Machine Learning Classification of Alzheimer's Disease Pathology Reveals Diffuse Amyloid as a Major Predictor of Cognitive Impairment in Human Hippocampal Subregions.

Analyzing Alzheimer's disease (AD) pathology within anatomical subregions is a significant challenge, often carried out by pathologists using a standardized, semi-quantitative approach. To augment traditional methods, a high-throughput, high-resolution pipeline was created to classify the distribution of AD pathology within hippocampal subregions. USC ADRC post-mortem tissue sections from 51 patients were stained with 4G8 for amyloid, Gallyas for neurofibrillary tangles (NFTs) and Iba1 for microglia. Machine learning (ML) techniques were utilized to identify and classify amyloid pathology (dense, diffuse and APP (amyloid precursor protein)), NFTs, neuritic plaques and microglia. These classifications were overlaid within manually segmented regions (aligned with the Allen Human Brain Atlas) to create detailed pathology maps. Cases were separated into low, intermediate, or high AD stages. Further data extraction enabled quantification of plaque size and pathology density alongside ApoE genotype, sex, and cognitive status. Our findings revealed that the increase in pathology burden across AD stages was driven mainly by diffuse amyloid. The pre and para-subiculum had the highest levels of diffuse amyloid while NFTs were highest in the A36 region in high AD cases. Moreover, different pathology types had distinct trajectories across disease stages. In a subset of AD cases, microglia were elevated in intermediate and high compared to low AD. Microglia also correlated with amyloid pathology in the Dentate Gyrus. The size of dense plaques, which may represent microglial function, was lower in ApoE4 carriers. In addition, individuals with memory impairment had higher levels of both dense and diffuse amyloid. Taken together, our findings integrating ML classification approaches with anatomical segmentation maps provide new insights on the complexity of disease pathology in AD progression. Specifically, we identified diffuse amyloid pathology as being a major driver of AD in our cohort, regions of interest and microglial responses that might advance AD diagnosis and treatment.

Pediatric Atypical Teratoid/Rhabdoid Tumors of the Brain: Identification of Metabolic Subgroups Using In Vivo 1H-MR Spectroscopy.

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.

Evaluating Practitioner Training to Improve Competencies and Organizational Practices for Engaging Fathers in Parenting Interventions.

Fathers are consistently underrepresented in parenting interventions and practitioners are an important target for change in interventions to enhance father engagement. This research examined the effects of two practitioner training programs in improving practitioner rated competencies and organizational father-inclusive practices. Two studies were conducted, each with a single group, repeated measures (pre, post and 2-month follow-up) design. Study 1 (N = 233) examined the outcomes of face-to-face training in improving practitioner ratings of competencies in engaging fathers, perceived effectiveness and use of father engagement strategies, organizational practices and rates of father engagement. Study 2 (N = 356) examined online training using the same outcome measures. Practitioners in both training formats improved in their competencies, organizational practices and rates of father engagement over time, yet those in the online format deteriorated in three competencies from post-training to follow-up. The implications for delivering practitioner training programs to enhance competencies and rates of father engagement are discussed.

Examining Practitioner Competencies, Organizational Support and Barriers to Engaging Fathers in Parenting Interventions.

Evidence-based parenting interventions have been developed and evaluated largely with mothers. This study examined practitioner reports of rates of father attendance, barriers to engagement, organizational support for father-inclusive practice, participation in training in father engagement, and competencies in working with fathers. It also explored predictors of practitioner competence and rates of father attendance. Practitioners (N = 210) who delivered parenting interventions completed an online survey. Participants reported high levels of confidence in engaging fathers, but only one in three had participated in training and levels of father attendance in parenting interventions were low. Logistic regressions showed that high levels of practitioner competence were predicted by participation in training. Moderate levels of father attendance (vs. low levels) were predicted by greater number of years of experience while high levels of attendance (vs. low levels) were predicted by greater experience, higher levels of competence and higher levels of organizational support. The implications of the findings to informing policy and practice for enhancing father engagement are discussed.

Mothers, Fathers, and Parental Systems: A Conceptual Model of Parental Engagement in Programmes for Child Mental Health-Connect, Attend, Participate, Enact (CAPE).

Parenting programmes are one of the best researched and most effective interventions for reducing child mental health problems. The success of such programmes, however, is largely dependent on their reach and parental engagement. Rates of parental enrolment and attendance are highly variable, and in many cases very low; this is especially true of father involvement in parenting programmes. This paper proposes a conceptual model of parental engagement in parenting programmes-the CAPE model (Connect, Attend, Participate, Enact) that builds on recent models by elaborating on the interdependent stages of engagement, and its interparental or systemic context. That is, we argue that a comprehensive model of parental engagement will best entail a process from connection to enactment of learned strategies in the child's environment, and involve consideration of individual parents (both mothers and fathers) as well as the dynamics of the parenting team. The model provides a framework for considering parent engagement as well as associated facilitators and mechanisms of parenting change such as parenting skills, self-efficacy, attributions, and the implementation context. Empirical investigation of the CAPE model could be used to further our understanding of parental engagement, its importance for programme outcomes, and mechanisms of change. This will guide future intervention refinement and developments as well as change in clinical practice.

