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Members of the calcium-dependent protein kinase (CDPK/CPK) and SNF-related protein kinase (SnRK) superfamilies are commonly found in plants and some protists. Our knowledge of client specificity of the members of this superfamily is fragmentary. As this family is represented by over 30 members in Arabidopsis thaliana , the identification of kinase-specific and overlapping client relationships is crucial to our understanding the nuances of this large family of kinases as directed towards signal transduction pathways. Herein, we used the kinase client (KiC) assay-a relative, quantitative, high-throughput mass spectrometry-based in vitro phosphorylation assay-to identify and characterize potential CPK/SnRK targets of Arabidopsis. Eight CPKs (1, 3, 6, 8, 17, 24, 28, and 32), four SnRKs (subclass 1 and 2), and PPCK1 and PPCK2 were screened against a synthetic peptide library that contains 2095 peptides and 2661 known phosphorylation sites. A total of 625 in vitro phosphorylation sites corresponding to 203 non-redundant proteins were identified. The most promiscuous kinase, CPK17, had 105 candidate target proteins, many of which had already been discovered. Sequence analysis of the identified phosphopeptides revealed four motifs: LxRxxS, RxxSxxR, RxxS, and LxxxxS, that were significantly enriched among CPK/SnRK clients. The results provide insight into both CPK- and SnRK-specific and overlapping signaling network architectures and recapitulate many known in vivo relationships validating this large-scale approach towards discovering kinase targets.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Varied mechanisms of injury contribute to the heterogeneity of this patient population as demonstrated by the multiple published grading scales and diverse required criteria leading to diagnoses from mild to severe. TBI pathophysiology is classically separated into a primary injury that is characterized by local tissue destruction as a result of the initial blow, followed by a secondary phase of injury constituted by a score of incompletely understood cellular processes including reperfusion injury, disruption to the blood-brain barrier, excitotoxicity, and metabolic dysregulation. There are currently no effective pharmacological treatments in the wide-spread use for TBI, in large part due to challenges associated with the development of clinically representative in vitro and in vivo models. Poloxamer 188 (P188), a Food and Drug Administration-approved amphiphilic triblock copolymer embeds itself into the plasma membrane of damaged cells. P188 has been shown to have neuroprotective properties on various cell types. The objective of this review is to provide a summary of the current literature on in vitro models of TBI treated with P188.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment., Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes., Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications., Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978)., Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters., Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45)., Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission., Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

A genealogy of the United States has been record-linked to National Veteran's Health Administration (VHA) patient data to allow non-identifiable analysis of familial clustering. This genealogy, including over 70 million individuals linked to over 1 million VHA patients, is the largest such combined resource reported. Analysis of familial clustering among VHA patients diagnosed with Post Traumatic Stress Disorder (PTSD) allowed a test of the hypothesis of an inherited contribution to PTSD. PTSD is associated strongly with military service and extended familial clustering data have not previously been presented. PTSD-affected VHA patients with genealogy data were identified by presence of an ICD diagnosis code in the VHA medical record in at least 2 different years. The Genealogical Index of Familiality (GIF) method was used to compare the average relatedness of VHA patients diagnosed with PTSD with their expected average relatedness, estimated from randomly selected sets of matched linked VHA patient controls. Relative risks for PTSD were estimated in first-, second-, and third-degree relatives of PTSD patients who were also VHA patients, using sex and age-matched rates for PTSD estimated from all linked VHA patients. Significant excess pairwise relatedness, and significantly elevated risk for PTSD in first-, second-, and third-degree relatives was observed; multiple high-risk extended PTSD pedigrees were identified. The analysis provides evidence for excess familial clustering of PTSD and identified high-risk PTSD pedigrees. These results support an inherited contribution to PTSD predisposition and identify a powerful resource of high-risk PTSD pedigrees for predisposition gene identification., (Copyright © 2021. Published by Elsevier Ltd.)

Traumatic brain injury can lead to fatal outcomes such as disability and death. Every year, it affects many patients all over the world. Not only the primary ischemic event, but also the subsequent reperfusion can cause severe brain injury. This so-called ischemia/reperfusion injury combined with mechanical forces lead to cellular disruption. Hence, this paper describes a special in-vitro model, mimicking traumatic brain injury by combining both hypoxia/reoxygenation and compression to simulate ischemia/reperfusion injury as well as the mechanical effects that occur concurrently when suffering traumatic brain injury. Through this approach, stroke, concussion, and traumatic brain injury can be studied on different cell lines in a simplified way. We used two primary mouse brain cell cultures, namely neurons and endothelial cells. Our results show that for the different cell types, different timelines of hypoxia and compression need to be explored to achieve the optimal amount of cellular damage in order to effectively mimic traumatic brain injury. Thus, this model will be useful to test potential treatments of brain injury in future in-vitro studies., (Published by Elsevier Inc.)

