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The most followed investigational treatments for Alzheimer's disease are small molecules (80/140 in development, 57%) and immunotherapies (32/140, 23%). These treatments have a clear regulatory path and are based on innovative scientific approaches that are generally patentable and marketable. The remaining 20% (28/140) of therapeutic approaches involve procedures, devices, supplements, combination treatments and others.A literature review was performed for all interventions in phase 2 or later as listed on Alzforum.org for any stage of Alzheimer's disease. Results were considered against the standard of the most progressive aspects of disease by either combining ADAS-cog, ADCS-ADL and a global outcome (CDR-sb, CIBIC or CGIC) or assessing a progression composite such as ADCOMS. This was to ensure comparable results across studies and relevance to disease progression. The percent slowing versus placebo was compared.Of the studies investigated, Souvenaid (mild cognitive impairment (MCI)) and AMBAR (mild-to-moderate) demonstrated the most compelling AD results to date. The Souvenaid results demonstrated a 36% slowing of progression over 24 months in MCI due to AD (ADCOMS). The AMBAR results (active vs control) demonstrated 59% slowing of progression over 14 months in Mild-to-Moderate AD (ADAS-cog, ADCS-ADL, and CDR-sb+CGIC). Neither of these treatments have major side effects.Regulatory approval increases visibility and availability of effective treatment to those suffering from AD. Unfortunately, no clear approval path is available for either of these promising treatments. If Souvenaid becomes available in the U.S., it will be considered one of many general supplements for cognitive health, despite the strong clinical trial data collected to a regulatory standard. Plasmapheresis is a procedure that is not subject to FDA regulation. The AMBAR treatment is available for other indications, and most plasmapheresis treatments are approved by payors if they are recommended by a plasmapheresis board, leading to a challenging regulatory path. Unless the regulatory playing field is leveled for non-traditional treatments, the safest and most promising treatments may be overlooked in favor of sexier treatments like immunotherapies and small molecules.

Purpose of ReviewTo provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study.Recent FindingsThe iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (p= 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months.SummaryThe iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.

Background Diet is associated with the onset of inflammatory bowel disease [IBD]. Up to half of IBD patients believe that diet contributes to flares. However, studies on this topic are sparse and merely focus on specific nutrients, food items or food groups. We aimed to analyse the association between dietary patterns and flare occurrence in two geographically distinct Dutch cohorts. Methods In this longitudinal study, 724 IBD patients [Northern cohort: n = 486, Southern cohort: n = 238] were included and followed for 2 years. Habitual dietary intake was obtained via semi-quantitative food frequency questionnaires at baseline. Principal component analysis [PCA] was conducted on 22 food groups to identify dietary patterns. Flare occurrence was analysed in 427 patients in remission at baseline, using multivariable Cox proportional hazards. Results Compared to the Southern cohort, patients in the Northern cohort were younger at diagnosis, comprised more females, and had lower overall energy intakes [all p Conclusions A dietary pattern, which can be seen as a ‘traditional [Dutch]’ or “Western’ pattern was associated with flare occurrence. Confirmation in prospective studies is needed.

