The Role of Anesthesiologists in Perioperative Limitation of Potentially Life-Sustaining Medical Treatments: A Narrative Review and Perspective.
No patient arrives at the hospital to undergo general anesthesia for its own sake. Anesthesiology is a symbiont specialty, with the primary mission of preventing physical and psychological pain, easing anxiety, and shepherding physiologic homeostasis so that other care may safely progress. For most elective surgeries, the patient-anesthesiologist relationship begins shortly before and ends after the immediate perioperative period. While this may tempt anesthesiologists to defer goals of care discussions to our surgical or primary care colleagues, we have both an ethical and a practical imperative to share this responsibility. Since the early 1990s, the American College of Surgeons (ACS), the American Society of Anesthesiologists (ASA), and the Association of Perioperative Registered Nurses (AORN) have mandated a "required reconsideration" of do-not-resuscitate (DNR) orders. Key ethical considerations and guiding principles informing this "required reconsideration" have been extensively discussed in the literature and include respect for patient autonomy, beneficence, and nonmaleficence. In this article, we address how well these principles and guidelines are translated into daily clinical practice and how often anesthesiologists actually discuss goals of care or potential limitations to life-sustaining medical treatments (LSMTs) before administering anesthesia or sedation. Having done so, we review how often providers implement goal-concordant care, that is, care that reflects and adheres to the stated patient wishes. We conclude with describing several key gaps in the literature on goal-concordance of perioperative care for patients with limitations on LSMT and summarize novel strategies and promising efforts described in recent literature to improve goal-concordance of perioperative care.


Potential intussusception risk versus health benefits from rotavirus vaccination in Latin America.
With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination. We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters. For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once. The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America.


Intraductal mono-octanoin for the direct dissolution of bile duct stones: experience in 343 patients.
The efficacy and safety of mono-octanoin, a cholesterol solvent for the direct dissolution of stones in the biliary tract, was assessed by collating case reports on 343 patients provided by 222 physicians who used the material between 1977 and 1983. Most patients had previously undergone cholecystectomy, with common duct exploration, the majority within the preceding six weeks. In most, sphincterotomy was impossible or if carried out, had not induced stone passage. Stone dissolution was considered preferable to surgery, especially in patients who were frail, elderly, or had multiple medical problems. Treatment was unequivocally successful in 88 patients (26%) and was a valuable adjunct to interventional treatment in another 29 subjects (8%). In 70 patients (20%), calculi became smaller, but remained within the biliary tree. Thus, mono-octanoin was judged to have been useful in 54% of patients. Treatment was ineffective in 124 cases (36%). In the remaining 32 patients (9%), treatment was aborted because of side effects. Such side effects were common, occurring in 67% of cases, and in 41% of patients they were multiple. Abdominal pain was the most common complication. Other side effects reported were nausea, vomiting, and diarrhoea. Side effects were usually dose related and responded to reduction in infusion rate. Side effects were life threatening in 12 patients (5%), but there were no permanent sequelae and no deaths occurred. These data indicate that mono-octanoin is moderately effective, generally second line, but sometimes first line, treatment for retained biliary duct calculi.


Ophthalmic nepafenac use in the Netherlands and Denmark.
To describe nepafenac use in the Netherlands and Denmark with reference to its approved indications. For context, we also describe the use of ketorolac and diclofenac. We identified users in the PHARMO Database Network (the Netherlands, 2008-2013) and the Danish national health registers (Denmark, 1994-2014). We described prevalence of cataract surgery and duration of use in patients with cataract surgery with and without diabetes. In the Netherlands, 9530 nepafenac users (mean age, 71 years; 60% women) contributed 12 691 therapy episodes, of which 21% had a recently recorded cataract surgery. Of 2266 episodes in adult non-diabetic patients with cataract surgery, 60% had one bottle dispensed (treatment duration ≤21 days). Of 441 episodes in adult diabetic patients with cataract surgery, 90% had up to two bottles dispensed (≤60 days). Denmark had 60 403 nepafenac users (mean age, 72 years; 58% women) and 73 648 episodes (41% had recorded cataract surgery). Of 26 649 nepafenac episodes in adult non-diabetic patients with cataract surgery, 92% had one bottle dispensed. Of 3801 episodes in adult diabetic patients with cataract surgery, 99.8% had up to two bottles dispensed. Use patterns of nepafenac, ketorolac and diclofenac were roughly similar in the Netherlands, but not in Denmark. Less than half of therapy episodes were related to cataract surgery; around 90% of episodes with surgery were within the approved duration. Underrecording of ophthalmic conditions and procedures was a challenge in this study.


The role of macrophages in thymocyte mitogenesis.
The thymic lymphocytes of CBA/J mice respond to the mitogen Concanavalin A (Con A) only in the presence of adherent cells of the monocyte-macrophage series. Depletion of adherent cells abrogates the response, and macrophage-rich population of cells restore it. The need for macrophages and mitogen is completely provided by irradiated splenic macrophages which have been exposed to Con A and washed free of the soluble mitogen. The mitogenmacrophage effect in this case is apparently not due to soluble factors. Even more striking than the effect of macrophages on fresh cultures of thymic lymphocytes is their ability to restimulate quiescent cells 72 hr after their first stimulation with Con A. The quiescent cells respond immediately and quantitatively to Con A in the presence of fresh macrophages. This stimulation, like that of fresh thymocytes, is also controlled by a lymphokine ("costimulator") produced by mixing macrophages, mitogen, ant T lymphocytes. Our data suggest a model in which two signals are required for mitogenesis. First, the interaction of macrophage, T cell, and mitogen elicits a soluble costimulator, which is itself not mitogenic. Secondly, in the presence of costimulator, the mitogen (either soluble, or, more efficiently, bound to macrophages) induces a proliferative response in the T cell.


Indian hedgehog, but not histidine decarboxylase or amphiregulin, is a progesterone-regulated uterine gene in hamsters.
Implantation occurs only in the progesterone (P4)-primed uterus in the majority of species, but little effort has been given to identify P4-mediated molecules in these species. Using hamsters as a model for P4-dependent implantation and three well-known uterine receptivity-associated P4-regulated genes, Indian hedgehog (Ihh), histidine decarboxylase (Hdc), and amphiregulin (Areg), in mice that require ovarian estrogen for uterine receptivity and implantation, our strategy aimed to determine whether P4 regulates uterine expression of these genes in hamsters and whether the event- and cell-specific uterine expression patterns of these genes during the periimplantation period in hamsters follow similarly with their patterns in mice. We report here that P4-mediated Ihh signaling is important for uterine receptivity and implantation in hamsters because uterine epithelial Ihh expression was regulated by P4 and its expression patterns during the periimplantation period of hamsters closely follow its pattern in mice. In contrast, we noted no hormonal regulation of Hdc and Areg in the hamster uterus. However, this did not diminish their importance in hamsters because their expression patterns and functions are event and cell specific during the periimplantation period: whereas Hdc was expressed exclusively in d 4 uterine glands and regulated by the blastocyst, Areg was expressed on the decidual area adjacent to the embryo from d 5 onward and involved in stromal cell proliferation. We conclude that similarities and dissimilarities exist in uterine expression pattern of implantation-related genes, including hormonal regulation and their event-specific importance.


Age does not increase rate of forgetting over weeks--neuroanatomical volumes and visual memory across the adult life-span.
The aim of the study was to investigate whether age affects visual memory retention across extended time intervals. In addition, we wanted to study how memory capabilities across different time intervals are related to the volume of different neuroanatomical structures (right hippocampus, right cortex, right white matter). One test of recognition (CVMT) and one test of recall (Rey-Osterrieth Complex Figure Test) were administered, giving measures of immediate recognition/recall, 20-30 min recognition/recall, and recognition/recall at a mean of 75 days. Volumetric measures of right hemisphere hippocampus, cortex, and white matter were obtained through an automated labelling procedure of MRI recordings. Results did not demonstrate a steeper rate of forgetting for older participants when the retention intervals were increased, indicating that older people have spared ability to retain information in the long-term store. Differences in neuroanatomical volumes could explain up to 36% of the variance in memory performance, but were not significantly related to rates of forgetting. Cortical volume and hippocampal volume were in some cases independent as predictors of memory function. Generally, cortical volume was a better predictor of recognition memory than hippocampal volume, while the 2 structures did not differ in their predictive power of recall abilities. While neuroanatomical volumetric differences can explain some of the differences in memory functioning between younger and older persons, the hippocampus does not seem to be unique in this respect.


MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma.
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in multiple sarcoma subtypes. First-generation allosteric inhibitors of mTORC1 (rapalogues) have been extensively tested with great preclinical promise, but have had limited clinical utility. Here, we report that MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2 and has potent in vitro and in vivo antitumor activity in multiple sarcoma subtypes. In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration-dependent fashion and shows striking antiproliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma. Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone. In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg b.i.d. t.i.w.). At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and Ewing sarcoma models. In addition, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma.


Sequential document visualization.
Documents and other categorical valued time series are often characterized by the frequencies of short range sequential patterns such as n-grams. This representation converts sequential data of varying lengths to high dimensional histogram vectors which are easily modeled by standard statistical models. Unfortunately, the histogram representation ignores most of the medium and long range sequential dependencies making it unsuitable for visualizing sequential data. We present a novel framework for sequential visualization of discrete categorical time series based on the idea of local statistical modeling. The framework embeds categorical time series as smooth curves in the multinomial simplex summarizing the progression of sequential trends. We discuss several visualization techniques based on the above framework and demonstrate their usefulness for document visualization.