Benefits of routine use of coronal and sagittal reformations in multi-slice CT examination of the abdomen and pelvis.

AIM: To evaluate the usefulness of coronal and sagittal reformations from isotropic abdomino-pelvic computed tomography (CT) examinations. METHODS: Fifty consecutive abdomino-pelvic CT examinations were reconstructed into two sets of axial source images: 0.9 mm section width with 0.45 mm reconstruction interval (isotropic) and 4 mm section width with 3 mm reconstruction interval. The isotropic dataset was reformatted into coronal and sagittal stacks with 4 mm section widths. Three readers independently reviewed the three image sets with 4 mm section widths. The coronal and sagittal reformations were compared with the axial images, in the same sitting, for depiction of lesions in various abdominal organs. RESULTS: There was better visualization of lesions in the liver, kidneys, mesentery, lumbar spine, major abdominal vessels, urinary bladder, diaphragm and hips on the coronal reformations compared with source axial images (p<0.05). Sagittal reformations scored better than axial source images for showing lesions in the liver, thoracic spine, abdominal vessels, uterus, urinary bladder, diaphragm and hips (p<0.05). The coronal and sagittal series showed significant additional information in 23 and 17% of patients, respectively. CONCLUSION: Radiologists should consider the routine review of at least one additional plane to the axial series in the interpretation of abdomino-pelvic CT studies.

Routine isotropic computed tomography scanning of the abdomen and pelvis.

For 30 years, abdominal CT has been imaged and reviewed in the axial plane. It is now possible to carry out isotropic imaging of the whole abdomen and pelvis using a 40-channel scanner. This allows creation of coronal and sagittal reformats with the same image quality as the axial images. In this study, we present our experience of reviewing routinely coronal and, occasionally, sagittal reformats. We discuss situations where these nonaxial reformats are most beneficial.

Hepatic peliosis (bacillary angiomatosis) in AIDS: CT findings.

Patients with acquired immunodeficiency syndrome are at risk of developing opportunistic infections and aggressive tumors. Computed tomographic examination is the usual method of evaluating the abdomen and pelvis in these patients. Although this technique is reasonably sensitive in detecting pathology, findings are often nonspecific. A case of hepatic peliosis (bacillary angiomatosis) in a patient with acquired immunodeficiency syndrome is presented.

Detection of occult metastasis in patients with breast cancer.

The most important factor affecting the outcome of patients with invasive cancer is whether the tumor has spread, either regionally (to regional lymph nodes) or systemically. However, a proportion of patients with no evidence of systemic dissemination will develop recurrent disease after primary "curative" therapy. Clearly, these patients had occult systemic spread of disease that was undetectable by routinely employed methods (careful pathological, clinical, biochemical, and radiological evaluation). In addition, the success of adjuvant therapy is assumed to stem from its ability to eradicate occult metastases before they become clinically evident. Therefore, methods for the detection of occult metastases in patients with the earliest stage of cancer, i.e., prior to detection of metastases by any other clinical or pathological analysis, have received a great deal of attention.

Occult metastases in patients with breast cancer.

The presence of occult metastases in the lymph nodes, bone marrow, or both of these compartments may not only define patients who are at higher risk for recurrence and death but also may identify biologically distinct mechanisms of tumor spread (e.g., lymphatic vs. vascular dissemination). Use of techniques to detect occult metastases may also allow the identification of a biologically important population of cells, i.e., those cells constituting the earliest metastatic population of tumor cells. Thus, techniques that identify occult metastases may be valuable in furthering our understanding of the events regulating tumor dissemination.

Occult metastasis.

The most important factor affecting the outcome of patients with invasive cancers is whether the tumor has spread, either regionally (to regional lymph nodes) or systemically. However, a proportion of patients with no evidence of systemic dissemination will develop recurrent disease after primary 'curative' therapy. Clearly, these patients had occult systemic spread of disease that was undetectable by methods routinely employed (careful pathological, clinical, biochemical and radiological evaluation). In addition, the success of adjuvant therapy is assumed to stem from its ability to eradicate occult metastases before they become clinically evident [1]. Therefore, methods for the detection of occult metastases in patients with the earliest stage of cancer, i.e., prior to detection of metastases by any other clinical or pathological analysis, have received a great deal of attention.

Industrial scale-up of countercurrent chromatography: predictive scale-up.

