Search

Precise photochemical control, using two-photon excitation (2PE), of the timing and location of activation of glutamate is useful for studying the molecular and cellular physiology of the brain. Antenna-based light harvesting strategies represent a general method to increase the sensitivity to 2PE of otherwise insensitive photoremovable protecting groups (PPGs). This was applied to the most commonly used form of "caged" glutamate, MNI-Glu. Computational investigation showed that a four- or six-carbon linker attached between the 4-position of thioxanthone (THX) and the 4-position of the 5-methyl derivative of MNI-Glu (MMNI-Glu) would position the antenna and PPG close to one another to enable Dexter energy transfer. Nine THX-MMNI-Glu conjugates were prepared and their photochemical properties determined. Installation of the THX antenna resulted in a red shift of the absorption (λ

The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of theHomo sapiensandMus musculusgenomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and availableviathe ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL;https://openwdl.org/) is publicly available in GitHub, with images available on Dockerhub (https://hub.docker.com), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environmentsviaCromwell. Access to the pipelines and dataviathe cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.Database URL:https://www.encodeproject.org/

Introduction: The SARS-CoV-2 global pandemic has resulted in a universal search for potential treatments of Coronavirus Disease 2019 (COVID-19). Initial reports of the therapeutic potential of chloroquine (CQ) and hydroxychloroquine (HCQ) and early non-randomized non-controlled studies were followed by subsequent trials refuting such properties. The use of CQ and HCQ in diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), prompted us to examine the prevalence of COVID-19 and proposed prophylactic and therapeutic properties of HCQ in this population. Methods: A total of 103 patients with RA and SLE aged 18 to 75 diagnosed with COVID-19 were identified. The patients were categorized as those taking HCQ (cases) and those not on HCQ (controls) for at least 6 months. Primary (mechanical ventilation, length of stay, death) and secondary outcomes were defined, data were collected, and results were compared and statistically analyzed between cases and controls. Results: No statistical difference was observed in demographic features, baseline comorbidities, and medications. Primary outcomes’ statistical analysis did not reveal any differences between cases and controls. Statistical analysis of secondary outcomes revealed that cases had a statistically higher chance of being tachypneic (p 0.034). D-Dimer (p 0.017) and LDH levels (p 0.044) were found to be significantly lower in cases versus controls. Conclusion: This study highlights the lack of clinical prophylactic and therapeutic efficacy of HCQ against COVID-19 when taken at regular doses for patients with RA and SLE. It also shows that the prevalence of COVID-19 was similar in RA and SLE patients regardless of baseline consumption of HCQ.

Background Typhoid fever incidence and complications, including intestinal perforation, have declined significantly in high-income countries, with mortality rates Methods We searched EMBASE, PubMed, Medline, and Cochrane databases for studies reporting mortality rates due to typhoid intestinal perforation in children, under 18 years old, in sub-Saharan Africa published from January 1995 through June 2019. Results Twenty-four papers from six countries were included. Reported mortality rates ranged from 4.6–75%, with 16 of the 24 studies between 11 and 30%. Thirteen papers included postoperative morbidity rates, ranging from 16–100%. The most documented complications included surgical site infections, intra-abdominal abscesses, and enterocutaneous fistulas. High mortality rates can be attributed to late presentation to tertiary centers, sepsis and electrolyte abnormalities requiring preoperative resuscitation, prolonged perforation-to-surgery interval, and lack of access to critical care or an intensive care unit postoperatively. Conclusions Current estimates of mortality related to typhoid intestinal perforation among children in sub-Saharan Africa remain unacceptably high. Prevention of typhoid fever is essential to reduce mortality, with the ultimate goal of a comprehensive approach that utilizes vaccination, improvements in water, sanitation, and hygiene, and greater access to surgical care.

