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Tiffany W Chow1–6, Ariel Graff-Guerrero4,6, Nicolaas PLG Verhoeff2–4,7, Malcolm A Binns3,8, David F Tang-Wai5,9, Morris Freedman1,3,5, Mario Masellis5,10, Sandra E Black3,5,10, Alan A Wilson4,6, Sylvain Houle4,6, Bruce G Pollock4,61Division of Neurology, 2Department of Psychiatry, 3Rotman Research Institute, Baycrest; 4Departments of Psychiatry, 5Medicine, Division of Neurology, University of Toronto; 6Centre for Addiction and Mental Health PET Centre; 7Kunin-Lunenfeld Applied Research Unit, Baycrest; 8Dalla Lana School of Public Health, University of Toronto; 9University Health Network Memory Clinic; 10LC Campbell Cognitive Neurology Research Unit, Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, Toronto, ON, CanadaBackground: Memantine has shown effects on cortical metabolism in Alzheimer's disease (AD), and the mechanism of action may not be specific to AD alone. We hypothesized that participants with frontotemporal dementia taking memantine would show an increased cortical metabolic activity in frontal regions, temporal regions, or in salience network hubs.Methods: Sixteen participants with behavioral or language variant frontotemporal dementia syndromes (FTD) were recruited from tertiary FTD clinics and treated with memantine hydrochloride 10 mg twice daily in this fixed-dose, open-label pilot study. The primary endpoint was enhancement of cortical metabolic activity after 7–8 weeks of treatment. Secondary endpoints were measures of mood and behavior disturbance, frontal executive function, and motor disturbance.Results: Voxel-wise parametric image analysis of positron emission tomography (PET) data from seven behavioral variant FTD patients, eight semantic dementia patients, and one progressive nonfluent aphasia patient, of mean age 64.3 years, mean duration of illness 4.25 years, and baseline mean sum of boxes Clinical Dementia Rating score 6.59, revealed an increase in [18F]-fluorodeoxyglucose (FDG) normalized metabolic activity in bilateral insulae and the left orbitofrontal cortex (P < 0.01). The increase on FDG-PET did not correlate with changes on behavioral inventories. Post hoc analysis indicated that semantic dementia participants drove this finding.Conclusion: This open-label clinical PET study suggests that memantine induces an increase in metabolism in the salience network in FTD. A placebo-controlled follow-up study is warranted.Keywords: Alzheimer's disease, frontotemporal dementia, metabolism, PET scan, semantic dementia

PURPOSE: This study was undertaken to investigate the chemical solubility and flexural strengths of 3 zirconia-based dental ceramics: In-Ceram Zirconia (IZ), In-Ceram 2000 YZ CUBES (YZ Zirconia) (Vita Zahnfabrik), and Cercon (Dentsply). A pressable lithium disilicate-reinforced glass ceramic (IPS Empress 2, Ivoclar Vivadent) was used as a control. MATERIALS AND METHODS: Ten block specimens (12 x 6 x 4 mm) of each ceramic material were prepared for chemical solubility testing. Each specimen was refluxed in 4% acetic acid solution for 16 hours. The percentage loss of mass and the loss of mass per unit of surface area for each specimen were calculated. Ten bar-shaped (21 x 5 x 2 mm) and 10 disk-shaped (16 mm diameter, 1.2 mm thickness) specimens of each ceramic material were prepared and tested for uniaxial flexural strength (UFS) and biaxial flexural strength (BFS). X-ray diffraction analyses were conducted to determine the relative amount of the monoclinic phase of the as-sintered and fractured surfaces of the zirconia ceramics. RESULTS: There were no significant differences among the ceramics in chemical solubility by percentage mass or mass/surface area. For UFS, YZ Zirconia (899 +/- 109 MPa) > Cercon (458 +/- 95 MPa) IZ (409 +/- 60 MPa) > Empress 2 (252 +/- 36 MPa). For BFS, YZ Zirconia (1,107 +/- 116 MPa) > Cercon (927 +/- 146 MPa) > IZ (523 +/- 51 MPa) > Empress 2 (359 +/- 43 MPa). The fractured YZ Zirconia surface contained approximately 5 times as much monoclinic phase compared to that of its intact surface. The fractured IZ and Cercon surfaces contained approximately twice as much monoclinic phase compared to those of intact surfaces. CONCLUSION: The ceramics tested all satisfied the chemical solubility allowance required of core ceramic material (type I, Class 1 or type II, Class 1) according to the International Organization for Standardization 6872:1995(E) specifications on dental ceramic. The zirconia-based ceramics possessed significantly higher flexural strengths than the control lithium disilicate ceramic. Their clinical application appears sufficiently promising for long-term clinical studies to be undertaken. [ABSTRACT FROM AUTHOR]

