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Abstract. Background: Data are scarce on assessing the impact of the COVID-19 pandemic on young people. Aim: To examine changes in crisis text patterns in the United States during the pandemic compared to the prepandemic period. Method: Nonintrusive data from a national digital crisis texting platform were analyzed using an interrupted time series design. Poisson regression with repeated-measures examined help-seeking patterns for stress, anxiety, depression, suicidal thoughts, and other mental health concerns in the pandemic (March 13 to July 20, 2020) compared to the prepandemic period (March 13 to July 20, 2019). Results: An abrupt increase in national crisis response texts occurred during the pandemic for stress and anxiety, substance abuse, bereavement, isolation, and abuse compared to the prepandemic period. Similar trends of excess texts for isolation and abuse were reported among children (relative risk [RR]abuse: 1.16, CI: 1.03, 1.31; RRisolation: 1.15, CI: 1.09, 1.21) and adolescents (RRabuse: 1.17, CI: 1.11, 1.24; RRisolation: 1.08, CI: 1.05, 1.11), bereavement among Black (RR: 1.31, CI: 1.12, 1.54) and Hispanic (RR: 1.28, CI: 1.10, 1.49) texters, and isolation and bereavement in female (RRisolation: 1.09, CI: 1.06, 1.11; RRbereavement: 1.21, CI: 1.13, 1.28) or nonconforming youth (RRisolation: 1.19, CI: 1.08, 1.32; RRbereavement: 1.50, CI: 1.08, 2.09) texters. Conversely, the risks of reporting bullying, depression, relationship issues, and suicidal thoughts as reasons for texting were significantly lower during COVID-19. Limitations: Results may underestimate crisis support-seeking in some groups because demographic data were not captured on all texters. Conclusion: Findings illuminated the real-time crisis response of young people across the United States and can inform more responsive interventions to alleviate the mental health consequences brought on by the COVID-19 pandemic.

Running can improve physical health and psychological wellbeing. However, the characteristics of conducive running environments are relatively unknown. This study determines neighborhood factors that attract running and explores how age and gender mediate built environment preferences. Spatial patterns of runners in Metro Vancouver were identified using crowdsourced fitness data from Strava, a popular application for tracking physical activities. The influence of socio-economic status (SES), green and/or blue space, and urbanicity on route popularity was assessed using a Generalized Linear Model (GLM). The influence of these neighborhood variables was also calculated for runners by age and gender. The results show high neighborhood SES, the presence of green and/or blue space, and high population density are associated with increased running activities in all age and gender groups. This study contributes a novel approach to understanding conducive running environments by demonstrating the utility of crowdsourced data in combination with data about urban environments. The patterns of this large group of runners can be used to inform planning for cities that promote running, as well as seek to encourage equal participation among different ages and genders.

Severe Maternal Morbidity (SMM) is a group of pregnancy complications in which a woman nearly dies. Despite its increasing prevalence, little research has evaluated geographic patterns of SMM and the underlying social determinants that influence excess risk. This study examined the spatial clustering of SMM across South Carolina, US, and its associations with place-based social and environmental factors.Hospitalized deliveries from 2012 to 2017 were analyzed using Kulldorff's spatial scan statistic to locate areas with abnormally high rates of SMM. SMM patients inside and outside risk clusters were compared using Generalized Estimating Equations (GEE) to determine underlying individual and community-level risk factors.GEE models revealed that the odds of living in a high-risk SMM21 (SMM including blood transfusions) cluster was 2.49 times higher among Black patients (p .001) compared to those outside of a high-risk cluster. Women residing in a high-risk SMM20 (SMM excluding blood transfusions) cluster were 1.38 times more likely to experience the most number of extremely hot days and 1.70 times more likely to present with obesity than women in a low-risk SMM cluster (p .001).This study is the first to characterize the geographic clustering of SMM risk in the US. Our geospatial approach contributes a novel understanding to factors which influence SMM beyond patient-level characteristics and identifies the impact of hot ambient temperature on maternal morbidity. Findings address an important literature gap surrounding place-based risk factors by explaining the contextual social and built environmental factors that drive SMM risk.