Traumatic brain injury (TBI) leads to morbidity and mortality worldwide. Reperfusion after ischemia adds detrimental injury to cells. Ischemia/reperfusion (I/R) injures cells in a variety of ways including cell membrane disruption. Hence, methods to improve endogenous membrane resealing capacity are crucial. Poloxamer (P) 188, an amphiphilic triblock copolymer, was found to be effective against I/R and mechanical injury in various experimental settings. The aim of this study was to establish an in vitro mouse neuronal TBI model and, further, to investigate if post conditioning with P188 directly interacts with neurons after compression and simulated I/R injury, when administered at the start of reoxygenation. Cellular function was assessed by cell number/viability, mitochondrial viability, membrane damage by lactated dehydrogenase (LDH) release and FM1-43 incorporation as well as apoptosis-activation by Caspase 3. Five hours hypoxia ± compression with 2 h reoxygenation proved to be a suitable model for TBI. Compared to normoxic cells not exposed to compression, cell number and mitochondrial viability decreased, whereas membrane injury by LDH release/FM1-43 dye incorporation and Caspase 3 activity increased in cells exposed to hypoxic conditions with compression followed by reoxygenation. P188 did not protect neurons from simulated I/R and/or compression injury. Future research is indicated.

Public genealogy websites, to which individuals upload family history, genealogy, and sometimes individual genetic data, have been used in an increasing number of public health, epidemiological, and genetic studies. Yet there is little awareness among researchers of the legal rules that govern the use of these online resources. We analyzed the online Terms of Use (TOU) applicable to 17 popular genealogy websites and found that none of them expressly permit scientific research, while at least 13 contain restrictions that may limit or prohibit scientific research using data obtained from those sites. In order to ensure that researchers who use genealogy and other data from these sites for public health and other scientific research purposes do not inadvertently breach applicable TOUs, we recommend that genealogy website operators consider revising their TOUs to permit this activity., (© The Author(s) 2020. Published by Oxford University Press on behalf of Duke University School of Law, Harvard Law School, Oxford University Press, and Stanford Law School. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Delivering well-coordinated care is essential for optimizing clinical outcomes, enhancing patient care experiences, minimizing costs, and increasing provider satisfaction. The Veterans Health Administration (VA) has built a strong foundation for internally coordinating care. However, VA faces mounting internal care coordination challenges due to growth in the number of Veterans using VA care, high complexity in Veterans' care needs, the breadth and depth of VA services, and increasing use of virtual care. VA's Health Services Research and Development service with the Office of Research and Development held a conference assessing the state-of-the-art (SOTA) on care coordination. One workgroup within the SOTA focused on coordination between VA providers for high-need Veterans, including (1) Veterans with multiple chronic conditions; (2) Veterans with high-intensity, focused, specialty care needs; (3) Veterans experiencing care transitions; (4) Veterans with severe mental illness; (5) and Veterans with homelessness and/or substance use disorders. We report on this workgroup's recommendations for policy and organizational initiatives and identify questions for further research. Recommendations from a separate workgroup on coordinating VA and non-VA care are contained in a companion paper. Leaders from research, clinical services, and VA policy will need to partner closely as they develop, implement, assess, and spread effective practices if VA is to fully realize its potential for delivering highly coordinated care to every Veteran.

Purpose: The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy., Methods: After developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation., Results: Of 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing., Conclusion: Only half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.

Objective: To show the potential of a resource consisting of a genealogy of the US record linked to National Veterans Health Administration (VHA) patient data for investigation of the genetic contribution to health-related phenotypes, we present an analysis of familial clustering of VHA patients diagnosed with Alzheimer disease (AD)., Methods: Patients with AD were identified by the International Classification of Diseases code. The Genealogical Index of Familiality method was used to compare the average relatedness of VHA patients with AD with expected relatedness. Relative risks for AD were estimated in first- to fifth- degree relatives of patients with AD using population rates for AD., Results: Evidence for significant excess relatedness and significantly elevated risks for AD in relatives was observed; multiple pedigrees with a significant excess of VHA patients with AD were identified., Conclusions: This analysis of AD shows the nascent power of the US Veterans Genealogy Resource, in early stages, to provide evidence for familial clustering of multiple phenotypes, and shows the utility of this VHA genealogic resource for future genetic studies.