Radiofrequency ablation (RFA) of Barrett's esophagus (BE) inflicts a wound spanning 3 epithelial types (stratified squamous, Barrett's metaplasia, gastric epithelium), yet the esophageal injury heals almost completely with squamous epithelium. Knowledge of how this unique wound heals might elucidate mechanisms underlying esophageal metaplasia. We aimed to prospectively and systematically characterize the early endoscopic and histologic features of RFA wound healing.Patients with nondysplastic BE had endoscopy with systematic esophageal photographic mapping, biopsy, and volumetric laser endomicroscopy performed before and at 1, 2, and 4 weeks after RFA.Seven patients (6 men; mean age 56.1 ± 10.9 years) completed this study. Squamous re-epithelialization of RFA wounds did not only progress exclusively through squamous cells extending from the proximal wound edge but also progressed through islands of squamous epithelium sprouting throughout the ablated segment. Volumetric laser endomicroscopy revealed significant post-RFA increases in subepithelial glandular structures associated with the squamous islands. In 2 patients, biopsies of such islands revealed newly forming squamous epithelium contiguous with immature-appearing squamous cells arising from esophageal submucosal gland ducts. Subsquamous intestinal metaplasia (SSIM) was found in biopsies at 2 and/or 4 weeks after RFA in 6 of 7 patients.RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands in which esophageal submucosal gland duct cells seem to redifferentiate into the squamous progenitors that fuel squamous re-epithelialization. SSIM can be found in most patients during the healing process. We speculate that this SSIM might underlie Barrett's recurrences after apparently successful eradication.

Transcription factors bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we undertook multiomic data profiling of chromatin and expression dynamics across epidermal differentiation to identify 40,103 dynamic CREs associated with 3,609 dynamically expressed genes, then applied an interpretable deep-learning framework to model the cis-regulatory logic of chromatin accessibility. This analysis framework identified cooperative DNA sequence rules in dynamic CREs regulating synchronous gene modules with diverse roles in skin differentiation. Massively parallel reporter assay analysis validated temporal dynamics and cooperative cis-regulatory logic. Variants linked to human polygenic skin disease were enriched in these time-dependent combinatorial motif rules. This integrative approach shows the combinatorial cis-regulatory lexicon of epidermal differentiation and represents a general framework for deciphering the organizational principles of the cis-regulatory code of dynamic gene regulation.

Optimal timing for anticoagulation resumption after polypectomy is unclear. We explored the association between timing of anticoagulation resumption and occurrence of delayed post-polypectomy bleeding (PPB) and thromboembolic (TE) events.We performed a post-hoc analysis of patients in an earlier study whose anticoagulants were interrupted for polypectomy. We compared rates of clinically important delayed PPB and TE events in relationship to timing of anticoagulant resumption. Late resumption was defined as 2 days after polypectomy.Among 437 patients, 351 had early and 86 late resumption. Compared to early resumers, late resumers had greater polypectomy complexity. PPB rate was higher (but not significantly) in the late versus early resumers (2.3% vs. 0.9%, 1.47% greater, 95% CI [- 2.58 to 5.52], p = 0.26). TE events were more frequent in late versus early resumers [0% vs. 1.2% at 30 days, 0% vs. 2.3%, 95% CI 0.3-8, (p = 0.04) at 90 days]. On multivariate analysis, timing of restarting anticoagulation was not a significant predictor of PPB (OR 0.97, 95% CI 0.61-1.44, p = 0.897). Significant predictors were number of polyps ≥ 1 cm (OR 4.14, 95% CI 1.27-13.66, p = 0.014) and use of fulguration (OR 11.43, 95% CI 1.35-80.80, p = 0.014).Physicians delayed anticoagulation resumption more commonly after complex polypectomies. The timing of restarting anticoagulation was not a significant risk factor for PPB and late resumers had significantly higher rates of TE events within 90 days. Considering the potentially catastrophic consequences of TE events and the generally benign outcome of PPBs, clinicians should be cautious about delaying resumption of anticoagulation after polypectomy.

Using recent anti-corruption investigation in China, we show that Chinese listed firms suffered an aggregate loss of USD 30 billion in firm value due to corruption. Furthermore, we show that anti-corruption investigation is more effective when top officials are targeted.

Performance share plans are an increasingly important component of executive compensation. They are equity-based, long-term incentive plans where the number of shares to be awarded is a quasi-linear function of a performance result over a fixed time period. We derive closed-form formulas for the value of a performance share plan when the performance measure is: (1) a non-traded measure following an Arithmetic Brownian Motion (e.g., earnings per share), (2) a non-traded measure following a Geometric Brownian Motion (e.g., revenue), or (3) a rank-order tournament of traded asset returns that are following Arithmetic Brownian Motions (e.g., percentile of ranked stock returns). Then we empirically test our valuation formulas. We find that our valuation formulas are more accurate for performance share plans based on earnings per share when forecasting using analyst consensus prior to the grant date. We also find that the efficiency of our valuation model greatly depends on the method used to forecast future firm performance. The policy implication is that FASB should consider requiring that grant date fair value be estimated using valuation formulas such as ours.

