different among feature categories and between the HM and NL, thus demonstrating a discriminatory power for the tissue type. Significant difference in the slope was found for GLCM homogeneity (NL slope = 0.004, slope difference 95% confidence interval [CI] 0.06-0.1, p <0.001), contrast (NL slope = 45, slope difference 95% CI 205-305, p <0.001), correlation (NL slope = 0.04, slope difference 95% CI 0.11-0.21, p <0.001), and dissimilarity (NL slope = 0.7, slope difference 95% CI 3.6-5.4, p <0.001). The GLCM energy (NL slope = 0.002, slope difference 95% CI -0.0005 to -0.0003, p <0.007), and entropy (NL slope = 1.49, slope difference 95% CI 0.07-0.52, p <0.009) exhibited size-dependence for both NL and HM, although demonstrating a difference in the slope between themselves. CONCLUSION: Radiomic features of breast cancer hepatic metastasis exhibited significant correlation with tumor size. This finding demonstrates the complex behavior of imaging features and the need to include feature-specific properties into radiomic models.

Antibiotics Drive Microbial Imbalance and Vitiligo Development in Mice.

Vitiligo is impacted by environmental triggers. We studied the contribution of the microbiome in FH mice, in which depigmentation is mediated by tyrosinase-reactive T cells. The mice received oral antibiotics and were monitored for depigmentation. The microbiome was studied in fecal and skin samples using 16S rRNA analysis. The resulting T-cell distributions were evaluated. In untreated mice, pigment loss did not expand to the pelage, whereas mice in the ampicillin group were approximately 1/3 depigmented at 30 weeks. In contrast to models of autoimmunity that are less dependent on IFN-γ, ampicillin but not neomycin treatment correlated with accelerated disease and reduced bacteria in the fecal pellets. Modified cytokine patterns in the tissue and serum suggest a response that transcends the gut. Ampicillin-induced depigmentation was accompanied by gut but not skin dysbiosis, and reduced T cell numbers in both sites. Neomycin induced a redistribution of gut T cells and an accumulation of skin regulatory T cells. This treatment spurred a Bacteroides-dominated population of fecal bacteria. Reduced diversity is prominent particularly after ampicillin treatment, when the gut is dominated by Pseudomonas species. In line with current concepts relating the microbiome and the immune system, we predict that dietary measures might promote skin health and delay vitiligo onset.

The Effects of a Multicomponent Colorectal Cancer Screening Intervention on Knowledge, Recommendation, and Screening among Underserved Populations.

This trial tested a multicomponent intervention to increase colorectal cancer (CRC) screening among underserved patients. Participants were randomized to: (1) physician + patient intervention, (2) physician-only intervention, or (3) usual care (UC). Study outcomes included patient knowledge, physician recommendation of CRC screening, and screening completion via colonoscopy or stool tests. Among 538 participants, those exposed to the physician + patient intervention had significantly increased knowledge over patients in physician-only (p=.0008) or UC arms (p=.0003). However, there were no statistically significant differences in completion of CRC screening, with 10%, 20%, and 16% of UC, physician-only, and physician + patient participants screened, respectively. In UC, all completed screenings were colonoscopy, whereas in the physician-only and physician + patient arms, 39% and 46% of completed tests were via stool test, respectively. The multicomponent intervention did not increase overall CRC screening, yet results underscore the need to provide patients options for completing CRC screening.

A Brief Dermatology Curriculum in Skin Cancer Detection and Prevention to Improve Medical Student Knowledge and Confidence.

Introduction: While the incidence of skin cancers continues to rise, there remains a disproportionate lack of introductory training on skin cancer screening and identification of modifiable behaviors in medical curricula. Trainees and students have cited low confidence in their ability to counsel patients and lack of instruction as barriers. Methods: To address this need, we created a 1-hour didactic lecture based on a cognitive teaching framework for third-year medical students during their core primary care clerkship. The session highlighted visual identification of different skin cancers, factors increasing individual risk, and photoprotective behaviors. Session content was based on American Academy of Dermatology recommendations for skin cancer prevention. An assessment of knowledge, behaviors, and attitudes given before, immediately following, and at 6 months after the session was used to determine efficacy. Results: One hundred eight students before and immediately after the session demonstrated significantly improved knowledge (mean correct: 71% presession vs. 99% postintervention, p < .0001). Based on 39 participants completing 6-month follow-up, knowledge remained improved (mean answered correctly: 80%, p < .0001). Confidence in patient counseling on preventive behaviors, risk assessment, and reported likelihood of counseling significantly increased across the three time points (p < .0001 for all attitude questions). Specific topics included appropriate referral to a dermatologist, sunscreen application, and dangers of indoor tanning bed usage. Discussion: Our session on skin cancer screening and prevention demonstrated improvements in medical student knowledge, confidence, and patient counseling likelihood. This introductory curriculum could be adapted for multiple core clerkships or specialties.

PLIN2 Functions As a Novel Link Between Progesterone Signaling and Metabolism in Uterine Leiomyoma Cells.