PURPOSE: To investigate 6 dental statuses as risk factors for malnutrition in geriatric patients admitted to a convalescent and rehabilitation hospital. MATERIALS AND METHODS: One hundred twenty (59 men and 61 women) geriatric patients admitted to a convalescent and rehabilitation hospital were recruited. Three biochemical and hematologic parameters (albumin, hemoglobin, and lymphocyte count) were used for analysis. Malnutrition was defined as Body Mass Index (BMI) below 18.5 and albumin level under 35 g/L. The number of natural or prosthetic teeth in the dentate patients, and the presence of one or both dentures in the edentate patients, were recorded. Risk factors associated with malnutrition were investigated, namely: (1) edentulism among all patients, (2) edentulism without a set of complete dentures among all patients, (3) edentulism without a set of complete dentures among the edentate patients, (4) decreased number (< 6) of occluding pairs of natural or prosthetic teeth among the dentate patients, (5) decreased number (< 5) of posterior occluding pairs of natural or prosthetic teeth among the dentate patients, and (6) absence of posterior occluding pairs of natural or prosthetic teeth among the dentate patients. One-way ANOVA and Bonferroni multiple comparisons were used to determine if significant differences in the anthropometric, biochemical, and hematologic parameters existed between the patients with different dental statuses. The odds ratio and significance of 6 dental statuses as risk factors of malnutrition were calculated (P = .05). RESULTS: BMI, albumin, and hemoglobin levels of the malnourished patients were significantly lower than those of nourished patients (P < .05). Lymphocyte count was not significantly different between the 2 patient groups (P > .05). The status of edentate patients without a set of complete dentures compared with other edentate and dentate patients was the only independent risk factor (P < .05) in the 6 statuses studied. CONCLUSION: Primary healthcare workers caring for hospitalized geriatric patients should identify edentate patients without a set of complete dentures for the possibility of malnutrition. [ABSTRACT FROM AUTHOR]

This clinical report presents the prosthodontic management of early peri-implant bone loss in a partially edentulous patient. Two narrow Branemark implants (3.3 mm in diameter) were placed to retain a mandibular implant prosthesis in the area of the mandibular left second premolar and first molar. Two weeks after the prosthesis was put into function, the distal implant exhibited soft tissue reactions. Radiographically, bone corresponding to 4 threads and 7 threads was lost at the mesial and distal sites, respectively. After occlusal load reduction was made to the existing prosthesis, bone was observed to have regenerated sufficiently to restore the defect radiographically, though not to the original level. The bone remained at a similar level at 36 months after treatment. [ABSTRACT FROM AUTHOR]

Objectives: To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open-label study of memantine in frontotemporal dementia (FTD).Methods: We repeated fluorodeoxyglucose positron emission tomography (FDG-PET) after 6 months of drug use and subjected the data to Statistical Parametrical Mapping (SPM) analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI) and the PET signal.Results: Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia (SD). The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p < 0.002) for five participants with SD. The 2-6-month interval revealed a late increase in normalized metabolic activity in the left insula (p < 0.013), right insula (p < 0.009), and left anterior cingulate (p < 0.005). The right anterior cingulate showed both an initial increase and a delayed further increase (2-6 months, p < 0.016). FBI scores worsened by 43.3%. One participant with SD opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases.Conclusions: Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Because one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure. [ABSTRACT FROM AUTHOR]

Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients' families. An informally observed 4-stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study, we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients with FTD and 47 patients with Alzheimer's disease (AD). We transformed the NPI scores into a single variable for each participant that represented the yearly rate of change in total NPI score and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive rate of change in NPI total score (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with yearly change in NPI total score in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary. [ABSTRACT FROM AUTHOR]

Objective: We explored whether prior findings of reduction in serotonin 2A receptor (5-HT(2A) R) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods: We derived 5-HT(2A) R nondisplaceable binding potentials (BP(ND) ) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results: The 5-HT(2A) R BP(ND) s decreased with age, a relationship best described by an exponential-decay regression. The BP(ND) s were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions: These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. [ABSTRACT FROM AUTHOR]

Background: The prevalence of dementia is placing an increased burden on specialists. Methods: Canadian neurologists responded to a structured questionnaire to assess reasons for referral and services provided as well as to compare the neurologists' perceptions of their practice characteristics against cases seen over a 3-month period. Results: The audit confirmed the participants' perception that family practitioners are the main referral source (358/453, 79%). Sixty-two percent of patients had undergone clinical investigation for dementia prior to being seen by the neurologist; 39% (177/453) were on pharmacotherapy at the time of referral, 68% were initiated on pharmacotherapy by the neurologist. A fifth of the referrals did not meet clinical criteria for dementia, which may be directly related to the prevalence of prior workup that did not include mental status testing. Conclusions: Neurologists currently treat patients referred for dementia who may already have been adequately evaluated and treated by primary care providers. [ABSTRACT FROM AUTHOR]

Localized severe chronic periodontitis is often seen in middle-aged patients, particularly when plaque control for malaligned teeth is not satisfactory. While orthodontic treatment can realign such teeth with reduced periodontal support, esthetics may be compromised by gingival recession due to preexisting bone loss and resolution of inflammation after periodontal treatment. This clinical report describes how a malaligned maxillary lateral incisor with severe periodontitis was replaced by an immediately placed implant and implant-supported crown with a good esthetic outcome. [ABSTRACT FROM AUTHOR]

