Reproducible Sex Differences in Personalized Functional Network Topography in Youth.

Background: A key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex. Aims: We aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks. Method: We leveraged person-specific atlases of functional brain networks defined using nonnegative matrix factorization in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout ("topography") of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants' sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression. Results: Sex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants' PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons. Conclusions: Sex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.

Normative trajectories of extra-axial cerebrospinal fluid during childhood and adolescence defined in a clinically-acquired MRI dataset.

Background: Extra-axial cerebrospinal fluid (eaCSF) refers to the CSF in the subarachnoid spaces that surrounds the brain parenchyma. Benign enlargement of the subarachnoid space (BESS), a condition marked by increased eaCSF thickness, has been associated with macrocephaly and may be associated with subdural collections. However, diagnosis of BESS is complicated by the lack of age-specific normative data which hinders rigorous investigation of its clinical associations. Growth charts of eaCSF could shed light on normal CSF dynamics while also providing a normative benchmark to assist the diagnosis of BESS and other associated conditions. Methods: We accessed clinically-acquired T1w MRI scans from 1226 pediatric patients to form a clinical control cohort. Nine scans from subjects with a diagnosis of BESS from a board-certified pediatric neuroradiologist were also reviewed. SynthSeg was used to segment each T1w scan into various tissue types, including eaCSF. Growth charts of eaCSF were modeled using the clinical control cohort. The confirmed BESS cases were then benchmarked against these charts to test the performance of eaCSF growth charts. Results: eaCSF thickness varied nonlinearly with age, steadily decreasing from birth to two years, then trending upwards in early adolescence. Seven of the nine patients with a clinical diagnosis of BESS were above the 97.5 th percentile for their age for at least one eaCSF measure. Centile scores were able to distinguish BESS cases from controls with an area under curve (AUC) greater than 0.95. Discussion: eaCSF thickness evolves in a dynamic pattern throughout childhood and adolescence. Patients with BESS can be differentiated from clinical controls using computational measurements of eaCSF thickness paired with normative modeling. Our findings demonstrate the feasibility of computational extraction of eaCSF with a potential point of clinical relevance, delineation of BESS diagnosis. Enhanced understanding of normative eaCSF is critical in further investigations its clinical associations.

Efficacy of gastric stimulator as an adjunct to pyloroplasty for gastroparesis: characterizing patients suitable for single procedure vs dual procedure approach.

BACKGROUND: Pyloroplasty is an effective surgery for gastroparesis. However, some patients fail to improve after pyloric drainage and may require subsequent gastric electric stimulation. There is a paucity of data on the efficacy of gastric stimulator as an adjunct to failed pyloroplasty. This study aimed to describe our experience with pyloroplasty, determine the efficacy of gastric stimulator for failed pyloroplasty, and compare the final outcomes of those who required pyloroplasty with and without gastric stimulator for gastroparesis. METHODS: Records of patients who underwent primary pyloroplasty for gastroparesis at our institution were reviewed. Patients with poor symptomatic improvement after pyloroplasty underwent subsequent gastric stimulator. Symptoms were assessed using the gastroparesis cardinal symptom index (GCSI) preoperatively and after each surgery. Severe gastroparesis was defined as GCSI total score ≥3. Outcomes were assessed after pyloroplasty in all patients and after stimulator in patients who failed pyloroplasty. Final outcomes were then compared between those who did and did not require adjunct gastric stimulator. RESULTS: The study population consisted of 104 patients (89.4% females) with a mean (SD) age of 42.2 years (11) and body mass index of 26.9 kg/m2 (7). Gastroparesis etiologies were 71.2% idiopathic, 17.3% diabetic, and 11.5% postsurgical. At 18.7 months (12) after pyloroplasty, there was a decrease in the GCSI total score (3.5 [1] to 2.7 [1.2]; P = .0012) and the rate of severe gastroparesis (71.9%-29.3%; P < .0001). Gastric emptying scintigraphy (GES) 4-hour retention decreased (36.5 [24] to 15.3 [18]; P = .0003). Adjunct gastric stimulator was required by 30 patients (28.8%) owing to suboptimal outcomes with no improvement in GCSI (P = .201) or GES (P = .320). These patients were younger (40.5 [10.6] vs 49.6 [15.2] years; P = .0016), with higher baseline GCSI total scores (4.3 [0.7] vs 3.7 [1.1]; P < .001) and more severe gastroparesis (100% vs 55.6%; P < .001). All other preoperative characteristics were similar. At 21.7 months (15) after gastric stimulator, there was improvement in GCSI (4.1 [0.7] to 2.6 [1.1]; P < .0001), severe gastroparesis (100%-33.3%; P < .0001), and GES 4-hour retention (21.2 [22] to 7.6 [10]; P = .054). Before gastric stimulator, those who failed pyloroplasty had significantly worse GCSI (P = .0009) and GES (P = .048). However, after gastric stimulator, GCSI and GES improved and were comparable with those who only required pyloroplasty (P > .05). CONCLUSION: Pyloroplasty improved gastroparesis symptoms and gastric emptying, yet 28% failed, requiring gastric stimulator. Younger patients and those with preoperative GCSI scores ≥3 were more likely to fail. Gastric stimulator improved outcomes after failed pyloroplasty, with comparable final GCSI and GES with those who did not fail.