This study describes how scale-up in countercurrent chromatography (CCC) can be simply predicted on a process scale CCC device by running a preliminary analytical-sized sample and having knowledge of the stationary-phase retention at scale-up conditions. Results have shown that simple experimentation can lead within a day to a process with the capability of several kilograms per day (tons per year) compound yield, and that this is feasible with benchtop CCC units.

Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging.

The presence of occult bone marrow metastases (OM) has been reported to represent an important prognostic indicator for patients with operable breast cancer and other malignancies. Assaying for OM most commonly involves labor-intensive manual microscopic analysis. The present report examines the performance of a recently developed automated cellular image analysis system (ACIS; ChromaVision Medical Systems, Inc.) for identifying and enumerating OM in human breast cancer specimens. OM analysis was performed after immunocytochemical staining. Specimens used in this study consisted of normal bone marrow (n = 10), bone marrow spiked with carcinoma cells (n = 20), and bone marrow obtained from breast cancer patients (n = 39). The reproducibility of ACIS-assisted analysis for tumor cell detection was examined by having a pathologist evaluate montage images generated from multiple ACIS runs of five specimens. Independent ACIS-assisted analysis resulted in the detection of an identical number of tumor cells for each specimen in all instrument runs. Additional studies were performed to analyze OM from 39 breast cancer patients with two pathologists performing parallel analysis using either manual microscopy or ACIS-assisted analysis. In 17 of the 39 cases (44%), specimens were classified by the pathologist as positive for tumor cells after ACIS-assisted analysis, whereas the same pathologist failed to identify tumor cells on the same slides after analysis by manual microscopy. These studies indicate that the ACIS-assisted analysis provides excellent sensitivity and reproducibility for OM detection, relative to manual microscopy. Such performance may enable an improved approach for disease staging and stratifying patients for therapeutic intervention.

Activity-based cost analysis: a method of analyzing the financial and operating performance of academic radiology departments.

PURPOSE: To develop a methodology for an activity-based cost (ABC) analysis in an academic radiology department, to test the hypothesis that the business of academic radiology can be separated into three distinct businesses-clinical activity, teaching, and research-and to determine the effect of the current teaching paradigm on clinical productivity. MATERIALS AND METHODS: Forty-seven key departmental activities were defined and distributed among the teaching, research, and clinical businesses. Individual radiologists determined the time spent in each of these activities by completing a detailed log of every activity performed during 2 weeks. All departmental revenue and costs were assigned to each activity in each of the three businesses. RESULTS: The methodology provided a successful understanding of the relative costs of each of the businesses of teaching, research, and clinical activity. It also provided the departmental costs of performing the separate activities typical of each business. Key findings included the following: Faculty spends 72% of time in clinical activities, research is the most expensive service per direct activity hour, and clinical reads (23%) are the single largest departmental cost element. CONCLUSION: ABC analysis can separate academic radiology into three businesses-teaching, research, and clinical-and provide a detailed understanding of the cost structure of each. This analysis identifies opportunities for improved quality of service, productivity, and cost within each business.

Calcium-induced modification of protein conformation demonstrated by immunohistochemistry: What is the signal?

A recent study by Morgan et al. on the mechanism of the heating antigen retrieval (AR) has raised an interesting issue concerning calcium-induced modification of protein conformation demonstrated by immunohistochemistry (IHC). The current study is based on calcium-induced modification of thrombospondin (TSP) and Ki-67, as demonstrated by IHC using seven monoclonal antibodies (MAbs) to TSP and an MAb MIB1. Experiments were carried out on frozen tissue sections of bladder carcinoma and lymph node. Frozen sections were incubated with solutions of 50 mM CaCl2 and/or 10 mM EDTA at 4C overnight before formalin or acetone fixation for TSP and Ki-67, respectively. Sections were then fixed in 10% neutral buffered formalin or acetone before immunostaining. Seven MAbs to TSP, named Ab1 to 7 representing clone numbers of A4.1, D4.6, C6.7, A6.1, B5.2, A2.5, and HB8432, respectively, and MIB1 were utilized as primary antibodies. ABC was used as the detection system and AEC as the chromogen for immunohistochemical staining. An extracellular immunostaining pattern represented a positive result for TSP, and nuclear staining for MIB1. Frozen sections preincubated in 50 mM CaCl2 overnight at 4C showed significant loss of staining and/or altered staining pattern for six of the seven antibodies to TSP and MIB1 compared to positive controls not exposed to CaCl2. Lack of immunostaining of TSP and MIB1 attributable to exposure to CaCl2 could be partially recovered by incubating the frozen sections in EDTA. Calcium-induced modification of protein structure was demonstrated more than 10 years ago on the basis of immunochemical techniques. In this study, similar calcium-induced modification of protein was detectable by IHC in frozen tissue sections, suggesting that calcium-induced modification of protein structure may occur independently of fixation-induced modification. The fact that calcium binding may affect IHC staining is not surprising in view of the fact that antibody/antigen interactions are protein structure-dependent. However, in this experiment the change occurred before and independent of formalin fixation and does not necessarily imply a role for calcium in AR. There may be a valuable role for the use of chemical modification in visualization of protein structure changes in tissue sections by IHC. (J Histochem Cytochem 47:463-469, 1999)

Phantom for calibration of preoperative imaging modalities in endoluminal stent-graft repair of aortic aneurysms.