STATEMENT OF PROBLEM: Although ceramic veneers have been proven to be clinically successful in longevity studies, there is little information on the contrast ratios and masking ability of the available ceramic systems because dental laboratory technology and expensive experimental equipment are required for the investigation. Moreover, the complexity in understanding how to evaluate translucent ceramic materials may also explain why information in this area is limited. PURPOSE: The purpose of this study was to determine the contrast ratios and masking abilities of 3 types of all-ceramic veneers by measuring their luminance and color difference over white and black backgrounds. MATERIAL AND METHODS: Disk-shaped specimens (8-mm diameter x 0.7-mm thickness) of Shade A2 (Vita Lumin) of 3 types of all-ceramic systems: Procera (n=8), Empress 2 (n=8), and Vitadur Alpha (n=10) were fabricated. The luminance (as Y) and color (as CIE L*a*b*) of the specimens were measured with a colorimeter. The contrast ratio (CR=Yb/Yw), defined as the ratio of illuminance (Y) of the test material when it is placed on the black background (Yb) to the illuminance of the same material when it is placed over a white background (Yw), was determined. The masking ability of a specimen was evaluated by calculating the color difference (DeltaE) of the veneers over white and black backgrounds. Both CR and DeltaE* data were analyzed with 1-way ANOVA and the Tukey HSD test (alpha=.05). RESULTS: The mean contrast ratios (SD) of Procera, Empress 2, and Vitadur Alpha specimens were 0.50 (0.02), 0.46 (0.05), and 0.39 (0.02), respectively. CR values were significantly different among the 3 materials (P<.001). Procera veneers had a significantly higher CR compared to Empress 2 (P=.01) or Vitadur Alpha (P=.01), whereas the CR of Empress 2 was significantly higher than that of Vitadur Alpha (P=.046). Color difference (DeltaE*) (SD) of Procera, Empress 2, and Vitadur Alpha specimens over black and white backgrounds were 24.46 (1.03), 25.80 (1.03), and 31.08 (1.19), respectively. DeltaE* values were statistically different among the 3 materials (P<.001). Vitadur Alpha specimens had significantly higher DeltaE* when compared with Procera (P<.001) or Empress 2 (P<.001), whereas DeltaE* values between Procera and Empress 2 were not significantly different (P=.331). CONCLUSIONS: Vitadur Alpha had significantly lower contrast ratio and poorer masking ability compared to Procera or Empress 2. The clinical application of Vitadur Alpha as a veneer material over discolored teeth is cautioned. Although the contrast ratio of Procera was significantly higher than that of Empress 2, the masking abilities of these materials were not significantly different. The clinical application of these 2 ceramics as a veneer material may still be limited when applied over intense tooth discoloration because neither can fully mask the color of a black background. [ABSTRACT FROM AUTHOR]

Subjects enrolled in the Autopsy Program at the University of Southern California Alzheimer's Disease Research Center may receive clinical diagnoses from primary care providers in the community or from specialists in neurology. We reviewed the autopsy concordance rates for 463 subjects for diagnoses made by both groups of clinicians. Seventy-seven percent of the sample met neuropathological criteria for Alzheimer's disease (AD). The overall diagnostic accuracy for this sample was 81 percent. Neurologists assessed 200 of the subjects (43 percent). The diagnostic accuracy for any clinical diagnosis among the non-neurologists was 84 percent, and 78 percent (p = 0.07) among neurologists. For AD, non-neurologists had a diagnostic concordance rate of 91 percent and neurologists 87 percent. Where neuropathological AD was missed, non-neurologists had failed to detect any cognitive impairment; neurologists had diagnosed Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Erroneous clinical diagnoses of AD missed dementia with Lewy bodies (DLB) or AD concurrent with Parkinson's disease (PD). Our findings identify specific foci for improving clinical diagnosis of dementia among all physicians managing dementia. [ABSTRACT FROM AUTHOR]

This study aimed to compare the retentive forces of cast cobalt-chromium (Co-Cr) and commercially pure titanium (cpTi) clasps. A clasp assembly comprising a pair of symmetrical clasps was made to fit the opposite halves of a hardened stainless-steel sphere. This twin clasp was designed to counterbalance the tipping forces when the clasp assembly was drawn from the sphere. A total of 120 clasp assemblies were fabricated in cast Co-Cr and cpTi and placed at undercut depths of 0.25 mm, 0.50 mm, and 0.75 mm (n = 20 for each). For Co-Cr clasps, the retentive forces at these undercuts depths were 2.34 +/- 0.23 N, 4.65 +/- 0.35 N, and 7.56 +/- 0.50 N, respectively. The corresponding retentive forces for cpTi clasps were 1.24 +/- 0.13 N, 2.34 +/- 0.23 N, and 3.70 +/- 0.27 N. The retentive force of cpTi clasps was approximately half that of Co-Cr clasps for the same undercut depth. [ABSTRACT FROM AUTHOR]