Quantum Dots (QDs) are becoming more prevalent in products used in our daily lives, such as TVs and laptops, due to their unique and tunable optical properties. The possibility of using QDs as fluorescent probes in applications, such as medical imaging, has been a topic of interest for some time, but their potential toxicity and long-term effects on the environment are not well understood. In the present study, we investigated the effects of yellow CdSe/ZnS-QDs on Saccharomyces cerevisiae. We utilized growth assays, RNA-seq, reactive oxygen species (ROS) detection assays, and cell wall stability experiments to investigate the potential toxic effects of CdSe/ZnS-QDs. We found CdSe/ZnS-QDs had no negative effects on cell viability, however, cell wall-compromised cells showed more sensitivity in the presence of 10 &micro, g/mL CdSe/ZnS-QDs compared to non-treated cells. In CdSe/ZnS-treated and non-treated cells, no significant change in superoxide was detected, but according to our transcriptomic analysis, thousands of genes in CdSe/ZnS-treated cells became differentially expressed. Four significantly differentiated genes found, including FAF1, SDA1, DAN1, and TIR1, were validated by consistent results with RT-qPCR assays. Our transcriptome analysis led us to conclude that exposure of CdSe/ZnS-QDs on yeast significantly affected genes implicated in multiple cellular processes.

Motivation Genome-wide profiles of chromatin accessibility and gene expression in diverse cellular contexts are critical to decipher the dynamics of transcriptional regulation. Recently, convolutional neural networks have been used to learn predictive cis-regulatory DNA sequence models of context-specific chromatin accessibility landscapes. However, these context-specific regulatory sequence models cannot generalize predictions across cell types. Results We introduce multi-modal, residual neural network architectures that integrate cis-regulatory sequence and context-specific expression of trans-regulators to predict genome-wide chromatin accessibility profiles across cellular contexts. We show that the average accessibility of a genomic region across training contexts can be a surprisingly powerful predictor. We leverage this feature and employ novel strategies for training models to enhance genome-wide prediction of shared and context-specific chromatin accessible sites across cell types. We interpret the models to reveal insights into cis- and trans-regulation of chromatin dynamics across 123 diverse cellular contexts. Availability and implementation The code is available at https://github.com/kundajelab/ChromDragoNN. Supplementary information Supplementary data are available at Bioinformatics online.

Purpose: Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e., therapies for which no single target mutation can cause resistance. Because the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes and prioritize pan-target inhibitors for indications where on-target mutations are most likely. Experimental Design: To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph+) leukemias with computational simulations. Results: A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) harbor multiple preexisting resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations. Conclusions: These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. Clin Cancer Res; 24(21); 5321–34. ©2018 AACR.

Advanced machine learning models applied to large-scale genomics datasets hold the promise to be major drivers for genome science. Once trained, such models can serve as a tool to probe the relationships between data modalities, including the effect of genetic variants on phenotype. However, lack of standardization and limited accessibility of trained models have hampered their impact in practice. To address this, we present Kipoi, a collaborative initiative to define standards and to foster reuse of trained models in genomics. Already, the Kipoi repository contains over 2,000 trained models that cover canonical prediction tasks in transcriptional and post-transcriptional gene regulation. The Kipoi model standard grants automated software installation and provides unified interfaces to apply and interpret models. We illustrate Kipoi through canonical use cases, including model benchmarking, transfer learning, variant effect prediction, and building new models from existing ones. By providing a unified framework to archive, share, access, use, and build on models developed by the community, Kipoi will foster the dissemination and use of machine learning models in genomics.

Each year, academic medical practices will have an influx of residents who need to be orientated to the clinical site. This chapter covers the multiple types of orientation for new residents, what can be included in orientation, and examples of orientation checklists.