Guideline-concordant cancer care is a priority within the Department of Veterans Affairs (VA). In 2009, the VA expanded its capacity to treat breast cancer patients within VA medical centers (VAMCs). We sought to determine whether male and female Veterans diagnosed with breast cancer received BRCA testing as recommended by the National Comprehensive Cancer Network (NCCN) guidelines on Genetic/Familial High-Risk Assessment in Breast and Ovarian Cancer (v. 1.2010-1.2012). Using the 2011-2012 VA Central Cancer Registry and BRCA test orders from Myriad Genetics, we conducted a retrospective study. The outcome variable was a recommendation for genetic counseling or BRCA testing, determined by chart review. Independent variables expected to predict testing included region, site of care, and patient characteristics. We performed descriptive analysis of all patients and conducted multivariable logistic regression on patients who sought care at VAMCs that offered BRCA testing. Of the 462 Veterans who met NCCN testing criteria, 126 (27 %) received guideline-concordant care, either a referral for counseling or actual testing. No BRCA testing was recommended in 49 (50 %) VAMCs that provide cancer treatment. Surprisingly, patients with second primary breast cancer were less likely to be referred/tested (OR 0.39; CI 0.17, 0.89; p = 0.025). For patients under age 51, a yearly increase in age decreased likelihood of referral or testing (OR 0.85; CI 0.76, 0.94; p < 0.001). There were no differences in testing by race. In conclusion, there was significant underutilization and lack of access to BRCA testing for Veterans diagnosed with breast cancer. Our research suggests the need for clinical decision support tools to facilitate delivery of guideline-concordant cancer care and improve Veteran access to BRCA testing.

The Euphorbiaceae family (commonly known as "spurge") is a large, diverse, and widely distributed family of plants that encompass around 300 genera and more than 8000 species. Their attractiveness and hearty nature have made them popular for both indoor ornamentation and outdoor landscaping. Despite their ubiquity, the potential to cause irritant contact dermatitis (ICD) is often overlooked in favor of more notorious causes of phytodermatitis, namely, Toxicodendron species and nettles. We examined case reports spanning 40 years and discovered that spurge-induced ICD tends to befall children and middle-aged adults who unwittingly encounter the plant through play or horticulture, respectively. Clinical presentation is pleomorphic. Erythema, edema, burning, vesicles, and pruritus of acute onset and rapid resolution are frequently observed. We present a classic case of ICD in a 12-year-old girl after exposure to Euphorbia myrsinites and review the literature on phytodermatitis caused by members of the Euphorbiaceae family.

Malignant melanoma is a rare, often fatal form of skin cancer with a complex multigenic etiology. The incidence of melanoma is increasing at an alarming rate. A number of heritable factors contribute to a patient's overall melanoma risk, including response to ultraviolet light, nevus number, and pigmentation characteristics, such as eye and hair color. Approximately 5%-10% of melanoma cases are familial, yet the majority of familial cases lack identifiable germ-line mutations in known susceptibility genes. Additionally, most familial melanomas lack germ-line mutations in genes that are commonly mutated in sporadic melanoma. Candidate and systematic genome-wide association studies have led to an improved understanding of the risk factors for melanoma and the identification of susceptibility genes. In this review, we provide an overview of the major risk factors and known genes implicated in familial melanoma susceptibility., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The perception of being a burden or self-perceived burden (SPB) is associated with suicide ideation in chronic pain patients (CPPs). The objective of this study was to determine if SPB is associated with five types of suicidality (wish to die, active suicide ideation, presence of suicide plan, history of suicide attempts, and preference for death over being disabled) in CPPs and acute pain patients (APPs)., Methods: Affirmation of SPB was statistically compared between community nonpatients without pain (CNPWP), APPs, and CPPs. APPs and CPPs who had affirmed any of the five types of suicidality were compared statistically for affirmation of SPB. Hierarchical regression analysis was utilized to determine the significance of SPB in predicting each of the five types of suicidality in APPs and CPPs controlling for age, gender, race, education status, and two types of measures of depression (current depression and vegetative depression)., Results: APPs and CPPs were statistically more likely to affirm SPB than CNPWPs and CPPs were more likely than APPs to do so. There were no differences between APPs and CPPs in affirming SPB in APPs and CPPs who had affirmed any of the five types of suicidality. In CPPs, SPB predicted each type of suicidality in a significant fashion utilizing both types of depression measures. For APPs, SPB predicted each type of suicidality in a significant fashion except for history of suicide attempt controlling for vegetative depression., Conclusions: SPB is associated with the vast majority of different types of suicidality in APPs and CPPs., (© 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The belief in medical care entitlement has recently resulted in major changes in the medical system in the United States. The objectives of this study were the following: to compare endorsement of three medical entitlement beliefs (I deserve the best medical care no matter what the cost [BMC], I am entitled to all of the medical care I want at no charge [NC], I shouldn't have to wait to see my doctors [W]) in community nonpatients without pain (CNPWP), acute pain patients (APPs), and chronic pain patients (CPPs) and to develop predictor models for these beliefs in APPs and CPPs., Design: CNPWP, APPs, and CPPs were compared statistically for frequency of endorsement of each belief. All available variables were utilized in logistic regression models to predict each belief in APPs and CPPs. Those affirming/nonaffirming each belief were compared by t-test for affirmation of narcissism, dependency, and antisocial practices on three scales from established inventories., Results: CPPs were significantly more likely than APPs to endorse BMC. No other comparisons were significant. The logistic regression models identified variables that related to narcissism, anger, doctor dissatisfaction, depression, and anxiety, which entered the models for both APPs and CPPs for some beliefs. Those APPs and CPPs who affirmed the beliefs of NC and W were more likely than their counterparts to affirm antisocial practices, but not narcissism or dependency., Conclusions: Patient medical entitlement beliefs may be related to some psychiatric/psychological issues., (© 2014 World Institute of Pain.)