Question: How effective and safe is Huperzine A for Alzheimer's disease?Outcomes: Changes in cognitive function (eg, from scores on Mini Mental State Examination (MMSE), Hasegawa Dementia Scale (HDS), or ADAS-Cog), changes to global clinical assessment (eg, from scores on Clinical Dementia Rating (CDR) or Clinician Interview-Based Impression (CIBIC-Plus)), all cause mortality, adverse events.METHODSDesign: Systematic review with meta-analysis.Data sources: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, CBM, AMED and relevant websites were searched in February 2006. Relevant journals and reference lists of studies were hand searched; unpublished material was identified by contacting experts in the field.Study selection and analysis: All RCTs of Huperzine A in adults with Alzheimer's disease (AD) of any severity were included. Participants had to be diagnosed with AD using standard criteria (ICD-9 or -10, DSM III, III-R or IV, or National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria). Comparators could include routine treatment or placebo. Missing data were sought from authors.MAIN RESULTSSix RCTs (454 participants) met inclusion criteria; all of these RCTs were carried out in China. Four RCTs were placebo controlled, one RCT compared Huperzine A plus Vitamin E versus placebo plus Vitamin E, and one RCT had two comparators: acupuncture and routine treatment. Huperzine A was given orally for between eight and 36 weeks in all trials, with doses ranging from 0.2 mg to 0.4 mg daily. The RCT comparing Huperzine A plus Vitamin E versus placebo plus Vitamin E trial was considered to be of relatively good quality, while the remainder were fair or poor. Efficacy versus placebo: Huperzine A improved general cognitive function when measured on the MMSE, although not on the Hasegawa Dementia Scale (HDS) (MMSE: 4 RCTs, 220 participants; WMD 2.81, 95% CI 1.87 to 3.76; HDS: 2 RCTs, 131 participants; WMD +2.78, 95% CI -0.17 to +5.73), and global clinical assessment (CDR: 1 RCT, 65 participants; WMD -0.80, 95% CI -0.95 to -0.65). Huperzine A plus Vitamin E improved general cognitive function and global clinical assessment at 12 weeks (1 RCT, 202 people; MMSE: WMD 2.51, 95% CI 1.74 to 3.28; ADAS-Cog: WMD -5.36, 95% CI, -7.08 to -3.64; improvement on CIBIC-plus: OR 4.33, 95% CI 2.37 to 7.90). Adding Huperzine A to routine care improved general cognitive performance (1 RCT, 21 participants; MMSE: WMD 5.38, 95% CI 3.72 to 7.04). Safety: Huperzine A was associated with mild cholinergic adverse events. There was no significant difference between Huperzine A and placebo in adverse events.CONCLUSIONSAlthough available trials indicate some benefits from Huperzine A for people with Alzheimer's disease, the trials were generally small and of limited quality. There is insufficient evidence to draw firm conclusions about the efficacy of Huperzine A. [ABSTRACT FROM AUTHOR]

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted.

Introduction: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population., Methods: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese., Results: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception., Discussion: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness., Highlights: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: This study aims to show the usefulness of incorporating a community-based geographical information system (GIS) in recruiting research participants for the Asian Cohort for Alzheimer's Disease (ACAD) study for using the subgroup of Korean American (KA) older adults. The ACAD study is the first large study in the USA and Canada focusing on the recruitment of Chinese, Korean and Vietnamese older adults to address the issues of under-representation of Asian Americans in clinical research., Methods: To promote clinical research participation of racial/ethnic minority older adults with and without dementia, we used GIS by collaborating with community members to delineate boundaries for geographical clusters and enclaves of church and senior networks, and KA serving ethnic clinics. In addition, we used socioeconomic data identified as recruitment factors unique to KA older adults which was analysed for developing recruitment strategies., Results: GIS maps show a visualisation of the heterogeneity of the sociodemographic characteristics and the resources of faith-based organisations and KA serving local clinics. We addressed these factors that disproportionately affect participation in clinical research and successfully recruited the intended participants (N=60) in the proposed period., Discussion: Using GIS maps to locate KA provided innovative inroads to successful research outreach efforts for a pilot study that may be expanded to other underserved populations across the USA in the future. We will use this tool subsequently on a large-scale clinical genetic epidemiology study., Policy Implication: This approach responds to the call from the National Institute on Aging to develop strategies to improve the health status of older adults in diverse populations. Our study will offer a practical guidance to health researchers and policymakers in identifying understudied and hard-to-reach specific Asian American populations for clinical studies or initiatives. This would further contribute in reducing the health and research disparity gaps among older minority populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene-expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug clinical data set that could be leveraged to research the unique biology of pediatric AML and sets the stage for realizing functional precision medicine for the clinical management of the disease., Significance: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476., (©2022 The Authors; Published by the American Association for Cancer Research.)

Macrophages comprise the front line of defense against various pathogens. Classically activated macrophages (M1), induced by IFN-γ and LPS, highly express inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4 and IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Ak4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP and maintains the homeostasis of cellular nucleotides which is essential for cell functions. However, its role in regulating the function of macrophages is not fully understood. Here we report that Ak4 expression is induced in M1 but not M2 macrophages. Suppressing the expression of Ak4 in M1 macrophages with shRNA or siRNA enhances ATP production and decreases ROS production, bactericidal ability and glycolysis in M1 cells. Moreover, Ak4 regulates the expression of inflammation genes, including Il1b, Il6, Tnfa, Nos2, Nox2 , and Hif1a , in M1 macrophages. We further demonstrate that Ak4 inhibits the activation of AMPK and forms a positive feedback loop with Hif1α to promote the expression of inflammation-related genes in M1 cells. Furthermore, RNA-seq analysis demonstrates that Ak4 also regulates other biological processes in addition to the expression of inflammation-related genes in M1 cells. Interestingly, Ak4 does not regulate M1/M2 polarization. Taken together, our study uncovers a potential mechanism linking energy consumption and inflammation in macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chin, He, Chow, Yu, Lai and Miaw.)

Importance: Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial., Objective: To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial., Design, Setting, and Participants: A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019., Interventions: Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices., Main Outcomes and Measures: The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months., Results: A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment., Conclusions and Relevance: In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort., Trial Registration: ClinicalTrials.gov Identifier: NCT01767909.