ComBatLS: A location- and scale-preserving method for multi-site image harmonization.

Recent work has leveraged massive datasets and advanced harmonization methods to construct normative models of neuroanatomical features and benchmark individuals' morphology. However, current harmonization tools do not preserve the effects of biological covariates including sex and age on features' variances; this failure may induce error in normative scores, particularly when such factors are distributed unequally across sites. Here, we introduce a new extension of the popular ComBat harmonization method, ComBatLS, that preserves biological variance in features' locations and scales. We use UK Biobank data to show that ComBatLS robustly replicates individuals' normative scores better than other ComBat methods when subjects are assigned to sex-imbalanced synthetic "sites". Additionally, we demonstrate that ComBatLS significantly reduces sex biases in normative scores compared to traditional methods. Finally, we show that ComBatLS successfully harmonizes consortium data collected across over 50 studies. R implementation of ComBatLS is available at https://github.com/andy1764/ComBatFamily.

Magnetic Sphincter Augmentation for Laryngopharyngeal Reflux: An Assessment of Efficacy and Predictors of Outcome.

INTRODUCTION: Magnetic sphincter augmentation (MSA) is an effective treatment for typical reflux symptoms, but data on its impact on laryngopharyngeal reflux (LPR) is limited. This study aimed to determine the efficacy of MSA for LPR and to identify predictors of outcome. METHODS: This was a retrospective review of 775 patients who underwent MSA between 2013 and 2021. LPR was defined as presence of atypical reflux symptoms and a reflux symptom index (RSI) score >13. Favorable outcome was defined as primary symptom resolution, freedom from proton pump inhibitors, and five-point improvement or RSI score normalization. Preoperative clinical, high-resolution manometry, and impedance-pH data were analyzed for impact on favorable outcome using univariate followed by multivariable analysis. RESULTS: There were 128 patients who underwent MSA for LPR. At a mean (SD) follow-up of 13 (5.4) months, favorable outcome was achieved by 80.4% of patients, with median (IQR) RSI score improving from 29 (22-35) to 9 (4-17), (P < 0.001). Independent predictors of favorable outcome on multivariable analysis included LPR with typical reflux symptoms [OR (95% CI): 8.9 (2.3-31.1), P = 0.001], >80% intact swallow on high-resolution manometry [OR (95% CI): 3.8 (1.0-13.3), P = 0.035], upper esophageal sphincter (UES) resting pressure >34 mmHg [OR (95% CI): 4.1 (1.1-14.1), P = 0.027] and short total proximal acid clearance time [OR (95% CI): 1.1 (1.0-1.1), P = 0.031]. Impedance parameters including number of LPR events, full column reflux and proximal acid exposure events were similar between outcome groups (P > 0.05). CONCLUSION: MSA is an effective surgery for patients with LPR. Patients with concomitant typical reflux symptoms, normal esophageal body motility, and competent UES benefit the most from surgery. Individual impedance-pH parameters were not associated with outcome.