ObjectivesSevere Maternal Morbidity (SMM) is a group of pregnancy complications in which a woman nearly dies. Despite its increasing prevalence, there is little research that evaluates geographic patterns of SMM and the underlying social determinants that influence excess risk. This study examines the spatial clustering of SMM across South Carolina, US, and its associations with place-based social and environmental factors.MethodsHospitalized deliveries from 1999 to 2017 were analyzed using Kulldorff’s spatial scan statistic to locate areas with abnormally high rates of SMM. Patients inside and outside risk clusters were compared using Generalized Estimating Equations (GEE) to determine underlying risk factors.ResultsFinal models revealed that the odds of living in a high-risk cluster were 84% higher among Black patients (OR=1.84, pConclusionsThis study is the first to characterize the geographic clustering of SMM risk in the US. Our geospatial approach contributes a novel understanding to factors which influence SMM beyond patient-level characteristics and identifies the impact of systemic racism on maternal morbidity. Findings address an important literature gap surrounding place-based risk factors by explaining the contextual social and built environment variables that drive SMM risk.SignificanceIt is not entirely clear why SMM is increasing in the US. Underlying health conditions, environmental, and social factors have been linked to higher SMM risk. This study is the first to assess these factors across space to determine the characteristics and locations where SMM likelihood is elevated.HighlightsFirst study to examine spatial patterning of severe maternal morbidity (SMM)SMM is geographically clustered and increasing in South Carolina, USAHighest risk for SMM in racially segregated low-income communitiesObesity and race were significant individual risk factorsHigh ambient temperatures corresponded with high SMM clustering

Purpose Few studies have examined grief and bereavement in the context of a pandemic, particularly among young people during the ongoing COVID-19 pandemic. Methods The objective of this study is to examine spatiotemporal clustering of bereavement using data from Crisis Text Line, an SMS-based intervention with widespread usage among youth and adolescents in the United States from January 2017 to September 2020. Results Results found significant spatial clustering of bereavement during the pandemic period in the late summer months compared with the onset of the pandemic. Conclusion Our study provides the first evidence of elevated bereavement in adolescents using a technique for rapidly identifying clusters of bereavement risk among this vulnerable subgroup. Findings can be leveraged for targeted interventions and supportive counseling in geographic hotspots.

Using EUV images and line-of-sight magnetograms from Solar Dynamics Observatory, we examine eight emerging bipolar magnetic regions (BMRs) in central-disk coronal holes for whether the emerging magnetic arch made any noticeable coronal jets directly, via reconnection with ambient open field as modeled by Yokoyama & Shibata. During emergence, each BMR produced no obvious EUV coronal jet of normal brightness, but each produced one or more faint EUV coronal jets that are discernible in AIA 193 Å images. The spires of these jets are much fainter and usually narrower than for typical EUV jets that have been observed to be produced by minifilament eruptions in quiet regions and coronal holes. For each of 26 faint jets from the eight emerging BMRs, we examine whether the faint spire was evidently made a la Yokoyama & Shibata. We find that (1) 16 of these faint spires evidently originate from sites of converging opposite-polarity magnetic flux and show base brightenings like those in minifilament-eruption-driven coronal jets, (2) the 10 other faint spires maybe were made by a burst of the external-magnetic-arcade-building reconnection of the emerging magnetic arch with the ambient open field, with reconnection directly driven by the arch's emergence, but (3) none were unambiguously made by such emergence-driven reconnection. Thus, for these eight emerging BMRs, the observations indicate that emergence-driven external reconnection of the emerging magnetic arch with ambient open field at most produces a jet spire that is much fainter than in previously reported, much more obvious coronal jets driven by minifilament eruptions.

Deaths from the COVID-19 pandemic have disproportionately affected older adults and residents in nursing homes. Although emerging research has identified place-based risk factors for the general population, little research has been conducted for nursing home populations. This GIS-based spatial modeling study aimed to determine the association between nursing home-level metrics and county-level, place-based variables with COVID-19 confirmed cases in nursing homes across the United States. A cross-sectional research design linked data from Centers for Medicare & Medicaid Services, American Community Survey, the 2010 Census, and COVID-19 cases among the general population and nursing homes. Spatial cluster analysis identified specific regions with statistically higher COVID-19 cases and deaths among residents. Multivariate analysis identified risk factors at the nursing home level including, total count of fines, total staffing levels, and LPN staffing levels. County-level or place-based factors like per-capita income, average household size, population density, and minority composition were significant predictors of COVID-19 cases in the nursing home. These results provide a framework for examining further COVID-19 cases in nursing homes and highlight the need to include other community-level variables when considering risk of COVID-19 transmission and outbreaks in nursing homes., Graphical abstract Unlabelled Image, Highlights • Nursing home COVID-19 cases are clustered in the Northeast and Southeast US. • Community-level factors had the strongest association with nursing home cases. • Nursing home quality did not predict COVID-19 cases.