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9 + cases had a significantly lower 5-year relapse-free survival rate than CD9 - cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9 + cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G 0 /G 1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.

Several physiologically-based pharmacokinetic (PBPK) models have been reported for intravenous (IV) and subcutaneous (SC) injections, but there has been a paucity of work for intramuscular (IM) injections. The primary objective of this work was a wide-scale evaluation of the predictive performance of IM PBPK models of therapeutic proteins. PBPK models for all administration routes available in the literature have regarded muscle as the total muscle (TM) in the body; however, anatomically, the body is composed of discrete muscle groups. Clinically, IM is administered to a specific muscle (SM). We explored the predictive performance of IM PBPK models with an SM or TM dosing site. The plasma concentration-time profiles of seven therapeutic proteins after an IM dose in humans served as the clinically observed data for model evaluation - this was a diverse group ranging from 30 to 149 kDa from six protein classes. Pharmacokinetic parameters C max , t max , AUC 0-∞ , and ka were estimated. SM and TM IM PBPK approaches were compared using Average Fold Error (AFE) and Pearson Chi-Square LineShape analyses. This work represents the first wide-scale validation of IM PBPK models and suggests that these models predict IM PBPK reasonably well. The SM and TM approach provided comparable performance.

1. The objective was to determine the ontogeny of stereoselective fluoxetine (FX) disposition in postnatal sheep from newborn to adulthood. 2. Catheters were implanted in a carotid artery and jugular vein. FX was administered intravenously, followed by serial arterial blood and cumulative urine collection. The concentrations of R,S -FX and R,S -norfluoxetine ( R,S -NFX) in samples were measured using a validated enantioselective LC/MS/MS analytical method. 3. The metabolism of FX at 4.2 ± 0.4 days was limited compared to adults, but had developed compared to the fetus. Total body clearance (Cl TB ) did not significantly increase up to 33.6 ± 0.9 days, but significantly increased at 98.5 ± 2.0 days, with no further changes up to 397.3 ± 8.5 days. Up to 13.4 ± 0.8 days, the disposition of FX included Phase I metabolism to NFX and trifluoromethylphenol (TFMP), and renal elimination. At 32.9 ± 0.9 days, metabolism included Phase II conjugates of FX and NFX. Renal elimination of these compounds was low. 4. The elimination of FX increased in a non-linear manner during the first year in sheep. The metabolism and disposition of FX and NFX in plasma and urine were stereoselective and this appeared due to both stereoselective protein binding and metabolism.

Importance: Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease., Objective: To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated., Design, Setting, and Participants: This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018., Interventions: AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks., Main Outcomes and Measures: Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers., Results: Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness., Conclusions and Relevance: Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures., Trial Registration: ClinicalTrials.gov identifier: NCT02167256.