Management of Septic Open Abdomen in a Morbid Obese Patient with Enteroatmospheric Fistula by Using Standard Abdominal Negative Pressure Therapy in Conjunction with Intrarectal One.
Introduction. Management of open abdomen (OA) with enteroatmospheric fistula (EAF) in morbid obese patient with comorbid disease is challenging. We would like to report the management of septic OA in morbid obese patient with EAF which developed after strangulated recurrent giant incisional hernia repair. We would also like to emphasize, in this case, the conversion of EAF to ileostomy by the help of second Negative Pressure Therapy (NPT) on ostomy side, and the chance of new EAF occurrence was reduced with intrarectal NPT. Case Presentation. 62-year-old morbid obese woman became an OA patient with EAF after strangulated recurrent giant hernia. EAF was converted to ostomy with pezzer drain by the help of second NPT on ostomy. Colonic distention was reduced with the third NPT application via rectum. Abdominal reapproximation anchor (ABRA) system was used for delayed abdominal closure. Conclusions. Using the 2nd NPT on ostomy side may help in the maturation of the ostomy created in a difficult condition in an open abdomen. Using the 3rd NPT through rectum may decrease the chance of EAF formation by reducing the pressure difference between intraluminal pressure and extraluminal pressure in hollow viscera.


The apoptotic effects and synergistic interaction of sodium butyrate and MG132 in human retinoblastoma Y79 cells.
This study deals with the apoptotic effect exerted on human retinoblastoma Y79 cells by both sodium butyrate and an inhibitor of 26S proteasome [z-Leu-Leu-Leu-CHO (MG132)] and their synergistic effect. Exposure to sodium butyrate (1-4 mM) induced an accumulation of cells in the G2-M phase that was already visible after 24 h of treatment, when morphological and biochemical signs of apoptosis appeared only in a small number of cells (5-10%). Thereafter, the apoptotic effects increased progressively with slow kinetics, reaching a maximum after 72 h of exposure, when they concerned a large fraction of cells (>75% with 4 mM sodium butyrate). Sodium butyrate stimulated the conversion of procaspase-3 into caspase-3 and also induced the cleavage of poly-(ADP-ribose) polymerase and lamin B, two hallmarks of apoptosis. All of the apoptotic signals were suppressed by benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone (a general inhibitor of caspase activities), whereas acetyl-Asp-Glu-Val-Asp aldehyde, a specific inhibitor of caspase-3 activity, only induced a partial reversion of the apoptotic effects. Sodium butyrate also decreased the Bcl-2 level, whereas it increased the Bax level and stimulated the release of cytochrome c from the mitochondria, an event that was most likely responsible for the activation of caspase-3. Finally, sodium butyrate activated 26S proteasome, the major extralysosomal degradative machinery, which is responsible for the degradation of short-lived proteins. Consequently, the levels of p53, N-myc, and IkappaBalpha (factors that play regulatory roles in apoptosis) diminished, whereas the nuclear level of nuclear factor kappaB concomitantly increased. Treatment of Y79 cells with MG132 induced apoptosis with more rapid kinetics than with sodium butyrate. The effects appeared after 8 h of incubation, reaching a maximum at 24 h, and they were accompanied by increased levels of N-myc, p53, and IkappaBalpha. MG132 also favored the release of cytochrome c from the mitochondria and increased the activity of caspase-3. When Y79 cells were exposed to combinations of sodium butyrate and MG132, the latter compound suppressed the decreasing effect induced by sodium butyrate on the levels of p53, N-myc, and IkappaBalpha and the increasing effect on the nuclear level of nuclear factor kappaB. Moreover, an increase in the level of Bax and an enhancement in the release of cytochrome c from the mitochondria were observed. Clear synergistic effects concerning the activation of both caspase-3 and apoptosis were induced by a combination of suboptimal doses of sodium butyrate and MG132. The results support the conclusion that MG132 potentiates the apoptotic effect of sodium butyrate by suppressing its stimulatory effect on 26S proteasome activity. Synergistic interactions between butyrate and inhibitors of proteasome could represent a new important tool in tumor therapy and, in particular, the treatment of retinoblastoma.


Assessment of Ambient Exposures Firefighters Encounter While at the Fire Station: An Exploratory Study.
Firefighters are at an increased risk for many types of cancer. Although most studies on this topic focus on exposures encountered while fighting fires, exposures at the fire station are also cause for concern. This pilot study aimed to describe air quality within a few fire stations in and around Boston, Massachusetts, and to investigate physical and organizational factors that may influence levels of contaminants in stations. Air sampling of particulate matter less than 2.5 μm in diameter (PM2.5) and particle-bound polycyclic aromatic hydrocarbons (PAHs) was completed at four fire stations in Spring, 2016. Sampling occurred in the kitchen, truck bay, and just outside the station. Data were analyzed to assess differences between and within stations. Interviews (n =7) were conducted with officers at each station to explore health and safety-related organizational policies and practices. Interviews were transcribed and analyzed for thematic content. At each station, levels of contaminants were higher in the truck bays than either the outdoors or kitchen, and varied the most throughout the day. The station with the highest exposures in the truck bay had the lowest levels in the kitchen, which was possibly explained by new building materials and effective separation between building zones. The age and layout of the stations appeared to determine the extent to which policies favoring exhaust capture were implemented. Levels of PM2.5 and PAH inside fire stations may contribute to firefighter cancer risk. Through understanding contaminant variability, we can begin to design and test interventions that improve cancer prevention.


Rapid discrimination of maggots utilising ATR-FTIR spectroscopy.
Entomological evidence is used in forensic investigations to indicate time since death. The species and age of maggots or flies that are present at the scene can be used when estimating how much time has passed since death. Current methods that are used to identify species and developmental stage of larvae and fly samples are highly subjective, costly and often time consuming processes and require the expertise of an entomologist or species identification via DNA analysis. The use of vibrational spectroscopy, as an alternative identification method, would allow for a quicker, cheaper and less subjective technique and would allow entomological evidence to be used more commonly in the forensic process. This proof of principle study shows the potential for using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) as a rapid tool for differentiating between various species of larvae, such as those commonly found at crime scenes. The proposed regime would provide a rapid and valuable tool resulting in reduced time for both species identification and life cycle determination, particularly in forensic situations.


Current practice and perception of screening for medication adherence in inflammatory bowel disease.
Adherence to medication in inflammatory bowel disease (IBD) improves outcomes. Current practices of screening for adherence to IBD medications are unknown. The goal of this study was to determine current practice and perception of screening for medication adherence among US-based gastroenterologists. A survey was mailed electronically to gastroenterologists whose electronic-mail address was listed in the American College of Gastroenterology database. Physicians who cared for IBD patients were invited to answer. About 6830 surveys were sent to gastroenterologists nationwide, and 395 physicians who cared for IBD patients completed the survey. The true response rate is unknown, as the number of physicians caring for IBD patients in the database is unknown. About 77% (n = 303) of physicians who responded stated they screen for adherence to medication. Of the 77% of physicians who screened for adherence, only 19% (n = 58) use accepted measures of screening for adherence (pill counts, prescription refill rates, or adherence surveys). The remaining 81% used patient interview to screen for adherence, a measure considered least accepted to determine adherence, as it overestimates adherence. The average number of IBD patients observed in 1 week had no statistical significance in predilection for screening (P = 0.82). Private practice physicians (P = 0.05), younger physicians (P = 0.03), and physicians with fewer years of experience (P = 0.02) all were more likely to screen. About 95% of responders thought determining a low adherer to medicine was important because an intervention can increase adherence. The majority of gastroenterologists surveyed recognize that adherence to medication is important and improves outcomes. The majority of physicians in this study are screening for nonadherence in IBD, but are not using accepted measures for adherence detection. If this study truly reflects the majority of physicians nationwide, changing the way physicians screen for adherence, may detect more low adherers to medication.


Development of a reverse genetics system for respiratory syncytial virus long strain and an immunogenicity study of the recombinant virus.
Respiratory Syncytial Virus (RSV) is an important human respiratory pathogen, particularly of infants and older adults, and despite several decades of research and development, no licensed vaccine is available. Studies have confirmed that enhancement of RSV disease does not occur after inoculation with RSV live-attenuated vaccine candidates, making such vaccines preferable. In this paper, reverse genetics was used to construct two recombinant viruses, a recombinant Long strain (rLong) and rLong-∆G-EGFP; rLong-∆G-EGFP is a recombinant mutant in which G was replaced with the EGFP gene, based on the Long strain of RSV. Both rLong and rLong-∆G-EGFP were constructed successfully and recovered in Hep-2 cells, and autofluorescence was observed in rLong-∆G-EGFP-infected cells during consecutive passages. Titers of rLong and rLong-∆G-EGFP were ~100-fold lower than the parental strain. Although virulence was attenuated, high titers of neutralizing antibodies were induced in BALB/c mice after being inoculated with recombinant viruses in a three-dose schedule. Unexpectedly, the neutralizing antibody titer in rLong-∆G-EGFP-immunized recipients did not decline significantly compared with the rLong strain. Protective efficacy of recombinant viruses in lung tissue was up to 100%, and the serum neutralizing antibody levels could stabilize at 21 days with no significant fall post-challenge. Enzyme-linked immunospot (ELISPOT) assays showed that both recombinant viruses were capable of inducing CD8+ T cell immune responses, which are crucial for virus clearance, and that rLong stimulated a higher level of IFN-γ production by comparison. In terms of inducing a balanced immune response, rLong-∆G-EGFP elicited slightly higher levels of IgG2a antibodies and lower levels of IgG1/IgG2a than the rLong virus. This study suggested that immunization with rLong and rLong-∆G-EGFP were immunogenic and protected against RSV infection in the lower respiratory tract of BALB/c mice better than in the nose. Because of a relative low IgG1/IgG2a ratio, rLong-∆G-EGFP was more inclined to make CD4+ T cells, shifting toward a Th1-type response, indicating that the generation of a more balanced Th1/Th2 response was desirable. This explorative study on the recombinant Long viruses also contributed to obtaining more RSV attenuated candidates by a reverse genetics approach.