Peroral Endoscopic Myotomy (POEM) and Laparoscopic Heller Myotomy with Dor Fundoplication for Esophagogastric Junction Outflow Obstruction (EGJOO): a Comparison of Outcomes and Impact on Physiology.

INTRODUCTION: Esophagogastric junction outflow obstruction (EGJOO) is an esophageal motility disorder characterized by failure of lower esophageal sphincter (LES) relaxation with preserved peristalsis. Studies have shown that Heller myotomy with Dor fundoplication (HMD) and per oral endoscopic myotomy (POEM) are effective treatments for EGJOO. However, there is paucity of data comparing the efficacy and impact of these two procedures. Therefore, the aim of this study was to compare outcomes and impact on esophageal physiology in patients undergoing HMD or POEM for primary EGJOO. METHODS: This was a retrospective review of patients who underwent either HMD or POEM for primary EGJOO at our institution between 2013 and 2021. Favorable outcome was defined as an Eckardt score ≤ 3 at 1 year after surgery. GERD-HRQL questionnaire, endoscopy, pH monitoring, and high-resolution manometry (HRM) results at baseline and 1 year after surgery were compared pre- and post-surgery and between groups. Objective GERD was defined as DeMeester score > 14.7 or LA grade C/D esophagitis. RESULTS: The final study population consisted of 52 patients who underwent HMD (n = 35) or POEM (n = 17) for EGJOO. At a mean (SD) follow-up of 24.6 (15.3) months, favorable outcome was achieved by 30 (85.7%) patients after HMD and 14 (82.4%) after POEM (p = 0.753). After HMD, there was a decrease GERD-HRQL total score (31 (22-45) to 4 (0-19); p < 0.001), and objective reflux (54.2 to 25.9%; p = 0.033). On manometry, there was a decrease in LES resting pressure (48 (34-59) to 13 (8-17); p < 0.001) and IRP (22 (17-28) to 8 (3-11); p < 0.001), but esophageal body characteristics did not change (p > 0.05). Incomplete bolus clearance improved (70% (10-90) to 10% (0-40); p = 0.010). After POEM, there was no change in the GERD-HRQL total score (p = 0.854), but objective reflux significantly increased (0 to 62%; p < 0.001). On manometry, there was a decrease in LES resting pressure (43 (30-68) to 31 (5-34); p = 0.042) and IRP (23 (18-33) to 12 (10-32); p = 0.048), DCI (1920 (1600-5500) to 0 (0-814); p = 0.035), with increased failed swallows (0% (0-30) to 100% (10-100); p = 0.032). Bolus clearance did not improve (p = 0.539). Compared to HMD, POEM had a longer esophageal myotomy length (11 (7-15)-vs-5 (5-6); p = 0.001), more objective reflux (p = 0.041), lower DCI (0 (0-814)-vs-1695 (929-3101); p = 0.004), and intact swallows (90 (70-100)-vs-0 (0-40); p = 0.006), but more failed swallows (100 (10-100); p = 0.018) and incomplete bolus clearance (90 (90-100)-vs-10 (0-40); p = 0.004). CONCLUSION: Peroral endoscopic myotomy and Heller myotomy with Dor fundoplication are equally effective at relieving EGJOO symptoms. However, POEM causes worse reflux and near complete loss of esophageal body function.

Brain Growth Charts for Quantitative Analysis of Pediatric Clinical Brain MRI Scans with Limited Imaging Pathology.