Objective: To prospectively evaluate patient-reported outcome measures (PROMs) and treatment outcomes of mandibular two-implant retained overdentures (IOD) in an edentulous geriatric cohort with history of deficient complete dentures (CD)., Materials and Methods: A total of 103 patients with deficient CD received new optimal CD. After a period of 3 months, 80 of the patients voluntarily received IOD. Outcomes collected at pre-, post-CD/post-IOD treatment annually up to 5 years, included (a) Clinical outcomes: denture-quality (Woelfel's index), complications, and maintenance events, (b) PROMs: patient complaints (maxillary, mandibular functional complaint scores, generic aesthetic complaint scores, frequency, and intensity of complaints) and patient satisfaction, and (c) Maintenance events: technical complications and adverse events., Results: Five-year data were collected from 67 patients (mean age at initiation = 71.3 years, mean observation = 5.9 years) with cumulative implant survival rate = 98.72%. Multiple comparisons for 8 time points showed significant improvements in denture quality and PROMs after new CD and IOD delivery. Further significant improvements were only after IOD delivery in: mandibular denture-quality, mandibular and generic functional complaints, frequency, intensity of complaints, and overall patient satisfaction score. Thereafter, denture-quality and PROMs remained stable. Maintenance events clustered on 1st year and within a minority of patients. Technical complications and overall maintenance events significantly correlated with overall patient satisfaction score at 1st year., Conclusions: Mandibular IOD was a beneficial treatment option for seniors with history of deficient CD, improving denture-quality, patient satisfaction, and reducing patient complaints up to 5 years. Maintenance events clustered on 1st year, showing no significant impact on long-term patient satisfaction and other PROMs., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To test a culturally tailored intervention to improve Alzheimer's disease (AD) literacy among African Americans., Design: A 3-arm randomized comparative effectiveness trial., Setting: Community sites in Los Angeles, CA., Participants: 193 African American community-dwelling adults, ages 45 to 95 years old., Intervention: All groups attended BrainWorks Live, a culturally tailored, 60-minute talk show and received standard printed educational materials on AD. From there: a) the BrainWorks Live group received no further contact until the post-test; b) one intervention group received a 1-month, culturally tailored, unidirectional, daily text-message program; and c) a second intervention group received daily text messages based on the printed educational materials that the general public would receive. AD literacy was measured at baseline and one month post intervention., Measurements: Alzheimer's disease literacy and demographic and health covariates., Results: At one month, participants who received culturally tailored text messages had the highest increase in AD literacy levels, followed by those in the BrainWorks Live arm. Participants who received general text messages had a lower overall increase in AD literacy levels compared to the other arms, but had higher mean AD literacy levels than the BrainWorks Live arm. There was a significantly greater increase in AD literacy levels among participants who received culturally tailored text messages compared with those who attended BrainWorks Live only. There were no other statistically significant differences between arms., Conclusions: AD literacy among African Americans can be improved after only one month through culturally competent, economically feasible educational formats., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Langerhans cell histiocytosis (LCH) is a rare disease with diverse clinical courses. Despite improvement in survival outcomes in the recent decades, sequelae of the disease remain a concern. This study aimed to provide information on the long-term outcomes in patients with LCH, particularly on the sequelae and any associated factors., Method: Medical records of patients with diagnosis of LCH and being managed in our centre were retrospectively reviewed. Data on the courses of illness, mortality, intervention, types and time of late events were collected and analysed., Results: 70 patients were included with a mean observation time of 12 years (median 10.7 years, range 1-31.3 years). Sequelae related to LCH were present in 56% (n=39), being more common in multisystem diseases and patients with reactivations. Prevalence of sequelae is as follows: orthopaedic related 27%, diabetes insipidus 19%, growth retardation 13%, cosmetic 10%, neurological 7%, hearing 7%, anterior pituitary hormone deficiency 7%, hepatobiliary 4% and ophthalmological 3%. Neurological sequelae could manifest even 10 years after initial diagnosis of LCH. Reactivations, presence of central nervous system (CNS) risk lesions and treatment with radiotherapy were associated with a higher rate of sequelae. The cumulative incidence of reactivation was 34%. Most reactivations occurred in the first 2.5 years after diagnosis., Conclusion: Sequelae were common after LCH, although some were mild. Neurological sequelae could be particularly severe and debilitating. Vigilant long-term follow-up would be essential for optimising patient outcomes. Further studies on the prevention and treatment of CNS disease of LCH are warranted., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs. The high-level organization of a typical mAb PBPK model consists of a whole-body PBPK model with organ compartments interconnected by both blood and lymph flows. The whole-body PBPK model is coupled with tissue-level submodels used to describe key mechanisms governing mAb disposition including tissue efflux via the lymphatic system, elimination by catabolism, protection from catabolism binding to the neonatal Fc (FcRn) receptor, and nonlinear binding to specific pharmacological targets of interest. The use of PBPK modeling in the development of therapeutic proteins is still in its infancy. Further application of PBPK modeling for therapeutic proteins will help to define its developing role in drug discovery and development., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of the present study was to compare the accuracy of radiographic measurements for dental implants planning using cone-beam computed tomography (CBCT) and helical computed tomography (HCT)., Methods: Six pig ribs were wrapped by putty impression material, with radiographic markers placed. Two CBCT and an HCT were taken following the standard protocols. Twenty-five locations were selected, with vertical and horizontal dimensions measured using the default software, as well as on the processed HCT films by a digital caliper. The actual dimensions of the ribs measured by the digital caliper served as the control. Differences between radiographic dimensions and the actual dimensions were tested by two-way analysis of variance., Results: No differences were found between measurements made by CBCT and HCT images using the default software (P > 0.05). However, both measurements were statistically-significantly lower than the control (P < 0.001), and the mean difference was 0.3 mm. Measurements made on HCT films were statistically-significantly greater than the control (P < 0.001), and the mean difference was 0.5 mm., Conclusion: The accuracy of CBCT and HCT are similar, and both are reliable tools for implant planning. It is preferable to perform the planning using default software, rather than making direct measurements on films., (© 2016 John Wiley & Sons Australia, Ltd.)