The Coronavirus Disease 19 (COVID-19) has quickly spread across the United States (U.S.) since community transmission was first identified in January 2020. While a number of studies have examined individual-level risk factors for COVID-19, few studies have examined geographic hotspots and community drivers associated with spatial patterns in local transmission. The objective of the study is to understand the spatial determinants of the pandemic in counties across the U.S. by comparing socioeconomic variables to case and death data from January 22nd to June 30th 2020. A cluster analysis was performed to examine areas of high-risk, followed by a three-stage regression to examine contextual factors associated with elevated risk patterns for morbidity and mortality. The factors associated with community-level vulnerability included age, disability, language, race, occupation, and urban status. We recommend that cluster detection and spatial analysis be included in population-based surveillance strategies to better inform early case detection and prioritize healthcare resources., Graphical abstract Unlabelled Image, Highlights • Cluster analysis, three-stage regression used to assess COVID-19 determinants in U.S. • COVID-19 hotspots predominantly in New England and the Southeast and Southwest • Urban, Black population among significant predictors of COVID-19 cases and deaths • Predictors significant at county, state levels despite behavior, policy differences

STUDY QUESTION What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. LIMITATIONS, REASONS FOR CAUTION The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. WIDER IMPLICATIONS OF THE FINDINGS As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. STUDY FUNDING/COMPETING INTERESTS This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare.

Bread wheat (Triticum aestivum L.) produces glutenin storage proteins in the endosperm. The HMW glutenins confer distinct viscoelastic properties to bread dough. The genetics of HMW glutenin proteins have been extensively studied, and information has accumulated about individual subunits, chromosomal locations and DNA sequences, but little is known about the regulators of the HMW glutenins. This investigation addressed the question of glutenin regulators. Expression of the glutenins was analyzed using QRT-PCR in ditelosomic (dt) Chinese Spring (CS) lines. Primers were designed for each of 4 CS glutenin genes and a control, non-storage protein endosperm-specific gene Agp-L (ADP-glucose pyrophosphorylase). Each line represents CS wheat, lacking one chromosome arm. The effect of a missing arm could feasibly cause an increase, decrease or no change in expression. For each HMW glutenin, results indicated there were, on average, 8 chromosome arms with an up-regulatory effect and only one instance of a down-regulatory effect. There were significant correlations between orthologous and paralogous HMW glutenins for effects of chromosome groups B and D. Some or all the glutenin alleles shared regulatory loci on chromosome arms 2BS, 7BS, 4DS, 5DS and 6DS, and Agp-L shared regulatory loci with glutenins on arms 7AS, 7BS, 2DS, 3DS, 4DS and 5DS. These results suggest a few chromosome arms contain putative regulatory genes affecting the expression of conserved cis elements of 4 HMW glutenin and Agp-L genes in CS. Regulation by common genes implies the regulators have diverged little from the common wheat ancestor, and furthermore, some regulation may be shared by endosperm-specific-genes. Significant common regulators have practical implications.