CONTEXT: Uterine leiomyoma (fibroids) are the most common tumors in women. Recently, perilipin-2 (PLIN2) was identified as a critical target gene of the progesterone receptor; however, its function in the pathogenesis of fibroids is unknown. OBJECTIVE: To determine the function of PLIN2 in leiomyoma cells. DESIGN: Tissue and primary cells from leiomyoma and myometrium were analyzed. PLIN2 function in leiomyoma was assessed using small interfering RNA. RNA-sequencing was performed to identify genome-wide effects of PLIN2 depletion. Metabolic activity was measured using the Seahorse XF96 analyzer. Real-time quantitative PCR and immunoblotting were also performed. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Forty-one premenopausal women undergoing surgery for fibroids. MAIN OUTCOME MEASURES: Gene expression, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and cell proliferation. RESULTS: PLIN2 gene expression was 2.4-fold lower in leiomyoma compared with adjacent myometrium, suggesting a link between PLIN2 deficiency and fibroids. A total of 3877 genes were differentially expressed after PLIN2 knockdown. Gene ontology analysis identified metabolism as the second-highest biological process affected by PLIN2 depletion. OCR (mitochondrial respiration) and ECAR (glycolysis) were significantly upregulated after PLIN2 knockdown; PLIN2-depleted cells had a greater basal metabolic activity and higher metabolic stress response. Cell proliferation was also significantly increased after PLIN2 knockdown. CONCLUSIONS: PLIN2 depletion increases mitochondrial respiration and glycolysis, suggesting that PLIN2 is a critical regulator of metabolic function in leiomyoma cells. PLIN2 deficiency also reprograms leiomyoma cells to a proproliferative phenotype. These findings introduce metabolomics as an area to explore to better understand leiomyoma tumorigenesis.

Follow-up approaches to a health literacy intervention to increase colorectal cancer screening in rural community clinics: A randomized controlled trial.

BACKGROUND: Significant disparities exist in colorectal cancer (CRC) screening rates among those of low socioeconomic status, with fewer years of education, lacking health insurance, or living in rural areas. METHODS: A randomized controlled trial was conducted to compare the effectiveness of 2 follow-up approaches to a health literacy intervention to improve CRC screening: automated telephone call or personal call. Patients aged 50 to 75 years residing in 4 rural community clinics in Louisiana were given a structured interview that assessed demographic, health literacy and CRC screening barriers, knowledge, and attitudes. All were given health literacy-informed CRC education, a patient-friendly CRC screening pamphlet, simplified fecal immunochemical test (FIT) instructions, and a FIT kit, and a "teach-back" method was used to confirm understanding. Patients were randomized to 1 of 2 telephone follow-up arms. If they did not mail their FIT kit within 4 weeks, they received a reminder call and were called again at 8 weeks if the test still was not received. RESULTS: A total of 620 patients were enrolled. Approximately 55% were female, 66% were African American, and 40% had limited literacy. The overall FIT completion rate was 68%: 69.2% in the automated telephone call arm and 67% in the personal call arm. Greater than one-half of the patients (range, 58%-60%) returned the FIT kit without receiving a telephone call. There was no difference noted with regard to the effectiveness of the follow-up calls; each increased the return rate by 9%. CONCLUSIONS: Providing FIT kits and literacy-appropriate education at regularly scheduled clinic visits with a follow-up telephone call when needed was found to increase CRC screening among low-income, rural patients. The lower cost automated call was just as effective as the personal call.

Apathy and Disinhibition Related to Neuropathology in Amnestic Versus Behavioral Dementias.

OBJECTIVES: Investigating the frequency of apathy and disinhibition in patients clinically diagnosed with dementia of the Alzheimer type (DAT) or behavioral variant frontotemporal dementia (bvFTD) with neuropathology of either Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). METHODS: Retrospective data from 887 cases were analyzed, and the frequencies of apathy and disinhibition were compared at baseline and longitudinally in 4 groups: DAT/AD, DAT/FTLD, bvFTD/FTLD, and bvFTD/AD. RESULTS: Apathy alone was more common in AD (33%) than FTLD (25%), and the combination of apathy and disinhibition was more common in FTLD (43%) than AD (14%; P < .0001). Over time, apathy became more frequent in AD with increasing dementia severity (33%-41%; P < .006). CONCLUSIONS: Alzheimer disease neuropathology had the closest association with the neuropsychiatric symptom of apathy, while FTLD was most associated with the combination of apathy and disinhibition. Over time, the frequency of those with apathy increased in both AD and FTLD neuropathology.

Development and Validation of a Nomogram to Predict Lymphedema After Axillary Surgery and Radiation Therapy in Women With Breast Cancer From the NCIC CTG MA.20 Randomized Trial.

PURPOSE: Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer. METHODS AND MATERIALS: Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785). RESULTS: In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval [CI], 1.03-1.08, P < .001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 [95% CI, 1.53-7.89] P = .004; 12-15 lymph nodes, 4.04 [95% CI, 1.76-10.26] P = .002; ≥16 nodes, 5.08 [95% CI, 2.26-12.70] P < .001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 [95% CI, 1.08-2.56] P = .02; for extensive, 2.31 [95% CI, 1.28-4.10] P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76). CONCLUSIONS: The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials.