Objective: The purpose of this prospective clinical study was to determine whether reduced bone mineral density (BMD) is correlated with a higher risk for dental implant therapy in an elderly patient population., Material and Methods: Seventy-nine patients recruited at the Prince Philip Dental Hospital were provided with 2-implant-supported mandibular overdentures. Skeletal BMD was recorded before the implant therapy. The World Health Organization Osteoporosis Diagnosis Classification (femoral neck score) was utilized to define the osteoporosis status of patients. Periapical radiographs were taken with a special radiographic holder at the time of implant loading (baseline) and at follow-up examinations. The mesial and distal marginal bone levels of each implant were measured. The mean marginal bone loss (mMBL) and greatest marginal bone loss (GBL) of four implant sites at patient level were recorded for data analysis. Clinical examination including plaque score (PI) and bleeding on probing (BOP) was recorded., Results: Of the 79 patients recruited in the study, the survival rate of implant was 98.7%. Sixty-three patients (79.7%) were finally available for data collection and statistical analyses. The mean follow-up time was 62.9 (SD = 15.2) months with the mean MBL 0.65 mm (SD = 0.67) and mean GBL 1.25 mm (SD = 0.83), respectively. The average BOP and PI of patients were 49.6% (SD = 30.8) and 47.4% (SD = 37.4). Only BOP was found significantly correlated with mMBL (r = 0.321, P = 0.01). Skeletal BMD was not associated with marginal bone loss (mean MBL: r = -0.094, P = 0.466; mean GBL: r = 0.04, P = 0.761)., Conclusions: Within the limits of this study, osteoporosis was not a contraindication for implant therapy, and reduced skeletal BMD was not associated with increased marginal bone loss around implants or other complications in an elderly population., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Objective: The relationship between repeated concussions and neurodegenerative disease has received significant attention, particularly research in postmortem samples. Our objective was to characterise retired professional ice hockey players' cognitive and psychosocial functioning in relation to concussion exposure and apolipoprotein ε4 status., Methods: Alumni athletes (N=33, aged 34-71 years) and an age-matched sample of comparison participants (N=18) were administered measures of cognitive function and questionnaires concerning psychosocial and psychiatric functioning., Results: No significant group differences were found on neuropsychological measures of speeded attention, verbal memory or visuospatial functions, nor were significant differences observed on computerised measures of response speed, inhibitory control and visuospatial problem solving. Reliable group differences in cognitive performance were observed on tests of executive and intellectual function; performance on these measures was associated with concussion exposure. Group differences were observed for cognitive, affective and behavioural impairment on psychosocial questionnaires and psychiatric diagnoses. There was no evidence of differential effects associated with age in the alumni athletes. Possession of an apolipoprotein ε4 allele was associated with increased endorsement of psychiatric complaints, but not with objective cognitive performance., Conclusions: We found only subtle objective cognitive impairment in alumni athletes in the context of high subjective complaints and psychiatric impairment. Apolipoprotein ε4 status related to psychiatric, but not cognitive status. These findings provide benchmarks for the degree of cognitive and behavioural impairment in retired professional athletes and a point of comparison for future neuroimaging and longitudinal studies., Competing Interests: Competing interests: BL provides expert consultation on medicolegal cases involving brain injury and neurodegenerative disease, and he receives royalties for sales and training for the Goal Management Training® intervention for executive function impairments. JLK has received speaker fees from pharmaceutical companies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Differential patterns of white matter disruption have recently been reported in the non-fluent (nfvPPA) and semantic (svPPA) variants of primary progressive aphasia (PPA). No single measure is sufficient to distinguish between the PPA variants, but connected speech allows for the quantification of multiple measures. The aim of the present study was to further investigate the white matter correlates associated with connected speech features in PPA. We examined the relationship between white matter metrics and connected speech deficits using an automated analysis of transcriptions of connected speech and diffusion tensor imaging in language-related tracts. Syntactic, lexical, and semantic features were automatically extracted from transcriptions of topic-directed interviews conducted with groups of individuals with nfvPPA or svPPA as well as with a group of healthy controls. A principal component analysis was performed in order to reduce the number of language measures and yielded a five-factor solution. The results indicated that nfvPPA patients differed from healthy controls on a syntactic factor, and svPPA patients differed from controls on two semantic factors. However, the patient groups did not differ on any factor. Moreover, a correlational analysis revealed that the lexical richness factor was significantly correlated with radial diffusivity in the left inferior longitudinal fasciculus, which suggests that semantic deficits in connected speech reflect a disruption of this ventral pathway, and which is largely consistent with the results of previous studies. Using an automated approach for the analysis of connected speech combined with probabilistic tractography, the present findings demonstrate that nfvPPA patients are impaired relative to healthy controls on syntactic measures and have increased radial diffusivity in the left superior longitudinal fasciculus, whereas the svPPA group was impaired on lexico-semantic measures relative to controls and showed increased radial diffusivity in the uncinate and inferior longitudinal fasciculus bilaterally.

This paper introduces a new framework for the organization of electronic books (e-books) and their corresponding authors using a multilayer self-organizing map (MLSOM). An author is modeled by a rich tree-structured representation, and an MLSOM-based system is used as an efficient solution to the organizational problem of structured data. The tree-structured representation formulates author features in a hierarchy of author biography, books, pages, and paragraphs. To efficiently tackle the tree-structured representation, we used an MLSOM algorithm that serves as a clustering technique to handle e-books and their corresponding authors. A book and author recommender system is then implemented using the proposed framework. The effectiveness of our approach was examined in a large-scale data set containing 3868 authors along with the 10500 e-books that they wrote. We also provided visualization results of MLSOM for revealing the relevance patterns hidden from presented author clusters. The experimental results corroborate that the proposed method outperforms other content-based models (e.g., rate adapting poisson, latent Dirichlet allocation, probabilistic latent semantic indexing, and so on) and offers a promising solution to book recommendation, author recommendation, and visualization.

Background/aims: Frank agrammatism, defined as the omission and/or substitution of grammatical morphemes with associated grammatical errors, is variably reported in patients with nonfluent variant primary progressive aphasia (nfPPA). This study addressed whether frank agrammatism is typical in agrammatic nfPPA patients when this feature is not required for diagnosis., Method: We assessed grammatical production in 9 patients who satisfied current diagnostic criteria. Although the focus was agrammatism, motor speech skills were also evaluated to determine whether dysfluency arose primarily from apraxia of speech (AOS), instead of, or in addition to, agrammatism. Volumetric MRI analyses provided impartial imaging-supported diagnosis., Results: The majority of cases exhibited neither frank agrammatism nor AOS., Conclusion: There are nfPPA patients with imaging-supported diagnosis and preserved motor speech skills who do not exhibit frank agrammatism, and this may persist beyond the earliest stages of the illness. Because absence of frank agrammatism is a subsidiary diagnostic feature in the logopenic variant of PPA, this result has implications for differentiation of the nonfluent and logopenic variants, and indicates that PPA patients with nonfluent speech in the absence of frank agrammatism or AOS do not necessarily have the logopenic variant.