Background Clinically acquired brain MRI scans represent a valuable but underused resource for investigating neurodevelopment due to their technical heterogeneity and lack of appropriate controls. These barriers have curtailed retrospective studies of clinical brain MRI scans compared with more costly prospectively acquired research-quality brain MRI scans. Purpose To provide a benchmark for neuroanatomic variability in clinically acquired brain MRI scans with limited imaging pathology (SLIPs) and to evaluate if growth charts from curated clinical MRI scans differed from research-quality MRI scans or were influenced by clinical indication for the scan. Materials and Methods In this secondary analysis of preexisting data, clinical brain MRI SLIPs from an urban pediatric health care system (individuals aged ≤22 years) were scanned across nine 3.0-T MRI scanners. The curation process included manual review of signed radiology reports and automated and manual quality review of images without gross pathology. Global and regional volumetric imaging phenotypes were measured using two image segmentation pipelines, and clinical brain growth charts were quantitatively compared with charts derived from a large set of research controls in the same age range by means of Pearson correlation and age at peak volume. Results The curated clinical data set included 532 patients (277 male; median age, 10 years [IQR, 5-14 years]; age range, 28 days after birth to 22 years) scanned between 2005 and 2020. Clinical brain growth charts were highly correlated with growth charts derived from research data sets (22 studies, 8346 individuals [4947 male]; age range, 152 days after birth to 22 years) in terms of normative developmental trajectories predicted by the models (median r = 0.979). Conclusion The clinical indication of the scans did not significantly bias the output of clinical brain charts. Brain growth charts derived from clinical controls with limited imaging pathology were highly correlated with brain charts from research controls, suggesting the potential of curated clinical MRI scans to supplement research data sets. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ertl-Wagner and Pai in this issue.

Clinical phenotypes of five patients with psychotic disorders carrying rare schizophrenia-associated loss-of-function variants.

The Schizophrenia Exome Meta-Analysis (SCHEMA) consortium identified 10 genes in which loss-of-function (LoF) variants are highly associated with schizophrenia (SZ). In a well-characterized sample of 988 patients with psychotic disorders, we investigated whether patients bearing a SCHEMA variant presented with unusual or unique signs, symptoms, or course of illness. We identified 5 patients who carried a LoF variant in a SCHEMA gene, each in a different gene. None of the patients with a SCHEMA variant had unique symptoms. However, compared to the average of patients in the sample, all of the patients with a SCHEMA variant had earlier onset of any mental illness and more hospitalizations. Also, among SCHEMA carriers, 80 % were treated with clozapine, 60 % with ECT, all with either clozapine or ECT and 40 % with both clozapine and ECT, compared to only 2 % treated with clozapine and 18 % treated with ECT in the comparison group of patients without SCHEMA variants. All 5 patients with a SCHEMA variant had polysubstance abuse, and all had attempted suicide. Fewer than half had such presentations in the group without SCHEMA variants. In this small sample, SCHEMA variants appear to be associated with earlier onset, less favorable response to standard first-line treatments, and more severe illness, but not unique presentations of illness.

Gender Differences in Emotional Connotative Meaning of Words Measured by Osgood's Semantic Differential Techniques in Young Adults.

Semantic differential techniques are a useful, well-validated tool to assess affective processing of stimuli and determine how that processing is impacted by various demographic factors, such as gender. In this paper, we explore differences in connotative word processing between men and women as measured by Osgood's semantic differential and what those differences imply about affective processing in the two genders. We recruited 94 young participants (47 men, 47 women, ages 18-39) using an online survey and collected their affective ratings of 120 words on three rating tasks: Evaluation (E), Potency (P), and Activity (A). With these data, we explored the theoretical and mathematical overlap between Osgood's affective meaning factor structure and other models of emotional processing commonly used in gender analyses. We then used Osgood's three-dimensional structure to assess gender-related differences in three affective classes of words (words with connotation that is Positive, Neutral, or Negative for each task) and found that there was no significant difference between the genders when rating Positive words and Neutral words on each of the three rating tasks. However, young women consistently rated Negative words more negatively than young men did on all three of the independent dimensions. This confirms the importance of taking gender effects into account when measuring emotional processing. Our results further indicate there may be differences between Osgood's structure and other models of affective processing that should be further explored.

White Matter Metabolite Relaxation and Diffusion Abnormalities in First-Episode Psychosis: A Longitudinal Study.