Congenitally missing maxillary lateral incisors: functional and periodontal aspects in patients treated with implants or space closure and tooth re-contouring.
To evaluate functional and periodontal aspects in patients with unilateral or bilateral congenitally missing maxillary lateral incisors, treated with either implants or space closure and tooth re-contouring. The sample consisted of 68 volunteers, divided into 3 groups: SCR - space closure and tooth re-contouring with composite resin (n = 26); SOI - implants placed in the area of agenesis (n = 20); and CG - control group (n = 22). A modified Helkimo questionnaire and the Research Diagnostic Criteria for Temporomandibular Disorders were used by a single, previously calibrated evaluator to assess signs and symptoms of temporomandibular joint disorder. The periodontal assessment involved the following aspects: plaque index, bleeding upon probing, pocket depth greater than 3 mm, gingival recession, abfraction, periodontal biotype and papilla index. The data were analyzed using Fisher's exact test and the nonparametric Mann-Whitney and Kruskal-Wallis tests (α=.05). No differences in periodontal status were found between treatments. None of the groups were associated with signs and symptoms of temporomandibular joint disorder. Both treatment alternatives for patients with congenitally missing maxillary lateral incisors were satisfactory and achieved functional and periodontal results similar to those of the control group.


Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway.
Interstrand cross-links (ICLs) block replication and transcription and thus are highly cytotoxic. In higher eukaryotes, ICLs processing involves the Fanconi anemia (FA) pathway and homologous recombination. Stalled replication forks activate the eight-subunit FA core complex, which ubiquitylates FANCD2-FANCI. Once it is posttranslationally modified, this heterodimer recruits downstream members of the ICL repairosome, including the FAN1 nuclease. However, ICL processing has been shown to also involve MUS81-EME1 and XPF-ERCC1, nucleases known to interact with SLX4, a docking protein that also can bind another nuclease, SLX1. To investigate the role of SLX4 more closely, we disrupted the SLX4 gene in avian DT40 cells. SLX4 deficiency caused cell death associated with extensive chromosomal aberrations, including a significant fraction of isochromatid-type breaks, with sister chromatids broken at the same site. SLX4 thus appears to play an essential role in cell proliferation, probably by promoting the resolution of interchromatid homologous recombination intermediates. Because ubiquitylation plays a key role in the FA pathway, and because the N-terminal region of SLX4 contains a ubiquitin-binding zinc finger (UBZ) domain, we asked whether this domain is required for ICL processing. We found that SLX4(-/-) cells expressing UBZ-deficient SLX4 were selectively sensitive to ICL-inducing agents, and that the UBZ domain was required for interaction of SLX4 with ubiquitylated FANCD2 and for its recruitment to DNA-damage foci generated by ICL-inducing agents. Our findings thus suggest that ubiquitylated FANCD2 recruits SLX4 to DNA damage sites, where it mediates the resolution of recombination intermediates generated during the processing of ICLs.


Integrating ion mobility mass spectrometry with molecular modelling to determine the architecture of multiprotein complexes.
Current challenges in the field of structural genomics point to the need for new tools and technologies for obtaining structures of macromolecular protein complexes. Here, we present an integrative computational method that uses molecular modelling, ion mobility-mass spectrometry (IM-MS) and incomplete atomic structures, usually from X-ray crystallography, to generate models of the subunit architecture of protein complexes. We begin by analyzing protein complexes using IM-MS, and by taking measurements of both intact complexes and sub-complexes that are generated in solution. We then examine available high resolution structural data and use a suite of computational methods to account for missing residues at the subunit and/or domain level. High-order complexes and sub-complexes are then constructed that conform to distance and connectivity constraints imposed by IM-MS data. We illustrate our method by applying it to multimeric protein complexes within the Escherichia coli replisome: the sliding clamp, (beta2), the gamma complex (gamma3deltadelta'), the DnaB helicase (DnaB6) and the Single-Stranded Binding Protein (SSB4).


Cutting needle biopsy in the diagnosis of clinically suspected non-carcinomatous disease of the lung.
Most patients referred for lung biopsy have a focal lesion that is likely to be a carcinoma, and fine needle aspiration is usually sufficient to confirm the diagnosis. When non-carcinomatous disease is suspected, tissue architecture is important and potential diagnostic techniques include percutaneous cutting needle biopsy (CNB). We retrospectively reviewed 37 CNBs performed for clinically suspected non-carcinomatous disease; recording the biopsy result, final diagnosis, radiological nature of the pulmonary abnormality, distance from the pleura of the lesion biopsied and biopsy complications. 9 patients had a single pulmonary nodule/mass; 13 had multiple nodules/masses; 8 had a lobar consolidation/mass; and 7 had multifocal consolidation. The lesion abutted the pleura in 31 cases, lying within 1 cm in the other 6 cases. The minor complication rate was 14%, with no major complications. Specific malignant diagnoses were made in 9 patients, and specific benign in 23, in all of whom clinicoradiological follow-up was concordant. CNB did not yield a specific diagnosis in five patients, including two lymphomas and one case of unsuspected tuberculosis in which the sample was not cultured. The overall accuracy of CNB was 32/37 (86%). CNB is a safe and accurate means of achieving a tissue diagnosis for patients with peripheral pulmonary parenchymal disease thought not to represent carcinoma.


The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies.
The lack of an official-stage classification system for thymic malignancies is an issue that hampers progress in this rare disease. A collaborative effort by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group is underway to develop proposals for such a system. A database of more than 10,000 cases worldwide has been assembled to provide a solid basis for analysis. This report outlines the structure of the effort and the process that has been designed.


rEHR: An R package for manipulating and analysing Electronic Health Record data.
Research with structured Electronic Health Records (EHRs) is expanding as data becomes more accessible; analytic methods advance; and the scientific validity of such studies is increasingly accepted. However, data science methodology to enable the rapid searching/extraction, cleaning and analysis of these large, often complex, datasets is less well developed. In addition, commonly used software is inadequate, resulting in bottlenecks in research workflows and in obstacles to increased transparency and reproducibility of the research. Preparing a research-ready dataset from EHRs is a complex and time consuming task requiring substantial data science skills, even for simple designs. In addition, certain aspects of the workflow are computationally intensive, for example extraction of longitudinal data and matching controls to a large cohort, which may take days or even weeks to run using standard software. The rEHR package simplifies and accelerates the process of extracting ready-for-analysis datasets from EHR databases. It has a simple import function to a database backend that greatly accelerates data access times. A set of generic query functions allow users to extract data efficiently without needing detailed knowledge of SQL queries. Longitudinal data extractions can also be made in a single command, making use of parallel processing. The package also contains functions for cutting data by time-varying covariates, matching controls to cases, unit conversion and construction of clinical code lists. There are also functions to synthesise dummy EHR. The package has been tested with one for the largest primary care EHRs, the Clinical Practice Research Datalink (CPRD), but allows for a common interface to other EHRs. This simplified and accelerated work flow for EHR data extraction results in simpler, cleaner scripts that are more easily debugged, shared and reproduced.


Proof of concept study: relating infarct location to stroke disability in the NINDS rt-PA trial.
The summed Alberta Stroke Program Early CT Score (ASPECTS) for noncontrast head CT scan represents the extent of early brain ischemia and has been shown to be useful for predicting stroke outcome. The ASPECTS template contains information on anatomical location which so far has not been used in analysis. This may not have been done because adjacent brain regions have related functions and share vascular territory. The task of relating neurological deficit to infarct localization requires brain imaging analysis tools which deal with this issue of relatedness or collinearity. We have previously used partial least squares with penalized logistic regression (PLR) to handle this problem of collinearity. A disadvantage of this method is that it cannot be performed at the bedside and requires processing and analysis in the imaging laboratory. PLR is a simpler analytic tool compared to partial least squares with PLR for dealing with this issue of relatedness (collinearity). It provides results in terms of β coefficients related to specific infarct locations in a manner that is intuitively understood by clinicians. In this exploratory analysis, we hypothesized that infarct location as represented by the individual ASPECTS region may be independently related to disability. ASPECTS from CT scans of patients in the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) Study were obtained. Due to the collinearity between the ASPECTS regions, we used PLR to determine the independent associations of exposures (rt-PA), demographic variables (age and sex), and imaging (ASPECTS location) with poor outcome as defined by a modified Rankin Scale score of >2. In 607/624 subjects with ASPECTS readings, variables significantly associated with poor outcome included: interactions between ASPECTS M6 region (primary motor cortex/parietal lobe) and age (p = 0.004), lentiform nucleus and age (p = 0.007), and blood sugar level and age (p = 0.01). The model suggested that older age or involvement of either M6 or lentiform nucleus slightly increased the odds of disability. However, the predominant effect was driven by rt-PA which reduced the odds of poor disability (OR 0.597, 95% CI 0.425-0.838, p = 0.003). This may potentially explain why certain patients have smaller gains from rt-PA treatments. At an older age, specific infarct locations may be associated with a poorer outcome in this exploratory re-analysis of the NINDS rt-PA Study.