PURPOSE: Successful deployment of an endoluminal prosthesis for repair of an abdominal aortic aneurysm (AAA) is critically dependent on accurate preoperative assessment of aneurysm morphology with use of such modalities as contrast aortography (CA), spiral computed tomography (CT), magnetic resonance (MR) imaging, and intravascular ultrasonography (IVUWS). The authors describe a new phantom that could be used both to calibrate these four imaging modalities and to determine which imaging technique(s) is (are) best for preoperative AAA sizing. MATERIALS AND METHODS: A life-sized AAA model was constructed of silicone elastomers with luminal access ports for introduction of contrast media and catheters. Contrast material-filled rings were positioned circumferentially along the length of the model as reference points for dimension measurements. The modalities were compared to each other relative to the actual dimensions of the model, as determined at its construction. RESULTS: In this pilot study, all modalities were relatively similar in their ability to measure the dimensions of the AAA model. Length measurements accounted for most of the interinstitutional and interobserver variability. MR imaging had the least variability. CONCLUSIONS: The authors developed a new phantom that can be imaged successfully with CA, CT, MR imaging, and IVUS in repetitive, reproducible fashion. Structural refinements and future larger scale, statistically significant evaluations of such models should establish this as a useful adjunct in multicenter endoluminal stent-graft trials to allow calibration of imaging modalities and to determine which modality or modalities is (are) best for preoperative AAA sizing.

Detection of occult metastases in lung carcinomas: progress and implications for lung cancer staging.

The ability to detect occult regional and systemic metastases in patients with operable lung carcinoma could have a significant impact on the management of the disease. Here, we review the literature, including studies from our own laboratory, regarding the clinical significance of the presence of occult metastases in patients with lung cancer. The accumulated evidence strongly suggests that the detection of occult regional and systemic metastases is an important predictor of disease progression. The use of this method should be considered in the future design of lung cancer clinical trials, at the very least. The detection of occult metastases should have an impact on lung cancer management; to reflect this, we propose a change in the TNM staging system to indicate the presence or absence of occult regional (lymph node) and systemic (bone marrow) metastases. The proposed change is TNnMm, where n and m are occult nodal and bone marrow metastases status.

Fixed-facility workplace screening mammography.

OBJECTIVE: Potential barriers to compliance with screening mammography guidelines include the cost and inconvenience involved with undergoing the procedure. Workplace screening with mobile mammography is one possible approach to the convenience barrier. However, fixed-facility workplace screening is a viable alternative for any company with a large workforce in one location. This paper describes our initial experience with one such fixed facility. MATERIALS AND METHODS: The facility was a cooperative venture by a large pharmaceutical company and an academic radiology department to provide convenient, no-cost (to the patient) screening mammography to employees, dependents, and retirees more than 40 years old. The pharmaceutical company built the facility within its corporate headquarters and the academic radiology department provided the equipment and personnel. The company was billed a fixed cost per examination. RESULTS: In the first 22 months of operation, 4210 (of 4559 scheduled) screening mammograms were obtained. The mean age of the population was 53 years old. Ninety percent of the screening mammograms were interpreted as negative or benign; 10% required additional workup. Of the screened population, 62 biopsies were recommended and 60 were performed. Of these, 42 were benign and 18 malignant. The cancer detection rate was 4.3 per 1000 (0.43%). At the time of diagnosis, six patients were stage 0, 10 patients were stage I, one patient was stage II, and one patient was stage III. Eleven of the 18 patients had minimal cancers. Of the patients who completed a satisfaction survey, 97% percent expressed a high degree of satisfaction with the screening process and stated they would use the facility in the future. CONCLUSION: A fixed facility for workplace screening mammography is a viable way to provide nearly barrier-free access to high-quality mammography. Patient acceptance is high.

Sonography of the breast.

Quality mammography remains the primary modality used to image the breast. Sonography currently is the most useful adjunctive technique to mammography, having roles in differentiating cystic from solid masses and in guiding interventional procedures. This article reviews these and other indications for breast ultrasound studies, including evaluation of palpable masses not visible in radiographically dense breasts, masses not completely evaluable with mammography, young patients especially susceptible to radiation damage, and abscesses. Ultrasound interpretation of cysts and solid masses are discussed, as are the relative disadvantages of ultrasound as a breast cancer screening tool.