Pelvic muscle pain syndromes are poorly understood and lack reliable diagnostic criteria. Furthermore, animal models suggest that somatic pain can influence the development of pelvic visceral pain dysfunction. To develop psychophysical measures to facilitate diagnosis of pelvic floor myofascial pain syndromes, this pilot was designed to preliminarily test the feasibility, reliability, and validity of pressure-pain thresholds (PPTs) to identify and quantify pelvic floor pain sensitivity.We conducted a cross-sectional study of pelvic floor PPTs using 19 healthy women. Using a prototype vaginal pressure algometer, we measured PPTs and calculated intraclass correlations for short-term and intermediate-term reliability. Validity was assessed by correlating numerical rating scores for pain (0 to 100) at standard pressure levels applied to the right iliococcygeus muscle.The mean PPT of all pelvic floor sites was 1.52 kg/cm (SD=0.62), whereas thresholds of nonmuscle vaginal sites (anterior and posterior wall) were 1.65 kg/cm (SD=0.64). Pain numerical rating scores were positively correlated with stimulus intensity at the right iliococcygeus (Pearson r=0.61). Intraclass correlation demonstrated good short-term reliability at this same site for the first versus second, and second versus third measurements (0.75, 0.64); 1-week repeat reliability was also good for the right pubococcygeus, iliococcygeus, and obturator (0.69, 0.84, and 0.61, respectively), and both nonmuscle vaginal sites.These data suggest that PPTs may prove to be valid and reliable measures of pelvic floor somatic pain sensitivity in healthy women. Broader studies including a pelvic pain cohort should be conducted to corroborate these results and determine the technique's external validity and clinical relevance.

Background Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. Methods Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta-analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV-based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio® 3D Digital PCR System. Results The meta-analysis identified 373 genome wide significant (p

The ubiquitin-proteasome system (UPS) is responsible for turnover of most cellular proteins in eukaryotes. Protein degradation by the UPS serves quality control and regulatory functions. Proteasome inhibition showed great promise in effectively treating cancer and restenosis. UPS dysfunction in cardiac hypertrophy and failure has recently been suspected but remains to be investigated. A system capable of monitoring dynamic changes in proteolytic function of the UPS in cardiac myocytes in situ would no doubt benefit significantly efforts to decipher the pathogenic significance of UPS dysfunction in the heart and to evaluate the effect of proteasome inhibition on cardiac myocytes. We successfully established such a system in cultured cardiac myocytes by delivering and expressing a modified green fluorescence protein (GFPu) gene using recombinant adenoviruses. GFPu contains a ubiquitination signal sequence fused to the COOH terminus. Fluorescence microscopy and Western blots revealed that protein abundance of modified green fluorescent protein (GFPu), but not wild-type green fluorescent protein, in cultured cardiac myocytes was incrementally increased when function of the proteasomes was inhibited in various degrees by specific inhibitors. The increase in GFPu protein levels and fluorescence intensity is paralleled by a decrease in the in vitro peptidase activity of the proteasomes. Our results demonstrate that GFPu can be used as a surrogate marker to monitor dynamic changes in proteolytic function of the UPS in cardiac myocytes in situ. Application of this novel system reveals that moderate levels of H2O2, a reactive oxygen species generator, impair proteolytic function of the UPS in cultured cardiac myocytes.

Reducing maladaptive cognitions is hypothesized to constitute an active therapeutic process in multidisciplinary pain programs featuring cognitive-behavioral interventions. A cross-lagged panel design was used to determine whether: a) early-treatment cognitive changes predicted late-treatment pain, interference, activity and mood changes, but not vice versa; b) three cognitive factors made unique contributions to outcome; c) substantial cognitive changes preceded substantial improvements in outcome. Sixty-five chronic pain patients, participating in a 4-week multidisciplinary program, completed measures of pain helplessness, catastrophizing, pain-related anxiety (process factors), pain severity, interference, activity level and depression (outcomes) at pre-, mid- and posttreatment. Results showed that early-treatment reductions in pain helplessness predicted late-treatment decreases in pain and interference, but not vice versa, and that early-treatment reductions in catastrophizing and pain-related anxiety predicted late-treatment improvements in pain severity, but not vice versa. Findings suggested that the three process factors predicted improvements mostly in common. However, little evidence was found that large early-treatment reductions in process variables preceded extensive improvements in pain. Findings replicate those of a recent report regarding cross-lagged effects, and offer support that cognitive changes may indeed influence late-treatment changes in outcomes.

Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal.We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum.We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum.These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.