Background The Real World Data [RWD] of the Dutch longitudinal IBD registries (population based IBD South Limburg cohort, Parelsnoer IBD, Initiative on Crohn and Colitis drug-registry) have proven to answer knowledge gaps regarding epidemiology, patient stratification, positioning and effectiveness and safety of new drugs. Life-long data-capture in registries for large cohorts is extremely labor intensive and expensive. Therefore, based on the database models of existing registries, we aim to develop a reusable and interoperable Real World IBD database model that will contribute re-use of every-day care data form hospital information systems and remote monitoring platforms. This project contributes to generation of high quality, multi-dimensional data for (inter)national IBD registries such as the United Registries for Clinical Assessment and Research [UR-CARE] registry and aforementioned registries. Methods The design process was iterative and involved the potential end-users of the registries. For the first iteration the database models of established Dutch IBD cohorts were taken as input, in combination with repeated discussions on the content with three principal IBD investigators. The second iteration was multifaceted including; 1) Five discussion sessions with 7 IBD researchers (MD medicine of which the majority practiced IBD care and were experienced with the hospital information system) discussing the content, and 2) four discussion sessions with researchers experienced in re-using hospital care data for research that evaluated the model on practical use and difficulties in data interpretation using the output of the first iteration. No data was analyzed, only codebooks describing variables and their values. Results The first iteration of the design phase resulted in a database model called IBD common data model [IBDCDM] v1 consisting out of 395 variables, and based on existing codebooks of Dutch IBD registries (figure 1). The database model, called IBD common data model [IBDCDM] v1 consists out of 27 independent modules on different themes important for the IBD disease course allowing for repeated data recordings (figure 2). The second iteration of the design phase resulted in pruning the modules’ content, removal of one module, merging and adding of modules. Conclusion An iterative design process involving end-users will result in higher data quality by optimizing practical usability and interpretability of the database model. Next step is to encode the model using medical standardized vocabularies (e.g. SNOMED, LOINC), for interoperability. The database model contributes towards producing reusable IBD datasets that use study hospital care data as a primary source to study the IBD disease course over several decades.

Background Inflammatory bowel disease (IBD) is associated with malnutrition, which can further impair disease course and quality of life. Therefore, guidelines advocate screening of patients in clinical practice. The prevalence of malnutrition in IBD-cohorts however, varies widely, mainly due to differences in parameters used. The primary aim of the present study was to assess the prevalence of malnutrition using single and a combined set of parameters (Global Leadership Initiative on Malnutrition (GLIM) criteria). Secondary aims were i) to evaluate the accuracy of screening recommendations given in current IBD guidelines and ii) to explore which patients have an increased risk of malnutrition. Methods Malnutrition was defined by the GLIM criteria, based on the combination of a phenotypic (i.e. non-volitional weight loss, low body mass index (BMI), or reduced muscle mass) and an etiologic criterium (i.e. reduced food intake or assimilation, and disease burden or inflammation). Malnutrition was also determined using single parameters for impaired body composition, muscle strength or caloric intake (Table 1), and the combination of low BMI and unintentional weight loss as advised in current IBD guidelines. To screen for malnutrition, the Short Nutritional Assessment Questionnaire (SNAQ) and Malnutrition Universal Screening Tool (MUST) were completed. Independent risk factors (i.e. clinical and demographic factors) for malnutrition were analyzed by multivariable logistic regression. Results Of the 200 included patients (139 CD, 61 UC), 41 (20.5%) fulfilled the GLIM criteria, 95 (47.5%) had at least one parameter for malnutrition impaired (Figure 1). The fat free mass index was most often affected. When unintentional weight loss and/or low BMI was used as screening marker for nutritional status in line with current IBD guidelines, 29 (14.5%) patients would have been identified (Figure 2). Screening for malnutrition using the SNAQ and MUST detected 44 (22.0%) and 23 (12.9%) patients with a positive score. Only female sex was associated with malnutrition when at least one parameter was impaired (OR 2.47, 95% CI 1.35–4.51). Conclusion Malnutrition prevalence among IBD outpatients according to the GLIM criteria was found to be 20.5%. Almost half of the IBD outpatients had malnutrition as defined by various single parameters and irrespective of disease characteristics. Screening instruments and/or markers according to current IBD guidelines, did not identify a substantial part of the patients. Therefore, screening for malnutrition is recommended for all IBD outpatients by multiple parameters, with special attention for assessing fat free mass and reduced intake.