Implementation of collaborative goal setting for diabetes in community primary care.
Collaborative goal setting (CGS) is a cornerstone of diabetes self-management support, but little is known about its feasibility and effectiveness during routine care. The aim of this study was to evaluate the implementation of an existing CGS intervention when integrated by primary care staff. Using a mixed-methods approach guided by the RE-AIM framework, intervention adoption, implementation, reach, and effectiveness were evaluated over 12 months. Three of four sites adopted the CGS intervention, in which 521 patients with type 2 diabetes (9-29 % of those targeted) received CGS. For those with suboptimal glycemic control (A1C ≥ 7.5 %), %A1C decreased by 1.1 for those receiving CGS (n = 204, p < 0.001) compared to 0.4 for a group who did not (n = 41, p = 0.23). Practice characteristics influenced adoption and implementation, while isolation of CGS from the remainder of clinical care likely influenced reach and effectiveness. CGS may benefit patients with diabetes, but a lack of integration by practice staff is a key barrier to overcome during implementation.


Theory of cell fate.
Cell fate decisions are controlled by complex intracellular molecular regulatory networks. Studies increasingly reveal the scale of this complexity: not only do cell fate regulatory networks contain numerous positive and negative feedback loops, they also involve a range of different kinds of nonlinear protein-protein and protein-DNA interactions. This inherent complexity and nonlinearity makes cell fate decisions hard to understand using experiment and intuition alone. In this primer, we will outline how tools from mathematics can be used to understand cell fate dynamics. We will briefly introduce some notions from dynamical systems theory, and discuss how they offer a framework within which to build a rigorous understanding of what we mean by a cell "fate", and how cells change fate. We will also outline how modern experiments, particularly high-throughput single-cell experiments, are enabling us to test and explore the limits of these ideas, and build a better understanding of cellular identities. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Cell Fates Models of Systems Properties and Processes > Cellular Models.


Amino acid usage is asymmetrically biased in AT- and GC-rich microbial genomes.
Genomic base composition ranges from less than 25% AT to more than 85% AT in prokaryotes. Since only a small fraction of prokaryotic genomes is not protein coding even a minor change in genomic base composition will induce profound protein changes. We examined how amino acid and codon frequencies were distributed in over 2000 microbial genomes and how these distributions were affected by base compositional changes. In addition, we wanted to know how genome-wide amino acid usage was biased in the different genomes and how changes to base composition and mutations affected this bias. To carry this out, we used a Generalized Additive Mixed-effects Model (GAMM) to explore non-linear associations and strong data dependences in closely related microbes; principal component analysis (PCA) was used to examine genomic amino acid- and codon frequencies, while the concept of relative entropy was used to analyze genomic mutation rates. We found that genomic amino acid frequencies carried a stronger phylogenetic signal than codon frequencies, but that this signal was weak compared to that of genomic %AT. Further, in contrast to codon usage bias (CUB), amino acid usage bias (AAUB) was differently distributed in AT- and GC-rich genomes in the sense that AT-rich genomes did not prefer specific amino acids over others to the same extent as GC-rich genomes. AAUB was also associated with relative entropy; genomes with low AAUB contained more random mutations as a consequence of relaxed purifying selection than genomes with higher AAUB. Genomic base composition has a substantial effect on both amino acid- and codon frequencies in bacterial genomes. While phylogeny influenced amino acid usage more in GC-rich genomes, AT-content was driving amino acid usage in AT-rich genomes. We found the GAMM model to be an excellent tool to analyze the genomic data used in this study.


A Care Step Pathway for the Diagnosis and Treatment of COVID-19-Associated Invasive Fungal Infections in the Intensive Care Unit.
In March 2020, the World Health Organization declared COVID-19, caused by the SARS-CoV-2 virus, a pandemic. Patients with severe cases resulting in hospitalization and mechanical ventilation are at risk for COVID-19-associated pulmonary aspergillosis, an invasive fungal infection, and should be screened for aspergillosis if they have persistent hemodynamic instability and fever. Early detection and treatment of this fungal infection can significantly reduce morbidity and mortality in this population. To develop an evidence-based care step pathway tool to help intensive care unit clinicians assess, diagnose, and treat COVID-19-associated pulmonary aspergillosis. A panel of 18 infectious disease experts, advanced practice registered nurses, pharmacists, and clinical researchers convened in a series of meetings to develop the Care Step Pathway tool, which was modeled on a tool developed by advanced practice nurses to evaluate and manage side effects of therapies for melanoma. The Care Step Pathway tool addresses various aspects of disease management, including assessment, screening, diagnosis, antifungal treatment, pharmacological considerations, and exclusion of other invasive fungal coinfections. The Care Step Pathway tool was applied in the care of a patient with COVID-19-associated aspergillosis. The patient was successfully treated. The Care Step Pathway is an effective educational tool to help intensive care unit clinicians consider fungal infection when caring for COVID-19 patients receiving mechanical ventilation in the intensive care unit, especially when the clinical course is deteriorating and antibiotics are ineffective.


Context-specific protein network miner--an online system for exploring context-specific protein interaction networks from the literature.
Protein interaction networks (PINs) specific within a particular context contain crucial information regarding many cellular biological processes. For example, PINs may include information on the type and directionality of interaction (e.g. phosphorylation), location of interaction (i.e. tissues, cells), and related diseases. Currently, very few tools are capable of deriving context-specific PINs for conducting exploratory analysis. We developed a literature-based online system, Context-specific Protein Network Miner (CPNM), which derives context-specific PINs in real-time from the PubMed database based on a set of user-input keywords and enhanced PubMed query system. CPNM reports enriched information on protein interactions (with type and directionality), their network topology with summary statistics (e.g. most densely connected proteins in the network; most densely connected protein-pairs; and proteins connected by most inbound/outbound links) that can be explored via a user-friendly interface. Some of the novel features of the CPNM system include PIN generation, ontology-based PubMed query enhancement, real-time, user-queried, up-to-date PubMed document processing, and prediction of PIN directionality. CPNM provides a tool for biologists to explore PINs. It is freely accessible at http://www.biotextminer.com/CPNM/.


Tibial intraneural ganglia in the tarsal tunnel: Is there a joint connection?
Intraneural ganglia are rare entities, and, as such, their pathogenesis has been extremely controversial. Recent evidence from intraneural ganglia occurring at more proximal sites-the peroneal nerve at the fibular neck (the most common site) and the tibial nerve at the knee-has suggested an articular origin rather than de novo formation. To our knowledge, of the 10 previous reports of tibial intraneural ganglia within the tarsal tunnel by others, a joint connection to the ankle joint was only identified in 2 cases. To support a hypothesis that tibial intraneural ganglia occurring within the tarsal tunnel region arise from neighboring joints, we analyzed 3 patients retrospectively, all of whom had magnetic resonance (MR) imaging and operative intervention. One of these patients was treated by a peripheral nerve surgeon specializing in foot and ankle surgery. The other 2 patients were the only ones previously published in the literature who had MR images available for reinterpretation. In none of these cases was a joint communication appreciated by radiologists interpreting the MR images preoperatively or by surgeons intraoperatively. Our review of these same cases demonstrated radiographic evidence of joint communications with the subtalar joints. Based on our findings in this article and our knowledge of intraneural ganglia occurring at more proximal sites, we believe that tibial intraneural ganglia within the tarsal tunnel originate from neighboring joints and that their connections to the joints (pedicles) are through articular branches. The importance of these connections is 2-fold: first, for their role in the pathogenesis of this entity, and second, for their potential therapeutic implications. As is highlighted by the clinical and radiographic follow-up in the 1 patient in this article and in many previously reported at other sites, intraneural cyst recurrence can occur if surgeons do not specifically address the articular connection.


Noninvasive monitoring of lactate dynamics in human forearm muscle after exhaustive exercise by (1)H-magnetic resonance spectroscopy at 7 tesla.
Despite its importance in energy metabolism, lactate in human skeletal muscle has been difficult to detect by noninvasive (1)H-magnetic resonance spectroscopy mainly due to interference from large water and lipid signals. Long echo-time acquisitions at 7 T effectively attenuates the water and lipid signals in forearm muscle allowing direct observation of both lactate resonances, the methine at 4.09 ppm and the methyl at 1.31 ppm. Using this approach, we were able to monitor lactate dynamics at a temporal resolution of 32 s. While lactate was not detectable at rest, immediately after an acute period of exercise to fatigue the forearm muscle, lactate rose to a level comparable to that of creatine (∼30 mmol/kg wet weight). In a typical (1)H-magnetic resonance spectrum collected using a echo-time of 140 ms, the lactate methine and methyl resonances both appear as doublets with an unusually large splitting of ∼20 Hz due to residual dipolar coupling. During muscle recovery following exercise, the lactate signals decay rapidly with a time constant of t½ = 2.0 ± 0.6 min (n = 12 subjects). This fast and simple lactate detection method may prove valuable for monitoring lactate metabolism in cancer and in sports medicine applications.


Trabecular bone ratio of mandible using micro-computed tomography in Korean.
Cortical bone and trabecular portion play important roles in maintaining the general structure of bone. It has been reported that a decrease in bone mineral density is related with increasing age, sex, and teeth loss. However, most of the studies were done with conventional radiographic analysis. In addition, data from Korean population are rare. The aim of this study was to analyze trabecular pattern of the mandible using micro-computed tomography. Thirty-nine specimens of the mandible were prepared. Specimens were scanned with micro-computed tomography and reconstructed three-dimensionally. Sections were made parallel to the axis of each tooth. Trabecular bone ratio (TBR) was measured. Data were statistically analyzed with 1-way analysis of variance (alpha = 0.05). There was a statistically significant difference of TBR between dentate and edentulous mandibles in the molar region. Trabecular bone ratio of edentulous mandible in males was greater than that in females. Trabecular bone ratio of dentate mandibles reduced regularly with increasing age, whereas that of edentulous mandibles did not. It could be concluded that there were statistically significant differences in TBR according to presence of tooth, sex, and increasing age on specific areas.