Objective The aim of this study was to describe the characteristics of patients referred with complex regional pain syndrome (CRPS) diagnosis to a tertiary care pain center. Method Descriptive chart review study of all patients referred by family physicians or community specialists as having CRPS (2006–2010). Data extraction included demographics, pain ratings, and diagnosis utilizing the Budapest CRPS criteria. Results The study population consisted of 54 subjects (male [M] = 7, female [F] = 47). Only 27.7% were classified as CRPS by the clinical expert. Four additional subjects carrying other diagnoses but found to have CRPS were added to the analysis. The non-CRPS group consisted of 39 subjects (M = 8, F = 31) and the CRPS group of 19 (M = 2, F = 17). CRPS patients were statistically significantly more likely to 1) have suffered a fracture; 2) report symptoms in each of the four symptom categories, as well as signs in three or four categories collectively; and 3) have allodynia/hyperalgesia alone or in combination (85/90%) as compared with the non-CRPS group (23/25%, respectively). The non-CRPS group was much more likely to report no symptoms or signs at all in the different symptom and sign categories. Of the 39 non-CRPS patients, 74% had other diagnosable entities (1/3 suffering from specific neuropathic pain conditions, e.g., radiculopathy, diabetic neuropathy, etc. and 2/3 from discreet musculoskeletal entities), while 18% were diagnosed with psychogenic pain disorders including conversion reaction associated with immobility or paralysis. Discussion Besides fulfilling the Budapest CRPS diagnostic criteria, the most important other factor for diagnosing CRPS is the exclusion of a neuropathic, musculoskeletal, or non-biomedical condition accounting for the presentation.

Long-term opioid therapy for chronic benign pain remains controversial. Most studies on the effectiveness of such regimens have been case series or case comparisons and very few randomized placebo-controlled studies are available. Overall, this research has produced mixed results. The current study sought to further explore issues regarding the effectiveness of opioids for chronic pain and to examine the use of adjunctive medications in these patients. A random sample of 100 patients taking daily opioids (Opioid) and 100 taking no opioids (Non-opioid) at evaluation were selected from the patient population of a tertiary care multidisciplinary pain program. Statistical analyses revealed that the two groups did not differ regarding pain type, duration, location, or surgical history. Non-Caucasians were less likely to be taking opioids than Caucasians (p < 0.05). Relative to the Non-opioid group, Opioid patients were less frequently taking non-steroidal anti-inflammatories (p < 0.01) and were more often taking anxiolytics (p < 0.05) and muscle relaxants (p < 0.01). Opioid patients reported higher (p < 0.05) current pain and more frequently (p < 0.05) reported current or past clinical depression or anxiety. No other significant differences were noted on measures of pain, psychological status, or functioning. Statistical removal of the effects of pain differences did not alter the pattern of results for psychological and functional measures. Although the study design employed did not allow determination of causality, it is consistent with previous work which has failed to reveal any advantage to use of daily opioids in the chronic pain population with regard to analgesia, decreased adjunctive medication use, or functional recovery. Well-designed, prospective, randomized studies are needed, but the current results suggest continued caution in the use of daily opioids until such studies become available. © 1997 Elsevier Science Ireland Ltd.

The goal of this study was to assess clinical consensus regarding whether myofascial pain syndrome (MPS) is a legitimate and distinct diagnosis as well as the signs and symptoms characterizing MPS.A standardized mailed survey with return postage provided.A total of 1,663 American Pain Society members in medically related disciplines listed in the 1996/1997 directory.A standardized survey assessing clinical opinion regarding whether MPS is a legitimate diagnosis, whether MPS is a clinical entity distinct from fibromyalgia, and the signs and symptoms believed to be "essential to," "associated with," or "irrelevant to" to the diagnosis of MPS.Of the 403 surveys returned, 88.5% respondents reported that MPS was a legitimate diagnosis, with 81% describing MPS as distinct from fibromyalgia. The only signs and symptoms described as essential to the diagnosis of MPS by greater than 50% of the sample were regional location, presence of trigger points, and a normal neurologic examination. Regarding the signs and symptoms considered to be essential or associated with MPS, more than 80% of respondents agreed on regional location, trigger points, normal neurologic examination, reduced pain with local anesthetic or "spray and stretch," taut bands, tender points, palpable nodules, muscle ropiness, decreased range of motion, pain exacerbated by stress, and regional pain described as "dull," "achy," or "deep." Sensory or reflex abnormalities, scar tissue, and most test results were considered to be irrelevant to the diagnosis of MPS by a large proportion of the respondents.There was general agreement across specialties that MPS is a legitimate diagnosis distinct from fibromyalgia. There was a high level of agreement regarding the signs and symptoms essential or associated with a diagnosis of MPS. Differences across specialties are discussed. This survey provides a first step toward the development of consensus-based diagnostic criteria for MPS, which can then be validated empirically.