A Highly Sensitive Sandwich ELISA to Detect CSF Progranulin: A Potential Biomarker for CNS Disorders.

Progranulin (PGRN) plays critical roles in inflammation, tumorigenesis, and neurodegeneration. PGRN levels in blood and cerebrospinal fluid (CSF) are being increasingly investigated as potential biomarkers for these disorders. However, the value of CSF PGRN as a biomarker has been limited because currently available commercial enzyme-linked immunosorbent assay (ELISA) kits have suboptimal sensitivity for detecting CSF PGRN. In this study, pairs of monoclonal antibodies (MAbs) were first screened from eleven monoclonal antiPGRN antibodies using indirect ELISA, then a sandwich ELISA was established using the 2 optimized MAbs. This system displayed high sensitivity, with a lower limit of detection of 60.0 pg/mL and a lower limit of quantification of 150 pg/mL. By using this ELISA system, we showed varied CSF PGRN levels in different brain disorders. For example, as compared with the normal controls, patients with Alzheimer disease or multiple sclerosis showed mildly increased CSF PGRN; those with aseptic encephalitis or neuropsychiatric systemic lupus erythematosus showed moderately increased CSF PGRN; those with bacterial leptomeningitis showed severely increased CSF PGRN. Additionally, determining CSF PGRN levels could monitor CNS metastasis and CSF seeding of carcinomas. These results indicate that this system can be valuable in studying the diagnostic and prognostic value of CSF PGRN in brain disorders.

Dose-volume relationship for laryngeal substructures and aspiration in patients with locally advanced head-and-neck cancer.

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.

HSP70iQ435A-Encoding DNA Repigments Vitiligo Lesions in Sinclair Swine.

Human HSP70iQ435A carries a single amino-acid modification within the dendritic cell activating region and tolerizes dendritic cells in vitro. The underlying DNA was used to prevent and treat disease in vitiligo mouse models through reduced dendritic cell activation and diminished skin T-cell infiltration, suggesting the same may be useful for patients. Physiologic differences between mouse and human skin then called for studies in large animals with human-like skin. We established the efficiency of DNA jet injection into swine skin before subcloning HSP70iQ435A into clinically suitable vector pUMVC3. Vitiligo lesions in Sinclair swine were treated with plasmid DNA to measure changes in depigmentation, T-cell infiltration, expression of HSP70i in skin, serum HSP70i, and anti-HSP70i serum titers. Remarkable repigmentation following HSP70iQ435A-encoding DNA treatment persisted throughout the 6-month follow-up period. Repigmentation was accompanied by an initial influx of T cells accompanied by increased CD4/CD8 ratios, waning by week 15. Melanocytes spanned the border of repigmenting skin, suggesting that melanocyte repopulation precedes skin melanization. Serum titer fluctuations were not treatment-associated. Importantly, treatment did not interfere with melanoma immunosurveillance. These data encourage clinical testing of HSP70iQ435A.

Labor Curves in Multiparous Women Related to Interbirth Intervals.

OBJECTIVE: Previous studies have shown that risk of cesarean section increases among multiparous women as interbirth interval increases. One possibility is that progress of labor may vary with interbirth interval, such that with longer intervals, labor curves of multiparas more closely resemble those of nulliparas. We sought to define labor curves among a cohort of multiparas with varying interbirth intervals. STUDY DESIGN: This was a retrospective cohort study of term multiparas with known interval from last delivery and only vaginal deliveries. Subjects were grouped by interval between the studied pregnancy and the most recent birth: 0 to 59, 60 to 119, and ≥120 months. Statistical analysis was performed using linear mixed effects model. Group slopes and intercepts were compared using model t-tests for individual effects. Length of second stage was compared using a Wilcoxon's rank-sum test. RESULTS: Groups did not differ significantly in demographic or obstetrical characteristics. Rate of dilation was similar between the 0 to 59 and 60 to 119 month groups (p = 0.38), but faster in the ≥120 month group compared with the 60 to 119 month group (p = 0.037). Median duration of second stage increased slightly with increased interbirth interval (p = 0.003). CONCLUSION: Prolonged interbirth interval is not associated with slower active phase of labor.

Analysis of hierarchical biomechanical data structures using mixed-effects models.

Rigorous statistical analysis of biomechanical data is required to understand tissue properties. In biomechanics, samples are often obtained from multiple biopsies in the same individual, multiple samples tested per biopsy, and multiple tests performed per sample. The easiest way to analyze this hierarchical design is to simply calculate the grand mean of all samples tested. However, this may lead to incorrect inferences. In this report, three different analytical approaches are described with respect to the analysis of hierarchical data obtained from muscle biopsies. Each method was used to analyze an actual experimental data set obtained from muscle biopsies of three different muscles in the human forearm. The results illustrate the conditions under which mixed-models or simple models are acceptable for analysis of these types of data.