Chromosome conformation is an important feature of metazoan gene regulation1,2; however, enhancer–promoter contact remodeling during cellular differentiation remains poorly understood3. To address this, genome-wide promoter capture Hi-C (CHi-C)1,4 was performed during epidermal differentiation5. Two classes of enhancer–promoter contacts associated with differentiation-induced genes were identified. The first class (‘gained’) increased in contact strength during differentiation in concert with enhancer acquisition of the H3K27ac activation mark. The second class (‘stable’) were pre-established in undifferentiated cells, with enhancers constitutively marked by H3K27ac. The stable class was associated with the canonical conformation regulator cohesin, whereas the gained class was not, implying distinct mechanisms of contact formation and regulation. Analysis of stable enhancers identified a new, essential role for a constitutively expressed, lineage-restricted ETS-family transcription factor, EHF, in epidermal differentiation. Furthermore, neither class of contacts was observed in pluripotent cells, suggesting that lineage-specific chromatin structure is established in tissue progenitor cells and is further remodeled in terminal differentiation.

We report complex phenomena arising among financial analysts, who gather information and generate investment advice, and elucidate them with the help of a theoretical model. Understanding how analysts form their forecasts is important in better understanding the financial market. Carrying out big-data analysis of the analyst forecast data from I/B/E/S for nearly thirty years, we find skew distributions as evidence for emergence of complexity, and show how information asymmetry or disparity affects financial analysts' forming their forecasts. Here regulations, information dissemination throughout a fiscal year, and interactions among financial analysts are regarded as the proxy for a lower level of information disparity. It is found that financial analysts with better access to information display contrasting behaviors: a few analysts become bolder and issue forecasts independent of other forecasts while the majority of analysts issue more accurate forecasts and flock to each other. Main body of our sample of optimistic forecasts fits a log-normal distribution, with the tail displaying a power law. Based on the Yule process, we propose a model for the dynamics of issuing forecasts, incorporating interactions between analysts. Explaining nicely empirical data on analyst forecasts, this provides an appealing instance of understanding social phenomena in the perspective of complex systems.

Introduction Appendicitis is the most common emergency operation in children. The rate of perforation may be related to duration from symptom onset to treatment. A recent adult study suggests that the perforation risk is minimal in the first 36 hours and remains at 5% thereafter. We studied a pediatric population to assess symptom duration as a risk factor for perforation. Methods We prospectively studied all children older than 3 years who underwent an appendectomy over a 22-month period. Results Of 202 patients undergoing appendectomies, 197 had appendicitis. Median age was significantly lower in the perforated group, but temperature and leukocytosis were not. As expected, length of hospital stay was longer in the perforated group (4-13 vs 2-6 days). The incidence of perforation was 10% if symptoms were present for less than 18 hours. This incidence rose in a linear fashion to 44% by 36 hours. Prehospital delays were greater in patients with perforated appendicitis. However, in-hospital delay (from presentation to surgery) was less than 5 hours in the perforated group and 9 hours in the nonperforated group. Discussion Appendiceal perforation in children is more common than in adults and correlates directly with duration of symptoms before surgery. Perforation is more common in younger children. Unlike in adults, the risk of perforation within 24 hours of onset is substantial (7.7%), and it increases in a linear fashion with duration of symptoms. In our experience, however, perforation correlates more with prehospital delay than with in-hospital delay.

SummaryHere we present Perturb-ATAC, a method which combines multiplexed CRISPR interference or knockout with genome-wide chromatin accessibility profiling in single cells, based on the simultaneous detection of CRISPR guide RNAs and open chromatin sites by assay of transposase-accessible chromatin with sequencing (ATAC-seq). We applied Perturb-ATAC to transcription factors (TFs), chromatin-modifying factors, and noncoding RNAs (ncRNAs) in ∼4,300 single cells, encompassing more than 63 unique genotype-phenotype relationships. Perturb-ATAC in human B lymphocytes uncovered regulators of chromatin accessibility, TF occupancy, and nucleosome positioning, and identified a hierarchical organization of TFs that govern B cell state, variation, and disease-associatedcis-regulatory elements. Perturb-ATAC in primary human epidermal cells revealed three sequential modules ofcis-elements that specify keratinocyte fate, orchestrated by the TFs JUNB, KLF4, ZNF750, CEBPA, and EHF. Combinatorial deletion of all pairs of these TFs uncovered their epistatic relationships and highlighted genomic co-localization as a basis for synergistic interactions. Thus, Perturb-ATAC is a powerful and general strategy to dissect gene regulatory networks in development and disease.HighlightsA new method for simultaneous measurement of CRISPR perturbations and chromatin state in single cells.Perturb-ATAC reveals regulatory factors that controlcis-element accessibility,trans-factor occupancy, and nucleosome positioning.Perturb-ATAC reveals regulatory modules of coordinatedtrans-factor activity in B lymphoblasts.Keratinocyte differentiation is orchestrated by synergistic activities of co-binding TFs oncis-elements.