A prospective study on the clinical performance of polysiloxane soft liners: one-year results.
The aim of the present study was to evaluate the clinical performance of four denture soft liners up to 12 months. Thirty-three edentulous patients who experienced difficulties when using hard denture bases because of changes in denture-supporting tissues were accepted for the study and randomly received Molloplast B, GC Reline Soft, Silagum Comfort, or Mollosil Plus relines. Performance of the materials was evaluated using nine criteria at 3, 6, and 12 months: physical integrity, surface detail, adhesion, color, odor, plaque accumulation, resilience, hygiene, and mucosal condition. A four-point categorized scale (1=poor, 2=fair, 3=good, 4=excellent) was used. Unscheduled maintenance events and the presence of fungal colonization were also recorded. The percentage of patients available at 3, 6, and 12 months were 91%, 91%, and 66%. Main reasons for dropouts and discontinuation were fractured dentures and patient dissatisfaction. At 6 months, 96% of the performance scores were good or excellent and the largest changes were observed for physical integrity, surface detail, color, and fungal colonization. Fungal colonization was the most commonly observed problem and was the only reason of failure at 12 months. The clinical performance of all soft liners was slightly impaired over the 12-month observation. Except for cases showing extensive fungal colonization, the observed changes in clinical performance did not necessitate remaking of the dentures. Mollosil Plus showed a performance comparable to that of Molloplast B, and the other materials had slightly lower performance especially in terms of fungal colonization.


One method for objective adherence measurement in mind-body medicine.
Home practice is frequently prescribed as part of mind-body medicine interventions, although rarely objectively measured. This brief methods report describes one method for objectively measuring home practice adherence using a custom monitoring software program. Methods for objectively measuring adherence were developed as part of a randomized controlled trial on the mechanisms of mindfulness meditation. The study was conducted at Oregon Health & Science University, Portland, Oregon. The subjects comprised 11 combat veterans with post-traumatic stress disorder. The method used was mindfulness meditation. There were subjective and objective adherence measurements of mindfulness meditation home practice. The first iteration of objective adherence monitoring used an iPod device and had limitations in participant usage and correctly capturing data. In the second iteration, objective data were easily collected, uploaded, and viewed using the custom software application, iMINDr. Participants reported that iMINDr was straightforward to use, and they returned the monitoring units as directed. The iMINDr is an example of a simple objective adherence measurement system that may help mind-body researchers examine how home practice adherence may affect outcomes in future clinical trials.


Long-term habitual physical activity is associated with lower distractibility in a Stroop interference task in aging: Behavioral and ERP evidence.
Aging is associated with compromised executive control functions. Several lines of evidence point to beneficial effects of physical activity on cognition which indicate that regular physical activity may counteract the age-related decline of some executive functions. Here, we investigate the effects of lifelong physical activity (about 50 years) on interference processing in two matched groups of 20 physically high active and 20 low active healthy older men using event-related potentials (ERPs). In a low interference block of the Stroop task, participants had to indicate the meaning of color-words, while color was either compatible or incompatible with the meaning. In the high interference block, participants were asked to respond according to the ink color of the word and to ignore its meaning. Physically active seniors showed faster reaction times, lower individual variability in reaction times, and higher accuracy compared to low active seniors, particularly in the high interference block. This result was confirmed in the classic paper-and-pencil version of the Stroop task showing higher interference score in the low active than high active individuals. ERPs revealed a shorter latency of the P2 and generally more negative amplitudes of the fronto-central N2 and N450 components in the high active group compared to the low active group. The amount of interference was negatively correlated with objectively measured fitness and self-reported physical activity. The positive effect of physical fitness on interference processing in the behavioral data was related to N2 and N450 amplitudes. Taken together, this suggests that seniors reporting long-term physical activity may exhibit generally enhanced activity in the frontal cortex which enables more efficient interference resolution in the Stroop task.


The Molecular Epidemiology and Antimicrobial Resistance of Neisseria gonorrhoeae in Australia: A Nationwide Cross-Sectional Study, 2012.
Antimicrobial resistance (AMR) by Neisseria gonorrhoeae is considered a serious global threat. In this nationwide study, we used MassARRAY iPLEX genotyping technology to examine the epidemiology of N. gonorrhoeae and associated AMR in the Australian population. All available N. gonorrhoeae isolates (n = 2452) received from Australian reference laboratories from January to June 2012 were included in the study. Genotypic data were combined with phenotypic AMR information to define strain types. A total of 270 distinct strain types were observed. The 40 most common strain types accounted for over 80% of isolates, and the 10 most common strain types accounted for almost half of all isolates. The high male to female ratios (>94% male) suggested that at least 22 of the top 40 strain types were primarily circulating within networks of men who have sex with men (MSM). Particular strain types were also concentrated among females: two strain types accounted for 37.5% of all isolates from females. Isolates harbouring the mosaic penicillin binding protein 2 (PBP2)-considered a key mechanism for cephalosporin resistance-comprised 8.9% of all N. gonorrhoeae isolates and were primarily observed in males (95%). This large scale epidemiological investigation demonstrated that N. gonorrhoeae infections are dominated by relatively few strain types. The commonest strain types were concentrated in MSM in urban areas and Indigenous heterosexuals in remote areas, and we were able to confirm a resurgent epidemic in heterosexual networks in urban areas. The prevalence of mosaic PBP2 harboring N. gonorrhoeae strains highlight the ability for new N. gonorrhoeae strains to spread and become established across populations.


Self-reported oral health among a community sample of people experiencing social and health inequities: cross-sectional findings from a study to enhance equity in primary healthcare settings.
To describe the self-reported oral health issues among a community sample of primary care clients experiencing socioeconomic disadvantages. As part of a larger mixed-methods, multiple case study evaluating an equity-oriented primary healthcare intervention, we examined the oral health of a sample of 567 people receiving care at four clinics that serve marginalised populations in two Canadian provinces. Data collected included self-rated oral health and experiences accessing and receiving healthcare, standard self-report measures of health and quality of life, and sociodemographic information. The prevalence of self-rated poor oral health was high, with almost half (46.3%) of the participants reporting poor or fair oral health. Significant relationships were observed between poor oral health and vulnerabilities related to mental health, trauma and housing instability. Our findings suggest that the oral health of some Canadian populations may be dramatically worse than what is reported in existing population health surveys. Our findings reinforce the importance of addressing oral health as part of health equity strategies. The health and oral health issues experienced by this client cohort highlight the need for interdisciplinary, team-based care that can address the intersections among people's health status, oral health and social issues.


Experimental investigation in nodal aberration theory (NAT) with a customized Ritchey-Chrétien system: third-order coma.
Nodal aberration theory (NAT) describes the aberration properties of optical systems without symmetry. NAT was fully described mathematically and investigated through real-ray tracing software, but an experimental investigation is yet to be realized. In this study, a two-mirror Ritchey-Chrétien telescope was designed and built, including testing of the mirrors in null configurations, for experimental investigation of NAT. A feature of this custom telescope is a high-precision hexapod that controls the secondary mirror of the telescope to purposely introduce system misalignments and quantify the introduced aberrations interferometrically. A method was developed to capture interferograms for multiple points across the field of view without moving the interferometer. A simulation result of Fringe Zernike coma was generated and analyzed to provide a direct comparison with the experimental results. A statistical analysis of the measurements was conducted to assess residual differences between simulations and experimental results. The interferograms were consistent with the simulations, thus experimentally validating NAT for third-order coma.


Yoga for chronic low back pain: a meta-analysis of randomized controlled trials.
To evaluate the efficacy of yoga as an intervention for chronic low back pain (CLBP) using a meta-analytical approach. Randomized controlled trials (RCTs) that examined pain and⁄or functional disability as treatment outcomes were included. Post-treatment and follow-up outcomes were assessed. A comprehensive search of relevant electronic databases, from the time of their inception until November 2011, was conducted. Cohen's d effect sizes were calculated and entered in a random-effects model. Eight RCTs met the criteria for inclusion (eight assessing functional disability and five assessing pain) and involved a total of 743 patients. At post-treatment, yoga had a medium to large effect on functional disability (d=0.645) and pain (d=0.623). Despite a wide range of yoga styles and treatment durations, heterogeneity in post-treatment effect sizes was low. Follow-up effect sizes for functional disability and pain were smaller, but remained significant (d=0.397 and d=0.486, respectively); however, there was a moderate to high level of variability in these effect sizes. The results of the present study indicate that yoga may be an efficacious adjunctive treatment for CLBP. The strongest and most consistent evidence emerged for the short-term benefits of yoga on functional disability. However, before any definitive conclusions can be drawn, there are a number of methodological concerns that need to be addressed. In particular, it is recommended that future RCTs include an active control group to determine whether yoga has specific treatment effects and whether yoga offers any advantages over traditional exercise programs and other alternative therapies for CLBP.


Externally visible thrombus partially predicts internal thrombus deposition in extracorporeal membrane oxygenators.
We sought to quantify the location and volume of thrombus in used hollow-fiber membrane oxygenators and correlate the volume of thrombus with patient demographics, flow characteristics and anticoagulation parameters. Hollow-fiber membrane oxygenators (Quadrox D, Maquet, Rastatt, Germany) were collected after clinical use in ECMO circuits and divided into sections. Each section was digitally imaged and analyzed using ImageJ software. The location and total volume (cm3) of thrombus was calculated for different sections. In an effort to predict thrombus formation, we correlated thrombus volume with possible aggravating and mitigating variables. We collected 41 oxygenators from 27 patients. Twenty-seven (66%) were configured in the veno-venous mode and 14 (34%) in the veno-arterial mode. The median duration of use was 131 hours (interquartile range 61-214 hours). Eighteen (44%) were removed when the patient recovered, six (15%) were removed after withdrawal of care and seventeen (41%) were exchanged. The median volume of thrombus was 11.4 cm3 (interquartile range 2.2-44.5 cm3). A multivariable linear regression model suggested that the combination of median flow, configuration of ECMO and visible thrombus partially predicted internal thrombus volume (adjusted R2=0.39).