Background: Many chronic pain patients (CPPs) cannot be cured of their pain, but can learn to manage it. This has led to research on pain "acceptance" which is defined as a behavior pattern with awareness of pain but not directed at changing pain., Objective: CPPs who have accepted their pain generally acknowledge that a cure is unlikely. Time with pain may be necessary to reach such an acknowledgment. It was therefore hypothesized that fewer acute pain patients (APPs) than CPPs should affirm that a cure is unlikely and that other described aspects of acceptance such as denial of disability status should be associated with cure is unlikely in both APPs and CPPs., Study Design: APPs and CPPs were compared for frequency of endorsement of 2 items/questions with face validity for cure is unlikely: little hope of getting better from pain (LH) and physical problem (pain) can't be cured (CBC). Demographic variables and variables reported associated with acceptance were utilized in logistic prediction models for the above items in APPs and CPPs., Setting: Rehabilitation programs/offices., Results: CPPs were statistically more likely than APPs to affirm both LH and CBC. In both APPs and CPPs, items reported associated with acceptance, e.g., denial of disability status, predicted LH and CBC., Limitations: Information gathered from CPP self-reports., Conclusions: APPs versus CPPs differ on their affirmation on acknowledgement that a cure is unlikely.

Objectives: Somatic/psychiatric symptoms are frequently found in chronic pain patients (CPPs). The objectives of this study were to determine 1) which somatic/psychiatric symptoms are more commonly found in acute pain patients (APPs) and CPPs vs community nonpatients without pain (CNPWPs) and 2) if somatic/psychiatric symptom prevalence differs between APPs and CPPs., Design: The above groups were compared statistically for endorsement of 15 symptoms: fatigue, numbness/tingling, dizziness, difficulty opening/closing mouth, muscle weakness, difficulty staying asleep, depression, muscle tightness, nervousness, irritability, memory, falling, nausea, concentration, and headaches., Results: After controlling for age, gender, and level of pain, APPs and CPPs had a statistically significantly greater prevalence (at a P < 0.01 level) for 11 and 13 symptoms, respectively, vs CNPWPs. After controlling for age, gender, and level of pain, CPPs had a statistically significantly greater prevalence (at a P < 0.01 level) for eight symptoms vs APPs. Symptoms were highly correlated in both APPs and CPPs., Conclusions: CPPs are characterized to a significantly greater extent than comparison groups by somatic/psychiatric symptoms that are highly intercorrelated. This has implications for clinical practice and future research., (Wiley Periodicals, Inc.)

The ease with which whole genome sequence (WGS) information can be obtained is rapidly approaching the point where it can become useful for routine clinical care. However, significant barriers will inhibit widespread adoption unless clinicians are able to effectively integrate this information into patient care and decision-making. Electronic health records (EHR) and clinical decision support (CDS) systems may play a critical role in this integration. A previously published technical desiderata focused primarily on the integration of genomic data into the EHR. This manuscript extends the previous desiderata by specifically addressing needs related to the integration of genomic information with CDS. The objective of this study is to develop and validate a guiding set of technical desiderata for supporting the clinical use of WGS through CDS. A panel of domain experts in genomics and CDS developed a proposed set of seven additional requirements. These desiderata were reviewed by 63 experts in genomics and CDS through an online survey and refined based on the experts' comments. These additional desiderata provide important guiding principles for the technical development of CDS capabilities for the clinical use of WGS information., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To further explore the controversy as to whether childhood molestation is associated with chronic pain in adulthood., Design: Community nonpatients without pain (CNPWP), community patients with pain (CPWP), acute pain patients (APPs), and chronic pain patients (CPPs) were compared for endorsement of affirmation of childhood molestation by chi-square. Logistic regression was utilized to predict affirmation in male and female CPPs., Results: A significantly higher percentage of male APPs affirmed molestation versus CNPWP and CPWP. No other comparisons were statistically significant for males. For females, no comparisons were significant. For male CPPs, the behavior health inventory-2 (BHI-2) survivor of violence scale and 1 item from this scale predicted affirmation. The following BHI-2 scales and items predicted affirmation for female CPPs: muscular bracing and survivor of violence scales; the item "I have been a victim of many sexual attacks"; and the item "My father was kind and loving to me when I was growing up" (scored opposite direction)., Conclusions: In female PWCP, the prevalence of childhood molestation is not greater than in a number of unique comparison groups. Unique predictors of childhood molestation are yet to be identified., (© 2013 World Institute of Pain.)