Background: Giant omphaloceles present a unique challenge to pediatric surgeons because of the difficulty in obtaining timely, tension-free closure of tissues over the defect. Reports of the use of tissue expanders in the subcutaneous space, intramuscular space, or intraabdominal cavity have illustrated the usefulness of this technique to provide biologic closure of abdominal wall defects. However, these reports have focused on use of tissue expanders as a second-line treatment after other options, such as silastic silos or attempted primary closure, have failed. Methods: We report 2 cases in which intraabdominal tissue expanders were used as a primary strategy to obtain closure of giant omphalocele defects. Case Reports: The first patient was a baby boy born at 36 weeks by date who was prenatally diagnosed with a giant omphalocele. An intraabdominal tissue expander was placed at 2 weeks of age. The tissue expander was removed and his abdomen was primarily closed at 8 weeks of age. The second patient was born at 25 weeks gestation as part of a twin gestation with severe intrauterine growth retardation (600 g birth weight). Bedside reduction was not attempted because of severe pulmonary hypertension and significant loss of abdominal domain because of herniated liver and bowel. At 8 months of age, she underwent laparoscopically assisted placement of an intraabdominal tissue expander. At 9 months of age, the tissue expander was removed, all abdominal viscera were reduced, and the defect was closed using only an 8 × 8-cm piece of AlloDerm (LifeCell, Branchburg, NJ). Both children are currently at home and doing well. Conclusions: We believe that early use of intraabdominal tissue expanders provides a more expedient method of obtaining closure of the defect in giant omphaloceles.

Objective: Providing incentives for research participation is widely practiced but minimally studied. In schizophrenia research, questions about capacity to consent and potential vulnerability may raise concerns when offering incentives for participation. Despite empirical attention focused on consent and decision-making capacity in schizophrenia, the issue of incentives has been essentially ignored. We examined willingness to participate in research, in relation to perceived risks and benefits, among people with schizophrenia and schizoaffective disorder. Method: Forty-six people with schizophrenia or schizoaffective disorder rated perceived risks and benefits of 5 hypothetical research vignettes. They also indicated whether they would be willing to participate at each of 5 incentive levels (including no compensation). Cognition was assessed with Mattis Dementia Rating Scale. Results: Ratings of risk and potential personal benefit were inversely correlated. For all scenarios, significant correlations were found between perceived risk and willingness to participate for greater compensation. Conversely, lower perceived likelihood of benefit was associated with a higher compensation threshold for participation in each scenario. Even at the highest proffered payment level for each scenario, however, a substantial proportion of respondents were not willing to participate. Risk assessment and willingness to participate (at all levels of compensation) were not associated with demographic variables or cognitive status. Conclusions: Determining whether incentives impede voluntarism remains an important task for empirical ethics research. Assessing potential research participants’ understanding and perceptions of risks, benefits, and alternatives to participation will help ensure that informed consent fulfills its mission—embodying the ethical principle of respect for persons.

Anxiety disorders are among the most common forms of psychiatric disorder, yet few investigations have examined the prevalence or service use of clients with anxiety disorders in the public mental health sector.We examined demographics, clinical information, and service use in clients with anxiety disorders enrolled in San Diego County Adult and Older Adult Mental Health Services in fiscal 2002-2003.Almost 15% of the sample had a diagnosis of an anxiety disorder based on administrative billing data. Most anxiety disorder clients had additional psychiatric diagnoses, most commonly depression. Clients with both anxiety disorders and depression were more likely than those with anxiety or depression alone to use emergency psychiatric services and outpatient services than those with depression alone. Those with anxiety disorders alone used more outpatient services than those with depression alone.Data were taken from an administrative database.Data indicate that anxiety disorders are not uncommon in public mental health settings and are associated with higher utilization of outpatient mental health services.