The ecoresponsive genome of Daphnia pulex.
We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia's genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The coexpansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes, including many additional loci within sequenced regions that are otherwise devoid of annotations, are the most responsive genes to ecological challenges.


Laser droplet heating: fast and slow heating regimes.
The heating of a laser-irradiated droplet is analyzed theoretically and numerically by solving the heat transport equation. Two regimes of droplet heating are considered, slow and fast heating. In the slow heating regime, the thermal diffusion term plays an important role and the droplet may not experience explosive vaporization during the lifetime of the laser pulse. In the fast heating regime, the vaporization term plays the dominant role and the temperature profile inside the droplet is similar to the heat production profile except for a thin shell near the surface. Numerical results are presented for the case of water droplets irradiated by 10.6microm laser radiation.


A complement of ten essential and pleiotropic arabidopsis COP/DET/FUS genes is necessary for repression of photomorphogenesis in darkness.
Two genetic screens, one for mutations resulting in photomorphogenic development in darkness and the other for mutants with fusca phenotype, have thus far identified six pleiotropic Arabidopsis COP/DET/FUS genes. Here, we characterized representative mutants that define four additional pleiotropic photomorphogenic loci and a null mutant allele of the previously defined DET1 locus. Dark-grown seedlings homozygous for these recessive mutations exhibit short hypocotyls and expanded cotyledons and are lethal before reaching reproductive development. Dark-grown mutant seedlings also display characteristic photomorphogenic cellular differentiation and elevated expression of light-inducible genes. In addition, analyses of plastids from dark-grown mutants reveal partial chloroplast differentiation and absence of etioplast development. Root vascular bundle cells of light-grown mutant seedlings develop chloroplasts, suggesting that these FUS gene products are important for suppression of chloroplast differentiation in light-grown roots. Double-mutant analyses indicate that these pleiotropic cop/det/fus mutations are epistatic to mutations in phytochromes, a blue-light photoreceptor, and a downstream regulatory component, HY5. Therefore, there is a complement of at least 10 essential and pleiotropic Arabidopsis genes that are necessary for repression of photomorphogenic development.


Salivary metabolite signatures of oral cancer and leukoplakia.
Oral cancer, one of the six most common human cancers with an overall 5-year survival rate of <50%, is often not diagnosed until it has reached an advanced stage. The aim of the current study is to explore salivary metabolomics as a disease diagnostic and stratification tool for oral cancer and leukoplakia and evaluate the potential of salivary metabolome for detection of oral squamous cell carcinoma (OSCC). Saliva metabolite profiling for a group of 37 OSCC patients, 32 oral leukoplakia (OLK) patients and 34 healthy subjects was performed using ultraperformance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry in conjunction with multivariate statistical analysis. The OSCC, OLK and healthy control groups demonstrate characteristic salivary metabolic signatures. A panel of five salivary metabolites including γ-aminobutyric acid, phenylalanine, valine, n-eicosanoic acid and lactic acid were selected using OPLS-DA model with S-plot. The predictive power of each of the five salivary metabolites was evaluated by receiver operating characteristic curves for OSCC. Valine, lactic acid and phenylalanine in combination yielded satisfactory accuracy (0.89, 0.97), sensitivity (86.5% and 94.6%), specificity (82.4% and 84.4%) and positive predictive value (81.6% and 87.5%) in distinguishing OSCC from the controls or OLK, respectively. The utility of salivary metabolome diagnostics for oral cancer is successfully demonstrated in this study and these results suggest that metabolomics approach complements the clinical detection of OSCC and stratifies the two types of lesions, leading to an improved disease diagnosis and prognosis.


Delta(13)C and tree-ring width reflect different drought responses in Quercus ilex and Pinus halepensis.
Holm oak (Quercus ilexL.) and Aleppo pine (Pinus halepensisMill) are representative of two different functional types of trees extensively found in the Mediterranean: evergreen sclerophyllous and drought-adapted conifers. The former is considered a partially drought-tolerant species, whereas the latter is a typically drought-avoiding, water-saving species. We postulated that contrasting strategies in response to water deficits in Q. ilex and P. halepensis would lead to a differential sensitivity to changes in water availability. To test this hypothesis, we compared the response of both species in growth rate (measured as radial increments) and intrinsic water use efficiency WUE(i), as inferred from carbon isotope discrimination (Delta(13)C) in wood samples] among sites from different provenance regions in NE Spain. We found significant differences in Delta(13)C and growth among provenance regions, partly explained by contrasting water availability. Wood Delta(13)C was positively related with precipitation and the ratio between precipitation and potential evapotranspiration (P/ E). However, these relationships were stronger in P. halepensis (for P / E, r(2)=0.67, P <0.001) than in Q. ilex ( r(2)=0.42, P <0.01). In addition, radial growth was positively related with precipitation and Delta(13)C in P. halepensis ( r(2)=0.32 and r(2)=0.35, respectively, P <0.01), but not in Q. ilex. We concluded that P. halepensis was more sensitive than Q. ilex to water availability, showing faster increase in WUE(i) in response to water stress. We also found that the effect of north/south aspect on Delta(13)C and growth was site-specific, and unrelated to climatic variables.


Symbiont photosynthesis in giant clams is promoted by V-type H+-ATPase from host cells.
Giant clams (genus Tridacna) are the largest living bivalves and, like reef-building corals, host symbiotic dinoflagellate algae (Symbiodinium) that significantly contribute to their energy budget. In turn, Symbiodinium rely on the host to supply inorganic carbon (Ci) for photosynthesis. In corals, host 'proton pump' vacuolar-type H+-ATPase (VHA) is part of a carbon-concentrating mechanism (CCM) that promotes Symbiodinium photosynthesis. Here, we report that VHA in the small giant clam (Tridacna maxima) similarly promotes Symbiodinium photosynthesis. VHA was abundantly expressed in the apical membrane of epithelial cells of T. maxima's siphonal mantle tubule system, which harbors Symbiodinium Furthermore, application of the highly specific pharmacological VHA inhibitors bafilomycin A1 and concanamycin A significantly reduced photosynthetic O2 production by ∼40%. Together with our observation that exposure to light increased holobiont aerobic metabolism ∼5-fold, and earlier estimates that translocated fixed carbon exceeds metabolic demand, we conclude that VHA activity in the siphonal mantle confers strong energetic benefits to the host clam through increased supply of Ci to algal symbionts and subsequent photosynthetic activity. The convergent role of VHA in promoting Symbiodinium photosynthesis in the giant clam siphonal mantle tubule system and coral symbiosome suggests that VHA-driven CCM is a common exaptation in marine photosymbioses that deserves further investigation in other taxa.


Characteristics influencing outcomes of excimer laser photorefractive keratectomy. Summit Photorefractive Keratectomy Phase III Study Group.
To identify preoperative and intraoperative characteristics associated with outcomes of photorefractive keratectomy (PRK). In the phase III multicenter clinical trials of the Summit Technology excimer laser for corrections of 1.5 to 6.0 diopters (D) of myopia, three principal outcomes of PRK on 612 patients were examined: (1) uncorrected visual acuity of 20/40 or better, (2) predictability of refractive outcome within 1.0 D of attempted correction, and (3) stability of refractive result between 12 and 24 months. Multiple logistic regression was used to test for independent associations of multiple preoperative and intraoperative characteristics with each of these outcomes. Older age was independently associated with lesser likelihood of achieving 20/40 or better uncorrected visual acuity (odds ratio = 1.08 per incremental year of age, 95% confidence interval [CI] = 1.04-1.12) and with decreased predictability, specifically with overcorrection (odds ratio = 1.09, 95% CI = 1.06-1.12), but age was not associated with stability of refraction. Greater attempted correction was associated independently with a decreased likelihood of 20/40 or better uncorrected visual acuity (odds ratio = 2.78 for corrections of 3.5-5.5 D, 95% CI = 1.18-6.75; odds ratio = 4.19 for corrections of > or = 5.5 D, 95% CI = 1.66-10.58), with decreased predictability (odds ratio = 1.72 for corrections of 3.5-5.5 D, 95% CI = 1.05-2.85; odds ratio = 2.95 for corrections of > or = 5.5 D, 95% CI = 1.65-5.26), and with a reduced likelihood of stability of refraction (odds ratio = 3.46 for corrections of > or = 5.0 D, 95% CI = 1.32-9.11). No intraoperative characteristics were associated with any of the outcomes assessed. Using this specific excimer laser system with an optical zone of 4.5 or 5.0 mm, patient age and attempted correction are important preoperative characteristics associated with postoperative uncorrected visual acuity and predictability of PRK. Stability of refraction is strongly associated with attempted correction. Such information may help guide patient selection, determine timing of fellow eye treatment, and suggest changes in the laser treatment algorithm for individual patients. Although these findings may be representative of PRK in general, similar analyses should be performed before modifying patient treatments using either a 6.0-mm treatment zone or other laser systems.