Microstructural abnormalities in the white matter (WM) are implicated in the pathophysiology of psychosis. In vivo magnetic resonance spectroscopy (MRS) can probe the brain's intracellular microenvironment through the measurement of transverse relaxation and diffusion of neurometabolites and possibly provide cell-specific information. In our previous studies, we observed differential metabolite signal abnormalities in first episode and chronic stages of psychosis. In the present work, longitudinal data were presented for the first time on white matter cell-type specific abnormalities using a combination of diffusion tensor spectroscopy (DTS), T2 MRS, and diffusion tensor imaging (DTI) from a group of 25 first episode psychosis patients and nine matched controls scanned at baseline and one and two years of follow-up. We observed significantly reduced choline ADC in the year 1 of follow-up (0.194 µm2/ms) compared to baseline (0.229 µm2/ms), followed by a significant increase in NAA ADC in the year 2 follow-up (0.258 µm2/ms) from baseline (0.222 µm2/ms) and year 1 follow-up (0.217 µm2/ms). In contrast, NAA T2 relaxation, reflecting a related but different aspect of microenvironment from diffusion, was reduced at year 1 follow-up (257 ms) compared to baseline (278 ms). These abnormalities were observed in the absence of any abnormalities in water relaxation and diffusion at any timepoint. These findings indicate that abnormalities are seen in in glial-enriched (choline) signals in early stages of psychosis, followed by the subsequent emergence of neuronal-enriched (NAA) diffusion abnormalities, all in the absence of nonspecific water signal abnormalities.

Abnormal Brain Bioenergetics in First-Episode Psychosis.

BACKGROUND: Converging evidence indicates impaired brain energy metabolism in schizophrenia and other psychotic disorders. Creatine kinase (CK) is pivotal in providing adenosine triphosphate in the cell and maintaining its levels when energy demand is increased. However, the activity of CK has not been investigated in patients with first-episode schizophrenia spectrum disorders. METHODS: Using in vivo phosphorus magnetization transfer spectroscopy, we measured CK first-order forward rate constant (k f ) in the frontal lobe, in patients with first-episode psychosis (FEP; n = 16) and healthy controls (n = 34), at rest. RESULTS: CK k f was significantly reduced in FEP compared to healthy controls. There were no differences in other energy metabolism-related measures, including phosphocreatine (PCr) or ATP, between groups. We also found increase in glycerol-3-phosphorylcholine, a putative membrane breakdown product, in patients. CONCLUSIONS: The results of this study indicate that brain bioenergetic abnormalities are already present early in the course of schizophrenia spectrum disorders. Future research is needed to identify the relationship of reduced CK k f with psychotic symptoms and to test treatment alternatives targeting this pathway. Increased glycerol-3-phosphorylcholine is consistent with earlier studies in medication-naïve patients and later studies in first-episode schizophrenia, and suggest enhanced synaptic pruning.

The method history report: an adaptable tool for communicating immunogenicity assay development and validation.

Over the developmental lifetime of a therapeutic protein, the immunogenicity assay validation history can become substantial, frustrating review of clinical immunogenicity within the biologics license application. In our experience, this can lead to questions by regulators, resulting in numerous information requests during the review process. To address this, we propose a new document, the method history report (MHR), which can comprehensively present the history of the immunogenicity assay for regulators, including assay development and validation. The flexibility of the MHR allows for adaptation to the specific needs of each therapeutic program, while maintaining a consistent template. Here, we detail the rationale, general outline and template for the MHR and recommend others consider adopting it for their biologics license application-related activities.

Mental Health Units in Correctional Facilities in the United States.

BACKGROUND: The prevalence of severe mental illness (SMI) in correctional settings is alarmingly high. Some correctional facilities have developed mental health units (MHUs) to treat incarcerated individuals with SMI. OBJECTIVE: To identify existing MHUs in the United States and collate information on these units. DATA SOURCES: A systematic review using Criminal Justice Abstracts, ERIC, PsycINFO, PubMed, and SocINDEX, plus an exploratory review using the Google search engine were conducted. MHUs were included if they were located within an adult correctional facility in the United States, specifically catered to SMI populations, and were in active operation as of June 2019. RESULTS: Eleven articles were identified through the peer-reviewed literature, but there were still major gaps in the information on MHUs. The Google search identified 317 MHUs. The majority of units were located within prisons (79.5%) and served only men (76%). The Google search found information indicating that 169 (53.3%) offered groups or programming to inmates; 104 (32.8%) offered individual therapy; and 89 (23%) offered both. One hundred sixty-six units (52.4%) had dedicated mental health staff, and 75 (23.7%) provided mental health training to correctional officers. Information on funding and outcomes of the MHUs is presented. LIMITATIONS: Use of the Google search engine and sources that have not been peer reviewed limits the robustness of conclusions about the MHUs. CONCLUSIONS: Standards for developing and implementing MHUs are not widespread. The shortcomings of current MHUs are discussed in the context of desired criteria for size, staffing, and programming.