Background: Symptom clusters have not been previously explored in acute pain patients (APPs) and chronic pain patients (CPPs) with non-cancer pain., Objectives: The objectives of this study were to determine in CPPs and APPs which somatic and non-somatic symptoms cluster with each other, the number of clusters, and if cluster number and cluster symptom makeup differ by pain level., Study Design: Study sample was 326 APPs and 341 CPPs who had completed a pool of questions that had included current symptom questions other than pain. Symptom cluster analyses were performed on 15 somatic and non-somatic symptoms for APPs and CPPs and for 2 CPP subgroups with moderate and severe pain., Setting:   APPs and CPPs were from rehabilitation facilities located in 30 states in all geographical regions of the United States., Results: APPs had 4 symptom clusters and CPPs had 5. For CPPs, the clusters represented memory, neurological, behavioral, somatic, and autonomic problems. CPPs with moderate and severe pain had 3 and 4 symptom clusters, respectively, and differed in cluster symptom constitution., Limitations: Patients selected themselves for study inclusion and were paid for their participation. This could have affected random selection. Lastly, we used the current time definitions of acute pain versus chronic pain (90 days) to separate our patients into these groups. Currently, no consensus exists regarding the optimal time duration to divide acute from chronic., Conclusions: APPs and CPPs are characterized by symptom comorbidities that form clusters. In CPPs, cluster number and cluster symptom makeup are affected by pain level. This has implications for clinical practice and future research.

Purpose: Creation of a genealogy of the United States and its ancestral populations is under way. When complete, this US genealogy will be record linked to the National Veteran's Health Administration medical data representing more than 8 million US veterans., Methods: Genealogical data are gathered from public sources, primarily the Internet. Record linking using data from relatives is accomplished to integrate multiple data sources and then to link genealogical data to the veteran's demographic data., Results: This resource currently includes genealogy for more than 22 million individuals representing the Intermountain West and the East Coast. The demographic data for more than 40,000 veteran patients using Veterans Hospital Administration services in Utah and Massachusetts have already been record linked., Conclusion: The resource is only in its second year of creation and already represents the largest such combination of genealogy and medical data in the world. The data sources, the creation of the genealogy, record-linking methods and results, proposed genetic analyses, and future directions are discussed.

OBJECTIVES.: The objectives of this study were to (1) compare the prevalence of smoking within chronic pain patients (CPPs) to community non-patients without pain (CNPWP), community patients with pain (CPWP), and acute pain patients (APPs); and (2) compare smokers to nonsmokers within CPPs, APPs, and CPWP for highest pain level. DESIGN.: CNPWP, CPWP, APPs, and CPPs were compared to each other for smoking status (nonsmoker, less than one pack per day, one pack/day or more, any amount per day). Within CPWP, APPs, and CPPs, smokers were also compared to nonsmokers by t-test for highest reported pain level. For both analyses, sub-analyses were performed controlling for age or gender, or race or education. RESULTS.: Utilizing all available patients, the prevalence of smokers within CPPs was significantly greater vs each of the comparison groups (CNPWP, CPWP, APPs). In the sub-analyses, only CPPs who were 38 or younger or male or White, or had some college or above were at greater risk than CPWP for smoking one pack or greater per day. CPP smokers were not significantly more likely than nonsmokers to have higher pain, and this was confirmed in the sub-analyses. CONCLUSIONS.: The prevalence of smokers could be significantly greater within CPPs vs CPWP. CPPs who smoke do not have higher levels of pain than nonsmoking CPPs., (Wiley Periodicals, Inc.)

To characterize protein phosphorylation in developing seed, a large-scale, mass spectrometry-based phosphoproteomic study was performed on whole seeds at five sequential stages of development in soybean (Glycine max), rapeseed (Brassica napus), and Arabidopsis (Arabidopsis thaliana). Phosphopeptides were enriched from 0.5 mg of total peptides using a combined strategy of immobilized metal affinity and metal oxide affinity chromatography. Enriched phosphopeptides were analyzed by Orbitrap tandem mass spectrometry and mass spectra mined against cognate genome or cDNA databases in both forward and randomized orientations, the latter to calculate false discovery rate. We identified a total of 2,001 phosphopeptides containing 1,026 unambiguous phosphorylation sites from 956 proteins, with an average false discovery rate of 0.78% for the entire study. The entire data set was uploaded into the Plant Protein Phosphorylation Database (www.p3db.org), including all meta-data and annotated spectra. The Plant Protein Phosphorylation Database is a portal for all plant phosphorylation data and allows for homology-based querying of experimentally determined phosphosites. Comparisons with other large-scale phosphoproteomic studies determined that 652 of the phosphoproteins are novel to this study. The unique proteins fall into several Gene Ontology categories, some of which are overrepresented in our study as well as other large-scale phosphoproteomic studies, including metabolic process and RNA binding; other categories are only overrepresented in our study, like embryonic development. This investigation shows the importance of analyzing multiple plants and plant organs to comprehensively map the complete plant phosphoproteome.