This article aims to help primary care physicians negotiate gaps in current guidelines for postherpetic neuralgia (PHN). The objectives of this article are to: 1) briefly review the available guidelines and identify their strengths and weaknesses; 2) review the gaps in the guidelines; 3) review new data that were not included in the most recent guidelines; 4) provide expert opinion on how the new data and current guidelines can be used to make treatment decisions; and 5) review several important dimensions of care (eg, tolerability, dosing) and provide guidance. In general, all guidelines recognize the α2δ ligands, tricyclic antidepressants (TCAs), opioids, and tramadol as efficacious systemic options, with topical lidocaine serving as an efficacious nonsystemic approach for localized PHN treatment. The first-line treatment options typically recommended in the guidelines are α2δ ligands and TCAs, while opioids and tramadol are often recommended as second- or third-line options. Since the latest guidelines were published, newer agents (eg, topical capsaicin [8%] patch and gastroretentive gabapentin) have met the standard as first-line therapy with the publication of ≥ 1 randomized controlled trial. However, gabapentin enacarbil has not met this standard due to a lack of a published randomized controlled trial in PHN.

The current article offers guidelines to systematically evaluate programs which treat chronic non-malignant pain syndrome patients. The guidelines represent a basic program evaluation strategy and include specific recommendations and choices on measurement-assessment tools based upon available research literature and common clinical practice. They are based on evaluation by objectives, which include the program's ability to reduce the misuse of medications, increase physical function, increase productive activity at home, work and socially, improve overall mood, reduce subjective pain intensity, reduce the use of healthcare, when applicable, achieve equitable case settlement, and minimize pain treatment program cost without compromising quality of care. The method and timing of assessing each of these objectives are delineated with an emphasis on using reliable, valid measures which can be applied effectively within a clinical setting. The guidelines also advocate patient and staff satisfaction assessment, thus offering a fully integrated program evaluation system which can measure effectiveness and allow ongoing improvement in care.

In a prospective, double-blind, randomized study, ketorolac 60 mg, meperidine 50 mg plus promethazine 25 mg, and normal saline given by intramuscular injection were compared as treatment for acute headache crises. Thirty patients (6 men and 24 women) presenting to an urban emergency department with any type of benign headache were randomized into three groups and filled out the McGill Short-Form Pain Questionnaire with a Pain Rating Index and a Visual Analogue Pain scale. They received one of the study medications and repeated the testing after 1 hour. The objective was to test the efficacy of ketorolac in this population. Separate analyses of the McGill Short-Form (Total, Sensory, Affective, and Pain Rating Index scales) and the Visual Analogue Pain scale responses showed that the three treatments produced a significant reduction in pain (P < .0001), but that pain reduction did not differ among the treatments. This profound reduction observed after administration of a placebo prevented accurate evaluation of the effects of ketorolac. The placebo response must be considered in the design of future trials using intramuscular medications in the acute intervention of headache crises. In addition, the use of a standard analgesic is necessary to demonstrate both assay sensitivity and magnitude of response to placebo.

To evaluate the toxic effects of prolonged exposure to chloroform vapors, female and male F344 rats were exposed to 0, 2, 10, 30, 90 and 300 p.p.m. chloroform by inhalation for 7 or 5 days/week for up to 13 weeks. The purpose of this study was to characterize a lesion that occurred in the livers of rats in the 300 p.p.m. exposure groups. Atypical glandular structures lined by intestinal-like epithelium and surrounded by dense connective tissue occurred in the livers of rats exposed to strongly hepatotoxic atmospheric concentrations of chloroform. Bile duct bromodeoxyuridine labeling indices as well as observations of the locations of the early lesions at the 3 and 6 week time points indicate that these lesions arose from a population of cells remote from the bile ducts. We refer to these lesions as intestinal crypt-like ducts with periductular fibrosis to distinguish them from true cholangiofibrosis. Here, intestinal crypt-like ducts with periductular fibrosis were seen only in rats exposed to 300 p.p.m. chloroform, and the multiplicity and severity of the lesions were greater in the right liver lobe. The lesion only occurred in association with liver necrosis and dramatic increases in hepatocyte labeling indices, while labeling indices in bile ducts in the same animals were not significantly different from controls. There was a treatment-related increase of transforming growth factor-alpha immunoreactivity in hepatocytes, bile duct epithelium, bile canaliculi and oval cells, and an increase in transforming growth factor-beta immunoreactivity in hepatocytes, bile duct epithelium and intestinal crypt-like ducts. Thus, intestinal crypt-like ducts with periductular fibrosis appeared to develop from a population of cells unrelated to bile ducts. Also, they occurred only in animals exposed to chloroform concentrations that induced significant hepatocyte necrosis and regenerative cell proliferation and were associated with increased growth factor expression or uptake.