Blood-primed cardiopulmonary bypass circuits are frequently necessary to achieve safe support during pediatric open-heart surgery. Literature is lacking regarding suitable prime constituents or methods for achieving a physiologically appropriate blood-primed circuit. We examined the chemistry and hematology of neonatal blood-primed circuits from the conclusion of the priming procedure until the initiation of bypass. Base deficit/excess, pH, pO(2), pCO(2), HCO(3), glucose, sodium, potassium, calcium, hematocrit, lactate, and osmolality were analyzed. Any deviation over time from the original prime value was compared for significance. Statistically significant changes were found between T0 and all time points for all parameters, except for pH and pO(2) out to 1 hour. Among all parameters, various rates of change were observed. Although most changes in the parameters were found to be statistically significant, those changes may not be clinically significant based on clinician interpretation. Attention to the prime quality beyond the immediate post-priming period may be beneficial. Should the time period between validation of the prime quality and initiation of bypass be extended, it may be advisable to reevaluate the prime quality.

Background Inflammatory bowel disease (IBD) has a substantial impact on quality of life (QoL). This can further be affected by modifiable psychosocial and lifestyle factors, like physical activity (PA). In the current study, we aimed to determine whether PA activity levels were associated with patient and disease characteristics, fatigue and QoL in IBD patients. Methods In this cross-sectional study, consecutive adult IBD outpatients were included. PA was assessed by the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH). Patients were considered to have adequate PA levels when exercising with moderate intensity during minimal 30 minutes for at least five days per week according to the Dutch Standards for Healthy Physical Activity. Body composition was assessed by body mass index (BMI) and fat-free mass using BodPod. Fatigue was measured with the Shortened Fatigue Questionnaire (SFQ) and QoL was determined using the SF-36. Patient and disease characteristics, fatigue, and QoL between patients with and without adequate PA levels were analyzed by a student’s t-test or X2-test when appropriate. Results Of the 200 patients (139 Crohn’s disease (CD), 61 ulcerative colitis (UC)), 53.3% were female, and 21.5% were active smoker. Mean disease duration was 11.4 [SD 9.9] years, and 28.6% had an exacerbation at inclusion. The Dutch Standards for Healthy Physical Activity were not met by 41.7%. CD patients (53.2%) were less likely to have adequate PA levels compared to UC (70.0%) patients (p=0.028). There were no other significant differences in patient and disease characteristics stratified by adequate PA level (i.e. sex, active smoking, age at inclusion, disease duration, Montreal classification, previous bowel resection, and disease activity). BMI and fat-free mass index were not associated with PA levels. However, patients not meeting PA standards were significantly more tired compared to patients meeting the standards (mean 17.4 [SD 7.0] vs. 13.5 [SD 7.2], p=0.015), and had lower physical and mental component scores (PCS: mean 43.5 [SD 9.7] vs. 46.0 [SD 8.5]; MCS: mean 46.2 [SD 11.3] vs. 52.3 [SD 9.5]) for QoL, reaching significance for SF-36 MCS (p=0.012). Conclusion IBD outpatients with low physical activity levels showed significantly higher fatigue and lower quality of life scores, regardless of disease characteristics. More research is necessary to identify contributing factors to further improve patients’ well-being by holistic management.

Cases of tick-borne diseases, including spotted fever rickettsioses, borreliosis, babesiosis, anaplasmosis and ehrlichiosis, in the United States and territories have more than doubled from 2004 to 2016 and account for 77% of all vector-borne disease reports. In an effort to inform control efforts, the presence of tick-borne pathogens and their vectors was assessed in a recreational park in Walker County, Texas. Here we report data from questing ticks collected on three dates from June 2017 to June 2018. The majority of ticks collected were Amblyomma americanum (96.69%) followed by three additional tick species: Dermacentor variabilis (2.59%), Ixodes scapularis (0.52%), and A. maculatum (0.21%). Ticks were pooled and tested for molecular evidence of bacterial and viral pathogens, respectively. All of the 68 pools of A. americanum had molecular evidence of the spotted fever group rickettsia, Rickettsia amblyommatis. Additionally, six (8.82%) of the A. americanum pools contained sequences matching Ehrlichia chaffeensis, the pathogen responsible for human monocytotropic ehrlichiosis, and 11 (16.18%) for E. ewingii. Three of the A. americanum pools demonstrated evidence of Borrelia lonestari. The presence of etiologic agents of known human disease in this study merits the continued surveillance efforts of ticks and their pathogens in areas where they could pose risks to public health.