Visual hallucinations associated with multimodal hallucinations, suicide attempts and morbidity of illness in psychotic disorders.

BACKGROUND: Visual hallucinations (VH) are a common, but understudied symptom of psychosis, experienced by individuals across diagnostic categories of psychotic and neuropsychiatric conditions. There are limited data on VH and associated clinical phenotypes in adult idiopathic psychotic disorders, which are needed to elucidate their relevance to psychotic illness paradigms. METHOD: In this cross-sectional study, we examined clinical risk factors for VH in a well-characterized sample of 766 patients with adult psychotic disorders across diagnostic categories of schizophrenia (n = 227), schizoaffective disorder (n = 210), and bipolar I disorder (n = 329). The Structured Clinical Interview for DSM-IV-TR was used for diagnosis and symptom measurements. RESULTS: The prevalence of VH was 26.1% (200/766). Multivariate logistic regression showed that VH were independently associated with the presence of hallucinations in other modalities, including auditory, tactile, olfactory, and gustatory hallucinations. History of a suicide attempt and catatonic behavior were also associated with VH. In addition, specific delusions were associated with VH, in particular, delusions of control, and religious, erotomanic and jealousy delusions. Diagnosis, negative symptoms, and family history of psychosis were not independent predictors of VH. CONCLUSIONS: Results showed the clinical and disease relevance of VH as they were associated with severe morbidity of illness, including suicide attempts and catatonic behavior. Findings also suggest a phenotype associated with hallucinations in other modalities and specific types of delusions. Based on our findings, VH may be a significant factor in assessing for suicidality and illness severity, warranting clinical attention and further study of underlying mechanisms.

Temporospatial components of brain ERPs as biomarkers for Alzheimer's disease.

INTRODUCTION: Developing biomarkers that distinguish individuals with Alzheimer's disease (AD) from those with normal cognition remains a crucial goal for improving the health of older adults. We investigated adding brain spatial information to temporal event-related potentials (ERPs) to increase AD identification accuracy over temporal ERPs alone. METHODS: With two-step principal components analysis, we applied multivariate analyses that incorporated temporal and spatial ERP information from a cognitive task. Discriminant analysis used temporospatial ERP scores to classify participants as belonging to either the AD or healthy control group. RESULTS: Temporospatial ERPs produced a cross-validated area under the curve of 0.84. Adding spatial information through a formal procedure significantly improves classification accuracy. DISCUSSION: A weighted combination of temporospatial ERP markers performs well in detecting AD. Because ERPs are noninvasive and inexpensive, they may be promising biomarkers for AD that can add functional information to other biomarker systems while providing the individual's probability of correct classification.

ERP C250 shows the elderly (cognitively normal, Alzheimer's disease) store more stimuli in short-term memory than Young Adults do.

OBJECTIVE: To determine how aging and dementia affect the brain's initial storing of task-relevant and irrelevant information in short-term memory. METHODS: We used brain Event-Related Potentials (ERPs) to measure short-term memory storage (ERP component C250) in 36 Young Adults, 36 Normal Elderly, and 36 early-stage AD subjects. Participants performed the Number-Letter task, a cognitive paradigm requiring memory storage of a first relevant stimulus to compare it with a second stimulus. RESULTS: In Young Adults, C250 was more positive for the first task-relevant stimulus compared to all other stimuli. C250 in Normal Elderly and AD subjects was roughly the same to relevant and irrelevant stimuli in Intratrial Parts 1-3 but not 4. The AD group had lower C250 to relevant stimuli in part 1. CONCLUSIONS: Both normal aging and dementia cause less differentiation of relevant from irrelevant information in initial storage. There was a large aging effect involving differences in the pattern of C250 responses of the Young Adult versus the Normal Elderly/AD groups. Also, a potential dementia effect was obtained. SIGNIFICANCE: C250 is a candidate tool for measuring short-term memory performance on a biological level, as well as a potential marker for memory changes due to normal aging and dementia.