Objective: To test the hypothesis that there is relative sympathetic hyperactivity in the affected limb in patients with sympathetically maintained pain syndromes by measuring serum norepinephrine and epinephrine in the affected versus the unaffected sides. Design: Venous pool samples were drawn just proximal to the affected area and from an identical site on the unaffected side. Serum norepinephrine and epinephrine were measured by high-pressure liquid chromatography with electrochemical detection. Subjects: Sixteen women and seven men with a mean age of 44.4 years diagnosed as having sympathetically maintained pain on the basis of a positive response to paravertebral block and a criteria-based diagnostic scheme. Results: The serum norepinephrine level was significantly lower in the affected limbs than the unaffected limbs (p = 0.024). The serum epinephrine level was not significantly different. Conclusions: These results are not consistent with the hypothesis of segmental sympathetic hyperactivity in the affected limb in sympathetically maintained pain and support a hypothesis of peripheral receptor upregulation with pathologic response to circulating catecholamines. Other possible explanations are discussed.

This study was performed to determine the incidence of surgical site infections (SSIs) after colorectal resection in patients without mechanical or antibiotic bowel preparation. A retrospective review of the medical records of 136 consecutive patients undergoing an elective colorectal resection between April 2004 and April 2006 was performed. Indications for colon resection in this series were malignant neoplasia (48%), inflammatory bowel disease (18%), diverticular disease (17%), or other benign disease (17%). Overall, an SSI occurred in 31 patients (23%). An SSI occurred in 16 of 90 patients (17.8%) who received antibiotics within 1 hour before surgery and in 15 of 46 patients (33.3%) who did not receive antibiotics in a timely manner (P0.05). An SSI occurred in seven of 15 patients (46.7%) who received bowel preparation but in only 24 of 121 patients (19.8%) who did not receive either mechanical or antibiotic bowel preparation (P0.029). SSIs were not associated with age, gender, diagnosis, length of procedure, preoperative steroid use, diabetes mellitus, or previous celiotomy. This series shows administration of perioperative antibiotics within 1 hour before surgery is associated with a significant decrease in the incidence of SSI and bowel preparation can be safely omitted.

An acylglycerol (AG) containing four acyl chains, (12-ricinoleoylricinoleoyl)diricinoleoylglycerol (RRRR), was positively identified for the first time in a natural source in castor oil using electrospray ionization tandem mass spectrometry (ESI-MS/MS). HPLC-purified RRRR from castor oil was subjected to ion trap and high-resolution ESI-MS/MS. The precursor and fragment ions of [RRRR + Na]+ showed the expected masses, and the sodiated fragment ions of both diacylglycerols and fatty acids were detected. Because fragment ions of fatty acids from [AG + NH4]+ adducts cannot be detected by ESI-MS/MS, [AG + Na]+ adducts are more informative. Radiolabeled triricinolein (RRR) was incorporated into RRRR in castor microsomes, indicating that RRRR is biosynthesized in castor bean. This newly identified and biosynthesized RRRR represents a new AG subclass of tetra-acylglycerols (or acylacyldiacylglycerol). Keywords: Castor oil; ricinoleate; acylglycerol; tetra-acylglycerol; acylacyldiacylglycerol; biosynthesis; HPLC;...