Event-related potentials (ERPs) are a physiological measure of cognitive function that have shown diagnostic and prognostic utility in Alzheimer's disease (AD). In this study, we used a novel eigenvector-based technique to better understand brain electrophysiological differences between subjects with mild AD and healthy controls (HC). Using ERPs from 75 subjects with mild AD and 95 HC, we first calculated cognitive task eigenvectors within each subject from three conditions and then calculated second-order eigenvector components to compare the AD group to the HC group. A MANOVA of the three second-level components discriminated between AD and HC multivariately (Wilks' lambda=.4297, p0.0001, R2 = .5703), and also on each of the three components univariately (all 3 p-values0.0001). The eigenvector-based technique used in this study accurately discriminated between the mild AD group and HC. As such, this analysis method adds to our understanding of the differences in ERP signal between AD and HC, and could provide a sensitive biomarker for diagnosis and monitoring of AD progression.

Biomorphs are complex, life-like structures that emerge from the precipitation of barium carbonate and amorphous silica in alkaline media. Despite their inorganic nature, these microstructures have non-crystallographic morphologies such as helices and cardioid sheets. At the nanoscale, biomorphs arrange thousands of crystalline nanorods as hierarchical assemblies that resemble natural biominerals suggesting novel approaches towards the production of biomimetic materials. We report the synthesis of silica-carbonate biomorphs in single-phase, gradient-free solutions that differ markedly from the typical solution-gas or gel-solution setups. Our experimental approach significantly increases the duration of biomorph growth and hence assembles networks in which individual helices extend to several millimeters. These unusually long biomorphs allow the first quantitative measurements of mesoscopic parameters such as the helix wavelength, period, width, and linear as well as tangential growth velocities. We find that the latter quantities are system-specific and tightly conserved during many hours of growth. Moreover, the average double helix wavelength of (19 ± 3) μm and width of (9.6 ± 0.8) μm vary by less than 12% when the initial carbonate concentration is changed by three orders of magnitude. We also delineate the single helix growth mechanism and report the occurrence of ribbon-like structures and highly regular "superhelices". Our experiments clearly demonstrate the robustness and consistency of biomorph growth under stable chemical conditions.

We present experimental results of the transmission coefficient of a metamaterial slab and the effect of the metamaterial on the radiation pattern of an antenna placed near the slab in the frequency range close to the plasma frequency of the slab. The metamaterial focuses the radiation from the patch antenna within a narrow cone close to the slab's normal. We give a new simple explanation of the focusing effect based on the index of refraction of the metamaterial being less than one and the attenuation of electromagnetic waves within the metamaterial slab.

Partial correlation is a method for identifying the correlation between two variables, with the effects of a third variable held constant. It is mathematically equivalent to the correlation between the residual scores of the two variables regressed upon the control variable. Partial correlation is conceptually related to, and an integral part of, a number of other useful statistical methods, including path analysis, structural equation modeling, factor analysis, and stepwise multiple regression. Keywords: partial correlation; zero-order correlation; control variable; first-order correlation

Canonical correlation is one of the least used of the multivariate methods. It is the thesis of this paper that it is seldom used because it is incomplete and gives little information by itself. However, it can be highly illuminating when used to create a linked context of two or more multivariate spaces that in and of themselves have interesting internal structure. That internal structure can be experimental (with a MANOVA analysis within each space), a time series pattern linked across the spaces, or even just loose internal groupings by a collection of exploratory categorical variables. Also, the linking across the multidimensional spaces can be causal (e.g., mutual fund performance as predicted by market indices), or merely parallel (e.g., convergent behavioral and physiological measures of performance on cognitive tasks). A demonstration is given of canonical correlation graphs for a time series internal structure in a causally linked space.