Hypothesis: Passive, active, and historical suicidality are associated with preference for death over disability., Design: Community nonpatients without pain, community patients with pain, and patients with acute and chronic pain were compared for endorsement of disability perception and preference for death over disability. Phi correlations and chi-square analyses were calculated between preference for death over disability and six suicidality items representing passive, active, and historical suicidality. Logistic regression was used to predict preference for death over disability in patients with acute and chronic pain., Results: For patients with acute and chronic pain, endorsement of preference for death over disability correlated significantly with all six suicidality items. The logistic regression models identified the following variables as predictors for preference for death over disability in patients with acute pain: the Behavior Health Inventory (BHI 2) family dysfunction scale, history of wanting to die, and disability perception. For patients with chronic pain, predictors were the BHI 2 Borderline scale, history of wanting to die, treated fairly by family item, frequent suicide ideation, people I trust turn on me item, and disability perception. Preference for death over disability was a statistically significant predictor in patients with chronic pain for disability perception, recent suicide ideation, having a suicidal plan, and a history of wanting to die but was not a significant predictor for any suicide items in patients with acute pain., Conclusion: Preference for death over disability is associated with passive and active suicide ideation and historical suicidality in patients with chronic pain., (Wiley Periodicals, Inc.)

Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships.

Objectives: (1) Determine and compare prevalence of forms of anger (FOA; anger, hostility, aggression, anger-in, anger-out, chronic anger) in community nonpatients (n=478), community patients (n=158), acute pain patients (APPs; n=326), chronic pain patients (CPPs; n=341); and (2) develop FOA predictor models in APPs and CPPs., Design: A large set of items containing the FOA items was administered to the above groups, who were compared statistically for FOA endorsement. APPs and CPPs affirming the anger and chronic anger items were compared with those not affirming on all available variables including the Battery for Health Improvement (BHI-2) with significant variables (P≤0.001) utilized in predictor models for anger and chronic anger in APPs and CPPs. Setting community plus rehabilitation facilities., Results: FOA affirmation ranged from 8.28% for chronic anger in nonpatients to 37.54% for anger in CPPs. Only CPPs were more likely to affirm anger (P≤0.04) and chronic anger (P≤0.01) at a significantly higher rate than community patients. In both APPs and CPPs, all FOA items except anger management-in were significantly correlated with other FOA items. For anger and chronic anger for CPPs and APPs, hostility was the strongest predictor. All models predicted anger and chronic anger significantly better than the base rate prediction., Conclusion: According to the results of this study anger and chronic anger are more frequently found in CPPs vs. community patients supporting the clinical perception that many CPPs are angry. As such,clinicians should actively screen CPPs for the presence of anger in order to engage these CPPs in anger management treatment., (© 2010 World Institute of Pain.)

Dermatitis herpetiformis (DH) is characterized by deposition of IgA in the papillary dermis. However, indirect immunofluorescence is routinely negative, raising the question of the mechanism of formation of these immune deposits. Sárdy et al. (2002. J. Exp. Med. 195: 747-757) reported that transglutaminase-3 (TG3) colocalizes with the IgA. We sought to create such deposits using passive transfer of Ab to SCID mice bearing human skin grafts. IgG fraction of goat anti-TG3 or control IgG were administered i.p. to 20 mice. Separately, sera from seven DH patients and seven controls were injected intradermally. Biopsies were removed and processed for routine histology as well as direct immunofluorescence. All mice that received goat anti-TG3 produced papillary dermal immune deposits, and these deposits reacted with both rabbit anti-TG3 and DH patient sera. Three DH sera high in IgA anti-TG3 also produced deposits of granular IgA and TG3. We hypothesize that the IgA class anti-TG3 Abs are directly responsible for the immune deposits and that the TG3 is from human epidermis, as this is its only source in our model. These deposits seem to form over weeks in a process similar to an Ouchterlony immunodiffusion precipitate. This process of deposition explains the negative indirect immunofluorescence results with DH serum.