Background Postoperative bowel obstruction (PBO) plagues patients of all ages after intraabdominal surgery. We examined the incidence, risk factors, and the need for operative intervention of PBO. Methods We reviewed all children who underwent a laparotomy or laparoscopy. Parameters included age, diagnosis, type and number of procedures, complications, time interval to PBO, treatment of PBO, morbidity, and mortality. Results From 2001 to 2005, 2187 abdominal operations were performed. Overall, 61 patients (2.8%) developed a PBO; 43 (70.5%) required reoperation. Postoperative bowel obstruction was more common in patients younger than 1 year (28/601, 4.7%) compared with older children (33/1586, 2.1%; P = .01, β = .80). In infants, PBO was not influenced by initial diagnosis ( P = .26) or whether the initial operation was clean/clean-contaminated or contaminated/dirty ( P = .12). In children older than 1 year, nonoperative treatment was more likely to be successful if PBO occurred within 12 weeks of initial operation (12/16 vs 3/14; P = .01). In contrast, all but one infant (16/17) with early PBO required reoperation. Conclusion The incidence of PBO is significantly higher in newborns and infants than in older children (who have rates comparable to those reported in adults). Infants are significantly more likely to require operative intervention, particularly if PBO occurs early after the initial operation.

Neuropsychiatric symptoms in dementia represent a major health burden for older adults. These symptoms are often more distressing, impairing, and costly than cognitive symptoms in dementia, yet they have been less coherently categorized in the various versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The preponderance of literature on psychiatric symptoms in dementia has been in patients with Alzheimer’s disease. Diagnostic criteria have been proposed for psychosis, depression, and sleep disturbance in Alzheimer’s disease. “Agitation” also appears to be a clinically important behavioral complication of dementia that warrants further study. Beginning with further validation of these proposed diagnostic criteria, future research can guide a more clinically meaningful description of these syndromes in DSM-V. Advancing biotechnology offers promise for discoveries related to the etiology and treatment of these syndromes. New research in this field should encompass diverse populations and different types of dementia. The high emotional and economic costs of neuropsychiatric symptoms in dementia implore diagnostic refinement to facilitate improved treatment. ( J Geriatr Psychiatry Neurol 2006; 19:160-171)

The best way to adjust proximal contacts of newly fabricated indirect restorations has been a long-standing unresolved issue in dentistry. Excessively tight contacts cause incomplete seating of indirect restorations and intrusion of adjacent teeth, which leads to patient discomfort, hypersensitivity, and recurrent dental caries at the crown margins. When seating indirect restorations, interproximal relief should be restored as it exists in natural dentition. This article presents an innovative method of crown seating using diamond strips. This simple, consistent, method makes it easier for clinicians to provide comfortable and long-lasting restorations with minimal time and effort. Laboratory technicians utilize diamond strips to provide properly fitting indirect restorations that require minimal adjustment upon clinical delivery. Diamond strips also allow for accurate determination of heavier proximal contacts, allowing dentists to adjust the proximal contact properly in the patients' mouths. Clinically, restoring natural proximal contacts is a critical factor to the success of indirect restorations. Using this method standardizes proper proximal contact adjustments of laboratory-fabricated indirect restorations between dental labs and dental offices. The method also helps to limit or eliminate the lingering proximal contact issue between clinicians and laboratory technicians.

Performance share plans are an increasingly important component of executive compensation. A performance share plan is an equity-based, long-term incentive plan where the number of shares to be awarded is a quasi-linear function of a performance result over a fixed time period. A special case is a performance-vested share plan, which provides a fixed number of shares whenever a performance result exceeds a threshold goal. We begin by documenting the size and importance of performance share plans and performance-vested share plans. Next, we derive closed-form formulas for the value of a performance share plan or performance-vested share plan when the performance measure is: (1) a non-traded measure following an Arithmetic Brownian Motion (e.g., earnings per share), (2) a non-traded measure following a Geometric Brownian Motion (e.g., revenue), or (3) a rank-order tournament of traded asset returns that are following Arithmetic Brownian Motions (e.g., percentile of ranked stock returns). Finally, we compare the actual payout of plans to our new valuation formulas, the reported values on proxy statements, and heuristic values. We find that our valuation formulas do significantly better or at least tie reported value and heuristic value in matching the magnitude of actual payout in all subsamples. We also find that our valuation formulas are more accurate or tie in all subsamples. The policy implication is that FASB should consider requiring that grant date fair value be estimated using valuation formulas such as ours.