A two-phase feasibility study was initiated in late 1996 to identify a way to expedite the removal of SNM from the CPP-651 vault. The first phase of this study provided preliminary information that appeared promising, but needed additional detailed planning and evaluate to validate the concepts and conclusions. The focus of Phase 2 was to provide the validation via resource-loaded schedules and more detailed cost estimates. Section 1 describes the purpose and objectives of the Phase 2 tasks and the programmatic drivers that influence related CPP-651 high-enriched uranium (HEU) management issues. Section 2 identifies the evaluation criteria and methodology and the transfer issues and barriers preventing shipment. Section 3 provides site-specific background information for the CPP-651 facility and the Idaho National Engineering and Environmental Laboratory (INEEL) and describes the development of the basic material removal schedule, the proposed base case plan for removal of SNM, and the proposed HEU material management/shipping issues and strategies. Section 4 identifies the proposed options for accelerated removal of SNM and how they were evaluated via detailed scheduling, resource histograms, and cost analysis. Section 5 summarizes principal tasks for implementing this plan and other related HEU CPP-651 management issues that require continued planning efforts to assure successful implementation of this proposed early removal strategy.

The clinical utility of FDG-PET imaging in the evaluation of patients with cardiac, oncologic and neurologic diseases is well documented. The major disadvantages of PET continue to be its high cost and limited availability.With the goal of providing equivalent diagnostic information using a widely available, less expensive modality, we evaluated the clinical utility of FDG-SPECT imaging with a conventional dual-headed camera as compared to PET in 21 patients.To compare the image quality of the two modalities, major physical parameters and phantom determinations were obtained. By using the 511-keV collimators, we achieved resolution and system volume sensitivity that were less than those for PET by factors of 2.6 and 8, respectively. The SPECT system, on the other hand, could easily resolve 2 x 0.5-cm cold defects in the heart phantom and 2-cm hot lesions in a 22-cm cylindrical phantom with a target-to-background ratio of 5:1. FDG-SPECT imaging of nine patients with heart disease yielded similar diagnostic information of the amount of viable myocardium present when compared to PET. In seven of eight patients, malignant tissue visualized with FDG-PET was seen equally well with SPECT. The lesions not visualized with FDG-SPECT were either small (or = 1.5 cm) or benign. SPECT imaging of four patients with cerebral lesions was inconclusive due to the small sample size but seemed promising.FDG-SPECT with 511-keV collimation is less expensive, more available and technically simpler than PET. We believe that FDG-SPECT has achieved sufficient sensitivity and resolution to detect myocardial viability and diagnose malignant tumorsor = 2 cm in diameter.

The phlebotomy team is receiving greater recognition than ever before for its contribution to the service image of the laboratory. Laboratory managers must recognize that phlebotomists are the laboratory's goodwill ambassadors. Because phlebotomists work on the front line, their technical skills and professional demeanor are prime factors in getting physician referrals and attracting patients to the facility. To recruit and retain a skilled professional phlebotomy team, laboratory managers must assess their operations and determine the skills, personal attributes, and education needed to perform the phlebotomy duties. To keep your best employees, try to continually upgrade your training, continuing education, and career advancement opportunities. To learn what makes a successful phlebotomy team, CLMR surveyed several CLMA members to find out how they are recruiting and developing their phlebotomists. Our special thanks go to all our respondents for sharing their expertise and experiences with us.

True pulmonic and aortic valvular stenoses were produced in dogs by chemical cautery of valve cusps during cardiopulmonary bypass. The intrinsic valve stenoses were confirmed by phonocardiography, gradient measurements, angiography, and pathologic examination. The lesion were similar to clinical valvular stenosis in several respects, including the presence of dystrophic calcification. Unlike the hitherto available models of supravalvular stenosis, the present preparation is amenable to a greater variety and spectrum of experimental studies.