Objectives: 1) Determine and compare prevalence for homicide-suicide (H-S) affirmation in community non-patients (N=478), community patients (N=158), acute pain patients (APPs; N=326), and chronic pain patients (CPPs; N=341); and 2) Develop H-S predictor models in APPs and CPPs., Design: A large set of items containing the H-S item was administered to the above groups, who were compared statistically for H-S endorsement. APPs and CPPs affirming the H-S item were compared with those not affirming on all available variables including the Battery for Health Improvement (BHI 2) with significant variables (P≤ 0.001) utilized in predictor models for H-S in APPs and CPPs., Setting: Community plus rehabilitation facilities., Results: The above population groups affirmed the H-S item according to the following percentages: healthy community 1.88%, community patients 3.16%, rehabilitation patients without pain 3.64%, rehabilitation AAPs 3.99%, and rehabilitation CPPs 4.40%. For both APPs and CPPs, the H-S item was significantly correlated with some suicidality items and some homicide items. The model for APPs identified "having a suicide plan" as being predictive of H-S affirmation. For CPPs, the items of having thoughts of revenge killing, being motivated to seek revenge without any verbal warning, and the Doctor Dissatisfaction Scale of the BHI 2 predicted H-S affirmation. The APPs model classified 96% of the APPs correctly, while the CPPs model classified 97% of the CPPs correctly. These predictor rates, however, were no better than the base rate., Conclusion: The prevalence of H-S affirmation within APPs and CPPs is not insignificant. The APPs predictor model points to a close association between H-S affirmation and suicidality. The CPPs model indicates that there is a close association between H-S affirmation, and anger/hostility and anger directed at physicians. These results, however, should not lead to the belief that CPPs are at greater risk for actual H-S completion for the following reasons: 1) H-S is an extremely rare event; and 2) predictive validity of the H-S item for actual H-S completion has not been determined., (Wiley Periodicals, Inc.)

In the United States, suicide rates consistently vary among geographic regions; the western states have significantly higher suicide rates than the eastern states. The reason for this variation is unknown but may be due to regional elevation differences. States' suicide rates (1990-1994), when adjusted for potentially confounding demographic variables, are positively correlated with their peak and capital elevations. These findings indicate that decreased oxygen saturation at high altitude may exacerbate the bioenergetic dysfunction associated with affective illnesses. Should such a link exist, therapies traditionally used to treat the metabolic disturbances associated with altitude sickness may have a role in treating those at risk for suicide.

To date, human skin phototype (SPT) has been determined subjectively by self- or trained investigator assessment using sun burning and/or sun tanning responses, ethnicity, hair, and eye color. This study evaluated objective reflectance spectrophotometer (RS) assessment of SPT in 353 males or females (18-72 years old with Fitzpatrick SPT I-VI) using the area-under-the-intensity curve (AUIC) over the 450-615 nm wavelength interval of reflected light (AUIC). Photoprotected constitutive skin color sites produced higher AUIC values than photo-exposed facultative skin color sites. Constitutive skin color at the upper volar arm was equal to the buttocks. Within-site and between-site AUIC reproducibility of constitutive skin color at the upper volar arm was 3 and 5% coefficient of variation (CV), respectively, which was similar to seasonal variability (8% CV). AUIC values decreased proportionately at both constitutive and facultative sites as a function of increasing SPT from I to VI (r=0.8). RS-measured constitutive skin color at the upper volar arm fit a quadratic equation (r(2)=0.94) that differentiated (P<0.05) between each of the six SPTs and agreed +/-1 SPT category with clinician-assessed SPT. Thus, RS assessment of constitutive skin color at the upper volar arm provides a quick, noninvasive, precise, and accurate method to objectively determine SPT.

Background: Dermatitis herpetiformis (DH) is a papulovesicular eruption caused by ingestion of gluten. It is characterized by the deposition of IgA in the dermal papillae. IgA antibodies directed at tissue transglutaminase (TG2) are elevated in gluten-sensitive diseases including DH and coeliac disease (CD). More recently, antibodies directed at epidermal transglutaminase (TG3) were identified in patients with DH, and this may be the dominant autoantigen in this disease., Objectives: To measure IgA antibodies to TG3 and TG2 in patients with DH and CD, and control populations., Methods: Serum IgA antibodies against TG2 and TG3 were measured from adults with DH, adults and children with CD, patients with psoriasis, adult Red Cross blood donors, and paediatric controls., Results: Patients with DH and CD had elevated levels of IgA anti-TG2 antibodies compared with control populations. The levels in the patients with DH and adults with CD were similar. IgA anti-TG2 antibodies were higher in the children with CD compared with adults with DH and CD, and with control populations. Patients with DH and adults with CD had elevated levels of IgA anti-TG3 antibodies compared with children with CD and control populations. There was a trend towards higher levels in the patients with DH compared with adults with CD., Conclusions: IgA antibodies to TG3 are elevated in patients with DH and adults with CD. The progressive expansion of the epitope-binding profile of IgA antitransglutaminase antibodies in patients with CD may explain the development of DH in patients with undiagnosed CD during their adult life.

Aim: The objective of this study was to compare hemoglobin A1c values in non-diabetic obese children and adolescents before enrollment and after completion of a 12-wk weight management program., Methods: Seventeen children and adolescents, age 10.8+/-2.5 y (mean+/-1 SD), joined a multidisciplinary weight management program. Hemoglobin A1c and body mass index were measured at the start and at the completion of the program in each participant., Results: Body mass index at the start of the program was 34.3+/-6.4 kg/m2. Body mass index at the end of the program was 33+/-6.6 kg/m2 (p<0.05). Hemoglobin A1c at the beginning of the program was 5.3+/-0.3%. Hemoglobin A1c at the completion of the program was 5+/-0.2% (p<0.05)., Conclusion: In this group of overweight children, hemoglobin A1c decreased significantly after participating in a multi-disciplinary weight loss program. These findings further point to the beneficial effect of lifestyle changes on the metabolic status of obese children.