The folate receptor alpha is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate.
Two major systems exist for folate cell entry: the reduced folate carrier (RFC) and the folate receptor (FR). Although defective RFC-mediated transport was frequently identified as a mechanism of methotrexate (MTX) resistance in osteosarcoma, the status of FR and its role in this disease are unknown. mRNA for FR alpha was measured in 107 osteosarcoma specimens using quantitative reverse transcription-PCR and was related to RFC expression. The effect of FR alpha overexpression on MTX resistance and natural folate uptake was studied using FR alpha non-expressing osteosarcoma 143B cells transfected with FR alpha cDNA in comparison with those transfected with sense or antisense RFC in the same genetic background. Eighty-four samples (78.5%) had detectable FR alpha mRNA, and 29.9% had higher levels than the ovarian cancer cell line SKOV-3. No correlation was found between mRNA levels of FR alpha and RFC (r(2)=0.002). FR alpha overexpression had minor effects on the transport of MTX and sensitivity to this drug. Among the transfected 143B sublines, only the 143B-FR alpha was able to uptake 5-methyltetrahydrofolate when the extracellular concentration was reduced to 2 nmol/L, which conferred a growth advantage in physiologic folate concentrations compared with vector-only-transfected cells. Importantly, this was not similarly achieved by RFC overexpression. This study suggests that FR alpha plays a role in the uptake of 5-methyltetrahydrofolate when the concentration gradient is insufficient for RFC-mediated transport. FR alpha overexpression is unlikely secondary to the decreased RFC expression in osteosarcoma.


Glucocorticoids reset circadian clock in choroid plexus via period genes.
The epithelial cells of choroid plexus (CP) in brain ventricles produce cerebrospinal fluid and act as the blood-cerebrospinal fluid barrier. In this study, we confirmed that CP in the 4th ventricle is composed of cellular oscillators that all harbor glucocorticoid receptors and are mutually synchronized to produce a robust clock gene expression rhythm detectable at the tissue level in vivo and in vitro. Animals lacking glucocorticoids (GCs) due to surgical removal of adrenal glands had Per1, Per2, Nr1d1 and Bmal1 clock gene rhythmicity in their CP significantly dampened, whereas subjecting them to daily bouts of synthetic GC analog, dexamethasone (DEX), reinforced those rhythms. We verified these in vivo effects using an in vitro model of organotypic CP explants; depending on the time of its application, DEX significantly increased the amplitude and efficiently reset the phase of the CP clock. The results are the first description of a PRC for a non-neuronal clock in the brain, demonstrating that CP clock shares some properties with the non-neuronal clocks elsewhere in the body. Finally, we found that DEX exhibited multiple synergic effects on the CP clock, including acute activation of Per1 expression and change of PER2 protein turnover rate. The DEX-induced shifts of the CP clock were partially mediated via PKA-ERK1/2 pathway. The results provide the first evidence that the GC rhythm strengthens and entrains the clock in the CP helping thus fine-tune the brain environment according to time of day.


First Report of Colletotrichum acutatum sensu lato Causing Anthracnose on Gooseberry Fruits in the Czech Republic.
Gooseberry (Ribes uva-crispa L.) is a commonly grown fruit tree or bush in the Czech Republic. Colletotrichum acutatum J. H. Simmonds is a polyphagous fungal plant pathogen. This pathogen has been reported causing anthracnose on strawberry in the Czech Republic (2), and recently it has become an important pathogen on the fruits of apple and tomato (4). In 2012, anthracnose symptoms were noticed on fruits of gooseberry (locality Pribyslavice, near Brno). The symptoms on fruit surfaces were round, brown, shriveled, sunken spots of 1.2 to 2.0 cm, with orange conidial masses on the spots. The pathogen was isolated from symptomatic fruits on PDA and cultured at 25 ± 2°C. The color of colonies varied with age from white to gray with occurrence of orange conidial masses. Conidia were colorless and fusiform, size 13 to 17 × 4 to 5 μm (n = 100). The morphological characteristics classified the pathogen as a Colletotrichum sp. To fulfill Koch's postulates, 25 disinfested healthy gooseberry fruits were pinpricked by sterile needle and 10 μl of spore suspension (1 × 105 conidia ml-1) was inoculated by pipetting into the wound. Control fruits were treated with sterile distilled water. The fruits were transferred to a growth cabinet and maintained at a temperature of 25 ± 2°C, relative humidity 70 ± 5%. Similar anthracnose symptoms were observed on all of gooseberry fruits a week after inoculation, whereas no symptoms appeared on control fruits. The pathogen was reisolated from infected fruits. Species determination of the isolates was confirmed by PCR. Specific primers designed in region ITS1, the 5.8S RNA gene, and region ITS2 of the pathogen DNA were selected. Specific primers CaInt2 and ITS4 were used to identify C. acutatum (3), and primers CgInt and ITS4 were used to determine C. gloeosporioides isolate CCM 177 (1), which was used as a control. Our isolates yielded PCR products (size 490 bp) only with primers designed for C. acutatum. The C. gloeosporioides isolate yielded PCR product (size 450 bp) only with CgInt and ITS4 primers. PCR products were sequenced and identified with the BLAST program. The sequence of the gooseberry fruit isolates (Accession No. JX843763 and JX843764) matched with 100% similarity to the C. acutatum sequences in GenBank. To our knowledge, this is the first report of C. acutatum sensu lato on gooseberry fruits in the Czech Republic. This pathogen can endanger the production of gooseberry fruits in this region. References: (1) P. R. Mills et al. FEMS Microbiol. Lett., 98:137, 1992. (2) D. Novotný et al. Plant Dis. 91:1516, 2007. (3) S. Sreenivasaprasad et al. Plant Pathol. 45:650, 1996. (4) J. Víchová et al. Plant Dis. 96:769, 2012.


Inclusive fitness affects both prosocial and antisocial behavior: target gender and insult domain moderate the link between genetic relatedness and aggression.
Although prior research has examined the relationship between genetic relatedness and helping behavior (Burnstein, Crandall, and Kitayama, 1994), less is known about its role in aggressive responses to insults (Fitzgerald and Ketterer, 2011). Drawing on inclusive fitness theory (Hamilton, 1964) and the Kinship, Acceptance, and Rejection Model of Altruism and Aggression (KARMAA; Webster, 2008; Webster et al., 2012), we designed a 2 (participant gender) × 2 (target gender) × 2 (insult: status vs. reproductive) × 3 (relatedness: stranger vs. cousin vs. sibling) between-person experiment in which 489 participants (a) read vignettes in which a stranger, cousin, or sibling was insulted and (b) reported their emotional reaction and retaliation likelihood (six-item α = .91) in response to the insult. Consistent with theory and prior research, men were significantly more aggressive than women, and people were significantly more aggressive responding to insults against kin than non-kin. These findings support theoretically-derived, dynamic, and domain-specific links among insults, gender, relatedness, and aggression.


The 'number needed to sample' in primary care research. Comparison of two primary care sampling frames for chronic back pain.
Sampling for primary care research must strike a balance between efficiency and external validity. For most conditions, even a large population sample will yield a small number of cases, yet other sampling techniques risk problems with extrapolation of findings. To compare the efficiency and external validity of two sampling methods for both an intervention study and epidemiological research in primary care--a convenience sample and a general population sample--comparing the response and follow-up rates, the demographic and clinical characteristics of each sample, and calculating the 'number needed to sample' (NNS) for a hypothetical randomized controlled trial. In 1996, we selected two random samples of adults from 29 general practices in Grampian, for an epidemiological study of chronic pain. One sample of 4175 was identified by an electronic questionnaire that listed patients receiving regular analgesic prescriptions--the 'repeat prescription sample'. The other sample of 5036 was identified from all patients on practice lists--the 'general population sample'. Questionnaires, including demographic, pain and general health measures, were sent to all. A similar follow-up questionnaire was sent in 2000 to all those agreeing to participate in further research. We identified a potential group of subjects for a hypothetical trial in primary care based on a recently published trial (those aged 25-64, with severe chronic back pain, willing to participate in further research). The repeat prescription sample produced better response rates than the general sample overall (86% compared with 82%, P < 0.001), from both genders and from the oldest and youngest age groups. The NNS using convenience sampling was 10 for each member of the final potential trial sample, compared with 55 using general population sampling. There were important differences between the samples in age, marital and employment status, social class and educational level. However, among the potential trial sample, there were no demographic differences. Those from the repeat prescription sample had poorer indices than the general population sample in all pain and health measures. The repeat prescription sampling method was approximately five times more efficient than the general population method. However demographic and clinical differences in the repeat prescription sample might hamper extrapolation of findings to the general population, particularly in an epidemiological study, and demonstrate that simple comparison with age and gender of the target population is insufficient.


A 6-month inhalation toxicology study in Apoe-/- mice demonstrates substantially lower effects of e-vapor aerosol compared with cigarette smoke in the respiratory tract.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease. Considerable attention has been paid to the reduced harm potential of nicotine-containing inhalable products such as electronic cigarettes (e-cigarettes). We investigated the effects of mainstream cigarette smoke (CS) and e-vapor aerosols (containing nicotine and flavor) generated by a capillary aerosol generator on emphysematous changes, lung function, and molecular alterations in the respiratory system of female Apoe-/- mice. Mice were exposed daily (3 h/day, 5 days/week) for 6 months to aerosols from three different e-vapor formulations-(1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine), or (3) test (base and flavor)-or to CS from 3R4F reference cigarettes. The CS and base/test aerosol concentrations were matched at 35 µg nicotine/L. CS exposure, but not e-vapor exposure, led to impairment of lung function (pressure-volume loop area, A and K parameters, quasi-static elastance and compliance) and caused marked lung inflammation and emphysematous changes, which were confirmed histopathologically and morphometrically. CS exposure caused lung transcriptome (activation of oxidative stress and inflammatory responses), lipidome, and proteome dysregulation and changes in DNA methylation; in contrast, these effects were substantially reduced in response to the e-vapor aerosol exposure. Compared with sham, aerosol exposure (carrier, base, and test) caused a slight impact on lung inflammation and epithelia irritation. Our results demonstrated that, in comparison with CS, e-vapor aerosols induced substantially lower biological and pathological changes in the respiratory tract associated with chronic inflammation and emphysema.