The relationship between carotid disease and modestly abnormal airflow in ex-smokers without chronic obstructive pulmonary disease (COPD) is not well-understood. We generated 3D ultrasound measurements of carotid vessel-wall-plus-plaque thickness (VWT) and vessel wall volume (VWV) to quantify and evaluate such carotid ultrasound measurements in ex- and never-smokers without airflow limitation. These patients did not fulfill the diagnostic criteria for COPD. We also investigated the relationship of carotid atherosclerosis with pulmonary phenotypes of COPD. We evaluated 61 subjects without a clinical diagnosis of pulmonary or vascular diseases including 34 never-smokers (72 ± 6 year) and 27 ex-smokers (73 ± 9 year). We measured mean VWT ([Formula: see text]) and mean VWT specific to carotid regions-of-interest ([Formula: see text]) and evaluated potential differences between ex- and never-smokers. Carotid ultrasound and pulmonary disease measurement relationships were also evaluated using correlation coefficients (r) and multivariate regression analyses. Ex-smokers had a significantly greater [Formula: see text] (p = 0.003) and [Formula: see text] (p < 0.00001) than never-smokers, whereas a significant difference between the two groups was not detected by VWV (p = 1.0). There were significant correlations between the ventilation defect percent (VDP) measured by MRI with [Formula: see text] (r = 0.42, p = 0.001) and [Formula: see text] (r = 0.56, p = 0.00001). Multivariate regression models showed that VDP significantly predicted [Formula: see text] (β = 0.38, p = 0.004) and [Formula: see text] (β = 0.50, p = 0.00001). VWT-based measurements detected differences in vessel-wall-plus-plaque burden in ex- and never-smokers, which were not revealed using VWV. There were significant correlations between cardiovascular and pulmonary disease biomarkers in these ex-smokers who did not have a clinical diagnosis of pulmonary or carotid disease.

Background: Pittsburgh compound B ([11C]-PIB) identifies amyloid-β (Aβ) deposition in vivo. Asymptomatic Aβ deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aβ deposition., Objective: Comparison of Aβ deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia., Methods: Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff., Results: The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD., Conclusions: Aβ deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aβ deposition. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In previous work we demonstrated how a confocal microscope with a spatial light modulator in the back focal plane could perform accurate measurement of the k-vector of a propagating surface plasmon. This involved forming an embedded interferometer between light incident close to normal incidence (reference beam) and light incident at the angle to excite surface plasmons (sample beam). The signal from the interferometer was extracted by stepping the phase of the reference beam relative to the sample beam using a spatial light modulator; this requires at least 3 phase steps, which limits the speed of operation. To overcome this and extract the same information with a single measurement, we project an azimuthal varying phase between 0 and 2π in the central region of the back focal plane; corresponding to small angles of incidence. This projects a vortex beam as the reference, so that the phase of the reference beam varies with azimuthal angle. By extracting the interference signal from different portions of the reference beam, different phase steps between the reference and the sample are obtained, so all the values required for phase reconstruction can be extracted simultaneously. It is thus possible to obtain the same information with a single shot measurement, at each defocus position, without additional changes to the back focal plane illumination. Results are presented to show that the vortex illuminated sample provides similar results to the phase stepped version, whose values are, in turn, validated with ellipsometry and surface profilometry.

Objective: This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls., Design: 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups--mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory--based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients., Results: The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures., Conclusions and Relevance: This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS-FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD.

Objective: To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias., Methods: Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer's disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups., Results: The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias., Conclusions: A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.

Cluster analysis of unlabeled data sets has been recognized as a key research topic in varieties of fields. In many practical cases, no a priori knowledge is specified, for example, the number of clusters is unknown. In this paper, grid clustering based on the polar self-organizing map (PolSOM) is developed to automatically identify the optimal number of partitions. The data topology consisting of both the distance and density is exploited in the grid clustering. The proposed clustering method also provides a visual representation as PolSOM allows the characteristics of clusters to be presented as a 2-D polar map in terms of the data feature and value. Experimental studies on synthetic and real data sets demonstrate that the proposed algorithm provides higher clustering accuracy and lower computational cost compared with six conventional methods.

Multilabel learning aims to predict labels of unseen instances by learning from training samples that are associated with a set of known labels. In this paper, we propose to use a hierarchical tree model for multilabel learning, and to develop the ML-Tree algorithm for finding the tree structure. ML-Tree considers a tree as a hierarchy of data and constructs the tree using the induction of one-against-all SVM classifiers at each node to recursively partition the data into child nodes. For each node, we define a predictive label vector to represent the predictive label transmission in the tree model for multilabel prediction and automatic discovery of the label relationships. If two labels co-occur frequently as predictive labels at leaf nodes, these labels are supposed to be relevant. The amount of predictive label co-occurrence provides an estimation of the label relationships. We examine the ML-Tree method on 11 real data sets of different domains and compare it with six well-established multilabel learning algorithms. The performances of these approaches are evaluated by 16 commonly used measures. We also conduct Friedman and Nemenyi tests to assess the statistical significance of the differences in performance. Experimental results demonstrate the effectiveness of our method.