A study of the distribution and geometry of incised meanders in 64 reaches encompassed approximately 600 km of the Green, Colorado, and San Juan Rivers in the central Colorado Plateau. The sinuosity, average planform size, and average cross-sectional symmetry of each reach were determined by map measurements and by spectral analysis of the curvature series for each reach, as determined from interpolations of the digitized traces of the channels. Possible controlling variables examined, including average channel gradient, drainage area, average bedrock erodibility, and bedrock structure, were compiled for each reach, using available maps. Gradients in the studied reaches are significantly correlated with bedrock type. Sinuous incised channels are generally found in low-gradient reaches. In the San Juan River, the channel is sinuous where it flows against the bedrock dip and generally straight in reaches where flow is downdip. This correlation is weak in the Green and Colorado Rivers. The average meander size of the sinuous reaches, as described by the median curvature value for each reach, is generally less in steeper reaches than in low-gradient reaches, although the relation of bend size to controlling variables is much less clear than for sinuosity or cross-section shape. Most meander cross sections in the area are relatively symmetrical, but highly ingrown forms are also present. In general, symmetric bends are associated with resistant bedrock units, whereas ingrown forms develop in massive sandstone and in highly erodible bedrock. Gradient significantly influences the distribution of ingrown bends, with asymmetric meanders concentrated in reaches of low average gradient; this correlation is stronger than that between cross-section shape and lithology itself. Incised meanders of the central Colorado Plateau are probably at least partly inherited from ancestral streams of unknown age that flowed across the area before the present canyons were cut. Correlation between meander distribution and regional structures suggests that the general location of low-gradient sinuous reaches has probably not changed during the incision of the present canyons. Incised meanders, however, are clearly able to modify their geometry in response to changes in bedrock resistance, as indicated by the strong correlation between bedrock type and cross-section symmetry. One mechanism of modification is abandonment of bends, which is documented by 18 cutoff meanders in the study area.

The clinical approach to complex regional pain syndrome (CRPS) is complicated by a lack of precision diagnostically, and a lack of evidence-based information for treatment. The vagaries of diagnosis were somewhat improved by the Orlando Conference (1993), where a consensus panel of experts developed a new taxonomy and criteria. Unfortunately the criteria can be based entirely on subjective grounds (patient history), and as such provides a very sensitive but not very specific device. There is some effort in the research community to amend these criteria to make them more specific. We encourage the practicing physician to include as much objective data along with the quasi-objective and subjective information currently used in formulating the diagnosis. This imprecision in diagnostic issues has significantly hampered treatment because it has not led to solid, generalizable, randomized controlled trials. To date there are no substantial scientific trials of any particular therapy or medication in the specific diagnosis of CRPS. Much can be inferred from the work with peripheral neuropathy and central pain. However, it is unlikely that this will be a perfect concordance with best therapy for CRPS. It remains our responsibility to diagnose each patient as best we can, supported by the best possible objective signs and testing. Once the diagnosis is made it is necessary to proceed in a pragmatic empirical way, following the best guidelines available. The guidelines should be considered a "rough sketch" and the key to clinical success will be flexibility, a vast fund of the available knowledge, patience, and compassion. To allow the deficiencies in the science to paralyze the clinical process is therapeutic nihilism, and not acceptable.

We investigated phylogenetic and biogeographic relationships within Juglans (walnuts), a Tertiary disjunct genus, using 15 species of Juglans and related (Juglandaceae) outgroups. The relationships were analyzed using nucleotide sequences of the chloroplast gene matK and its flanking spacers and of the internal transcribed spacers (ITS) and 5.8S gene of the nuclear ribosomal DNA. The DNA sequences provided 246 informative characters for parsimony analysis. ITS data supported as monophyletic groups the four generic sections, Cardiocaryon, Dioscaryon, Rhysocaryon, and Trachycaryon. Within Rhysocaryon, the temperate black walnuts and the tropical black walnuts were supported as monophyletic groups. When the two data sets were combined, J. cinerea was nested within Cardiocaryon. Combined analysis with published nuclear DNA restriction site data placed J. cinerea in a monophyletic group with Cardiocaryon. These analyses consistently supported Juglans as a monophyletic group and as the sister group to the genus Pterocarya. The results of this work are consistent with the known geological history of Juglans. The fossil record suggests that the butternuts had evolved by the early Oligocene in North America. The presence of butternuts in Eurasia could be the result of migration from North America to Eurasia during the warming trend of the mid Oligocene.

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.