Phenotypic characteristics of members of a melanoma prone kindred with a V126D CDKN2A gene mutation were monitored over approximately 15 y. Thirty-eight previously studied subjects were recruited. Participants underwent a complete skin examination by the same dermatologist who examined them initially. The size and location of all nevi were recorded on a body map diagram. Total nevus number (TNN) and total nevus density (TND) were determined. CDKN2A sequencing verified 13 mutation carriers and 16 non-carriers. Nine participants were spouse controls without a history of melanoma and did not carry a CDKN2A mutation. Mutation carriers demonstrated a greater mean TNN and TND at initial and follow-up examinations compared with non-carriers and continued to develop nevi rather than show nevus regression seen in non-carriers and spouse controls. Non-carriers showed an intermediate nevus phenotype between mutation carriers and spouse controls. Four of the 13 mutation carriers and one non-carrier have developed invasive melanoma. Over a 15-y interval, TNN and TND were increased in mutation carriers compared with non-carriers and spouse controls. Continued accumulation of nevi in mutation carriers supports a nevogenic role for this CDKN2A mutation. An intermediate nevus phenotype in non-carrier family members suggests the presence of additional modifier genes.

IgA is present in the skin in several dermatoses, including dermatitis herpetiformis, linear IgA bullous dermatosis, and Henoch-Schoenlein purpura. The neutrophilic infiltration in the area of the IgA deposition suggests that IgA is responsible for the associated inflammatory events. The mechanism for this process is unproven, but is likely to involve IgA-mediated neutrophil chemotaxis with inhibition of chemotaxis by dapsone. Elucidation of the mechanism of IgA-mediated inflammation will require an animal model. We have established a model for linear IgA bullous dermatosis as a prototype disease to be studied. IgA mouse monoclonal antibodies against a linear IgA bullous dermatosis antigen have been passively transferred to SCID mice with human skin grafts. This has produced neutrophil infiltration and basement membrane vesiculation in 4 of 12 mice tested. We conclude that an animal model for the pathogenesis of IgA dermatoses with IgA deposition and inflammation can be produced by passive transfer of mouse IgA antibodies against a linear IgA antigen.

Nevoid basal cell carcinoma (NBCC) syndrome is an autosomal dominant disorder characterized by distinctive congenital malformations and a variety of benign and malignant neoplasms, including ovarian fibromas. We describe pathologic and cytogenetic findings in a large unilateral ovarian fibroma from a 12-year-old female with NBCC syndrome. The pathologic findings were characteristic for ovarian fibroma, but were unusual for the ovarian fibromas associated with NBCC syndrome because of the absence of calcification, the lack of bilaterality, and the presence of focal hypercellularity. The karyotype of tumor tissue showed complex numerical and structural abnormalities. Although there is frequent loss of heterozygosity of 9q22.3 and mutations in the PTCHgene in Gorlin syndrome, the ovarian fibroma in this case did not have cytogenetically detectable abnormalities of chromosome 9., (Copyright 2002 Wiley-Liss, Inc.)

To establish an in vitro model of drug incorporation into hair and to elucidate the potential roles of hair cell selectivity and hair color in the incorporation of certain drugs into hair, the basic drug amphetamine and its nonbasic analog N-acetylamphetamine (N-AcAp) were analyzed for influx and efflux into and out of keratinocytes, pigmented melanocytes (PM), and nonpigmented melanocytes (NPM) as a model for incorporation and efflux of these drugs from hair cells. NPM were of the same melan-a cell line as PM, but cultured in the presence of the tyrosinase inhibitor phenylthiocarbamide. Results show that PM take up large amounts of the basic drug amphetamine (levels of uptake dependent on melanin content), whereas keratinocytes and NPM take up only small amounts of amphetamine. None of the cells take up N-AcAp above background levels. Interestingly, whereas keratinocytes and NPM quickly efflux most of the influxed drug, PM are slow to efflux and only efflux approximately 65% of influxed drug, if efflux media is not refreshed. (If efflux media is periodically refreshed, PM will eventually redistribute essentially all influxed drug back into the media.) These results demonstrate that pigmented cells take up greater amounts of the basic drug amphetamine, and efflux it more slowly than nonpigmented cells. Also, these results are consistent with previous data for in vivo incorporation of amphetamine in animal hair. In combination with previous data, an overall comparison of the amphetamine and N-AcAp incorporation data support a non-diffusion mediated model for drug incorporation into hair cells., (Copyright 2002 Wiley-Liss, Inc.)