Memory timeline: Brain ERP C250 (not P300) is an early biomarker of short-term storage.

Brain event-related potentials (ERPs) offer a quantitative link between neurophysiological activity and cognitive performance. ERPs were measured while young adults performed a task that required storing a relevant stimulus in short-term memory. Using principal components analysis, ERP component C250 (maximum at 250 ms post-stimulus) was extracted from a set of ERPs that were separately averaged for various task conditions, including stimulus relevancy and stimulus sequence within a trial. C250 was more positive in response to task-specific stimuli that were successfully stored in short-term memory. This relationship between C250 and short-term memory storage of a stimulus was confirmed by a memory probe recall test where the behavioral recall of a stimulus was highly correlated with its C250 amplitude. ERP component P300 (and its subcomponents of P3a and P3b, which are commonly thought to represent memory operations) did not show a pattern of activation reflective of storing task-relevant stimuli. C250 precedes the P300, indicating that initial short-term memory storage may occur earlier than previously believed. Additionally, because C250 is so strongly predictive of a stimulus being stored in short-term memory, C250 may provide a strong index of early memory operations.

Cell- and developmental stage-specific Dicer1 ablation in the lung epithelium models cystic pleuropulmonary blastoma.

Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of-function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm pleuropulmonary blastoma (PPB), which arises during lung development. DICER1 regulates many biological processes critical in development and disease pathogenesis. Significant challenges in defining the role of DICER1 in human disease are identifying cause-effect relationships and generating manipulatable systems that model the complexity of organ development and disease pathogenesis. Here we report the generation of a murine model for PPB and demonstrate that precise temporal and cell type-specific Dicer1 ablation is necessary and sufficient for the development of cystic lungs that histologically and phenotypically model PPB. Dicer1 ablation in the distal airway epithelium during early stages of lung development resulted in a cystic lung phenotype indistinguishable from PPB, whereas DICER1 function was not required for development of the proximal airway epithelium or during later stages of organogenesis. Mechanistic studies demonstrate that Dicer1 loss results in epithelial cell death, followed by cystic airway dilatation accompanied by epithelial and mesenchymal proliferation. These studies define precise temporal and epithelial cell type-specific DICER1 functions in the developing lung and demonstrate that loss of these DICER1 functions is sufficient for the development of cystic PPB. These results also provide evidence that PPB arise through a novel mechanism of non-cell-autonomous tumour initiation, in which the genetic abnormality initiating the neoplasm does not occur in the cells that ultimately transform, but rather occurs in a benign-appearing epithelial cell component that predisposes underlying mesenchymal cells to malignant transformation.

Synthesis of N,N-Diethylbenzamides via a Non-Classical Mitsunobu Reaction.

The use of the Mitsunobu reaction for the synthesis of N,N-diethylbenzamides affords ortho-, meta-, and para-substituted benzamides, containing both electron-donating and electron-withdrawing groups. While the preparation of numerous functional groups has been efficiently demonstrated employing the Mitsunobu reaction, our methodology represents the first application of the Mitsunobu reaction for the construction of benzamides using benzoic acid and amine starting materials. Moreover, this synthetic transformation is believed to proceed via a non-classical mechanism involving the existence of an acyloxyphosphonium ion.

The impact of AD drug treatments on event-related potentials as markers of disease conversion.

This paper investigates how commonly prescribed pharmacologic treatments for Alzheimer's disease (AD) affect Event-Related Potential (ERP) biomarkers as tools for predicting AD conversion in individuals with Mild Cognitive Impairment (MCI). We gathered baseline ERP data from two MCI groups (those taking AD medications and those not) and later determined which subjects developed AD (Convert->AD) and which subjects remained cognitively stable (Stable). We utilized a previously developed and validated multivariate system of ERP components to measure medication effects among these four subgroups. Discriminant analysis produced classification scores for each individual as a measure of similarity to each clinical group (Convert->AD, Stable), and we found a large significant main Group effect but no main AD Medications effect and no Group by Medications interaction. This suggested AD medications have negligible influence on this set of ERP components as weighted markers of disease progression. These results provide practical information to those using ERP measures as a biomarker to identify and track AD in individuals in a clinical or research setting.