Toxic inhalation fatalities of US construction workers, 1990 to 1999.
Construction workers account for a disproportionately large number of occupational fatalities. A small percentage of these deaths is attributable to poisoning. Risk factors for such deaths using national data have not been reported previously. Construction poisoning fatalities from 1990 to 1999 in the Occupational Safety and Health Administration Integrated Management and Information System data set were analyzed. Risk and risk factors were determined using Bureau of Labor Statistics and census data. Eighty-seven poisoning deaths of construction workers are characterized, all attributable to toxic inhalation. Cellular and simple asphyxiants accounted for the largest numbers of fatalities. The majority of these deaths occurred in confined spaces. Water, sewer, and utility line workers are at increased risk for poisoning fatality. Toxic inhalation fatalities in the construction industry are preventable. Extending the Occupational Safety and Health Administration's confined space standard could save lives, particularly among water, sewer, and utility line industry workers.


Habitat management: a tool to modify ecosystem impacts of nitrogen deposition?
Atmospheric nitrogen deposition has been shown to affect both the structure and the function of heathland ecosystems. Heathlands are semi-natural habitats and, as such, undergo regular management by mowing or burning. Different forms of management remove more or less nutrients from the system, so habitat management has the potential to mitigate some of the effects of atmospheric deposition. Data from a dynamic vegetation model and two field experiments are presented. The first involves nitrogen addition following different forms of habitat management. The second tests the use of habitat management to promote heathland recovery after a reduction in nitrogen deposition. Both modelling and experimental approaches suggest that plant and microbial response to nitrogen is affected by management. Shoot growth and rates of decomposition were lowest in plots managed using more intensive techniques, including mowing with litter removal and a high temperature burn. Field data also indicate that ecosystem recovery from prolonged elevated inputs of nitrogen may take many years, or even decades, even after the removal of plant and litter nitrogen stores which accompanies the more intensive forms of habitat management.


Risk equalisation and voluntary health insurance markets: The case of Australia.
In April 2007, Australia introduced a risk equalisation (RE) scheme (de facto a claims equalisation scheme), which replaced an extant reinsurance scheme that had operated since 1976. This scheme is one of a number of policy measures that the Australian Government has instituted to support the voluntary private health insurance (PHI) market which is subject to mandatory community rating and the attendant problem of selection. The latter has been a persistent concern in the Australian PHI market since the introduction of Australia's universal, compulsory national health insurance scheme Medicare. This paper presents a brief overview of Australia's health care financing arrangements and, in particular, focuses on the history, structure and functioning of the RE scheme. It provides an exposition of the operation of the scheme and empirical evidence of the scheme's effects in its first full year of operation, 2007-08. The paper makes three contributions: first, it provides the only detailed overview of the functioning of the Australian RE scheme published to date; second, it presents the first empirical measures of the scheme's operation at the level of the 38 individual PHI funds; and third, it describes the systematic differences in the scheme's operation with respect to large and small funds. Thus, this paper provides a number of insights into the operation and outcomes of the Australian RE scheme following its first year of operation.


Inappropriate Use of Ultrasound in Management of Pediatric Cryptorchidism.
There is a limited role for ultrasound in the management of an undescended testicle (UDT). We hypothesized that ultrasound remains overused by referring physicians. Our goal was to characterize the trends, patterns, and impact of ultrasound use for UDT and to reaffirm its limited diagnostic value for this indication. The records of boys aged 0 to 18 years with UDT in Ontario, Canada, between 2000 and 2011 were reviewed by using health administrative data housed at the Institute for Clinical and Evaluative Sciences (ICES). A second review of boys referred to our institution with UDT between 2007 and 2011 was conducted to complement the health administrative data. Trends in frequency, distribution, and costs of ultrasound use were assessed. Time delays between diagnosis and definitive management were compared between the ultrasound and non-ultrasound groups. Using our institutional data, we analyzed demographic patterns of ultrasound use and compared its diagnostic accuracy by using surgical findings as the gold standard. Ultrasound was used in 33.5% of provincial referrals and 50% of institutional referrals. Children who underwent ultrasound experienced an approximate 3-month delay in definitive surgical management. Ultrasound correctly predicted physical examination findings in only 54% of patients. Physicians in community practice, and those with fewer years in practice, were more likely to order ultrasound. Ultrasound has limited value for the management of UDT but remains widely overused, with an increasing trend over time. This practice has negative implications for access to care and cost-containment. Widespread educational efforts should be undertaken, targeting current and future referring physicians.


Changes in level of the conus after corrective surgery for scoliosis: MRI-based preliminary study in 31 patients.
Detection of postoperative spinal cord level change can provide basic information about the spinal cord status, and electrophysiological studies regarding this point should be conducted in the future. To determine the changes in the spinal cord level postoperatively and the possible associated factors, we prospectively studied 31 patients with scoliosis. All the patients underwent correction and posterior fusion using pedicle screws and rods between January 2008 and March 2009. The pre- and postoperative conus medullaris levels were determined by matching the axial magnetic resonance image to the sagittal scout image. The patients were divided according to the change in the postoperative conus medullaris level. The change group was defined as the patients who showed a change of more than one divided section in the vertebral column postoperatively, and the parameters of the change and non-change groups were compared. The mean pre- and postoperative Cobb's angle of the coronal curve was 76.80° ± 17.19° and 33.23° ± 14.39°, respectively. Eleven of 31 patients showed a lower conus medullaris level postoperatively. There were no differences in the pre- and postoperative magnitude of the coronal curve, lordosis and kyphosis between the groups. However, the postoperative degrees of correction of the coronal curve and lumbar lordosis were higher in the change group. There were also differences in the disease entities between the groups. A higher percentage of patients with Duchenne muscular dystrophy had a change in level compared to that of the patients with cerebral palsy (83.3% vs. 45.5%, respectively). The conus medullaris level changed postoperatively in the patients with severe scoliosis. Overall, the postoperative degree of correction of the coronal curve was higher in the change group than that in the non-change group. The degrees of correction of the coronal curve and lumbar lordosis were related to the spinal cord level change after scoliosis correction.


Spatiotemporal clustering and association of Ephestia kuehniella (Lepidoptera: Pyralidae) and two of its parasitoids in bulk-stored wheat.
To assess the spatiotemporal distribution of insects in a flat storage containing wheat (Triticumn spp.), probe traps were suspended in the wheat bulk and inspected for captured insects at 15-d intervals, from June 2001 to August 2002. The grain bulk was 1 m in height, and traps were placed at the upper and the lower 0.5 m of the bulk. During the entire trapping period, 17 insect taxa were recorded. The most abundant species were Ephestia kuehniella Zeller (Lepidoptera: Pyralidae) and its larval parasitoids Harbobracon hebetor (Say) (Hymenoptera: Braconidae) and Venturia canescens (Gravenhorst) (Hymenoptera: Ichneumonidae). Most individuals were found in the upper bulk part. The highest E. kuehniella trap catches were found between August and November 2001 and during June and July 2002. Of the two parasitoids, H. hebetor was more abundant than V. canescens, with the exception of winter and early spring, when both species occurred at low numbers, especially H. hebetor. Spatial analysis by distance indices (SADIE) spatiotemporal analysis showed significant clustering of species, especially during summer and autumn. Early in the season and during spring 2002, at low host numbers, V. canescens occupied the locations where E. kuehniella mainly aggregated, but with the increase of E. kuehniella population, H. hebetor occupied these host groups and replaced V canescens. Although the two parasitoids competed for the same host species, both species coexisted in the storage facility during the entire trapping period.


Assessing referrals for pharmacotherapy: a comparison of therapist and client report.
The primary goal of this study was to assess whether therapist self-reported use of referrals for pharmacotherapy with clients for the treatment of substance abuse disorders is consistent with actual rates of referrals experienced by clients. Participants were 20 substance abuse counselors and 120 clients at a large, multisite substance abuse treatment center. Therapists were asked to complete a brief measure of their current use of referrals for pharmacotherapy, including agonist and antagonist approaches. Clients were asked to complete a brief measure indicating whether their individual counselor had discussed with them a referral for medication. Counselor reports were linked to their individual clients and compared for validation. Results indicate that therapist self-report is significantly correlated with client report of referrals for pharmacotherapy. These results indicate that although therapist self-report of adherence to more involved treatment approaches is often unreliable, substance abuse counselors are able to reliably report their use of referrals.


Gross and fine motor function in fibromyalgia and chronic fatigue syndrome.
This paper aimed to investigate motor proficiency in fine and gross motor function, with a focus on reaction time (RT) and movement skill, in patients with fibromyalgia (FM) and chronic fatigue syndrome (CFS) compared to healthy controls (HC). A total of 60 individuals (20 CFS, 20 FM, and 20 HC), age 19-49 years, participated in this study. Gross motor function in the lower extremity was assessed using a RT task during gait initiation in response to an auditory trigger. Fine motor function in the upper extremity was measured during a precision task (the Purdue Pegboard test) where the number of pins inserted within 30 s was counted. No significant differences were found between FM and CFS in any parameters. FM and CFS groups had significantly longer RT than HC in the gait initiation (p=0.001, and p=0.004 respectively). In the Purdue Pegboard test, 20% in the FM group, 15% in the CFS groups, and 0% of HC group, scored below the threshold of the accepted performance. However, there were no significant differences between FM, CFS, and HC in this task (p=0.12). Compared to controls, both CFS and FM groups displayed significantly longer RT in the gait initiation task. Generally, FM patients showed the worst results in both tests, although no group differences were found in fine motor control, according to the Purdue Pegboard test.