Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network.
Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5-14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3-12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications. Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.


Multicenter evaluation of the in vitro activities of three new quinolones, sparfloxacin, CI-960, and PD 131,628, compared with the activity of ciprofloxacin against 5,252 clinical bacterial isolates.
The in vitro activities of three new quinolones (sparfloxacin, CI-960, and PD 131,628) were compared with that of ciprofloxacin against 5,252 routine clinical aerobic and facultatively anaerobic bacterial isolates. Overall, CI-960 was the most active drug in vitro (MIC for 90% of the strains tested, 0.13 micrograms/ml); ciprofloxacin and sparfloxacin were the least active (MIC for 90% of the strains tested, 1.0 micrograms/ml). All three new quinolones, but particularly CI-960 and PD 131,628, exhibited significantly greater activity than ciprofloxacin against enterococci and staphylococci.


Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial.
New therapeutic options are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). Repurposing existing pharmaceuticals provides an immediate treatment opportunity. We assessed the efficacy of sofosbuvir and daclatasvir with ribavirin for treating patients with COVID-19. This was a single-centre, randomized controlled trial in adults with moderate COVID-19 admitted to the Ghaem Shahr Razi Hospital in Mazandaran Province, Iran. Patients were randomly assigned to 400 mg sofosbuvir, 60 mg daclatasvir and 1200 mg ribavirin (intervention group) or to standard care (control group). The primary endpoint of this study was length of hospital stay. This study is registered by IRCT.ir under the ID: IRCT20200328046886N1. Between 20 March 2020 and 8 April 2020, 48 patients were recruited; 24 patients were randomly assigned to the intervention group and 24 to the control group. The median duration of hospital stay was 6 days in both groups (P = 0.398). The number of ICU admissions in the sofosbuvir/daclatasvir/ribavirin group was not significantly lower than the control group (0 versus 4, P = 0.109). There was no difference in the number of deaths between the groups (0 versus 3, P = 0.234). The cumulative incidence of recovery was higher in the sofosbuvir/daclatasvir/ribavirin arm (Gray's P = 0.033). This randomized trial was too small to make definitive conclusions. There were trends in favour of the sofosbuvir/daclatasvir/ribavirin arm for recovery and lower death rates. However, there was an imbalance in the baseline characteristics between the arms. Larger randomized trials should be conducted to investigate this treatment further.


Application of fluorescence in situ hybridization in distinguishing acral melanoma in situ from acral junctional melanocytic nevus on the volar skin in Japanese patients.
Four-colored fluorescence in situ hybridization (FISH) is an ancillary diagnostic tool for melanoma. However, most studies that have investigated the usefulness of FISH primarily focused on advanced melanomas. The aim of the current study was to evaluate the effectiveness of FISH in distinguishing acral melanoma (AM) in situ from benign acral junctional nevus (AJN), two types of lesions that are difficult to differentiate via traditional clinical means. The authors investigated the usefulness of FISH in 91 acral melanocytic lesions, including 50 lesions with diagnostic discrepancies between dermoscopic and pathologic approaches or difficulty diagnosing between AM in situ and AJN, on the volar skin of Japanese patients. The authors classified the lesions based on the diagnosis of dermatologists and pathologists into four groups: (I) lesions with a unanimous diagnosis by dermatologists and pathologists as AM in situ or AJN (n = 41); (II) lesions with a unanimous diagnosis by dermatologists only as AM in situ or AJN (n = 21); (III) lesions with a unanimous diagnosis by pathologists only as AM in situ or AJN (n = 15); and (IV) all other lesions (n = 14). The dermatologists diagnosed the lesions by clinical and dermoscopic photographs alone, while the pathologists diagnosed the lesions by microscopy of hematoxylin and eosin-stained slides alone. In group I (AM in situ [n = 20] and AJN [n = 21]), four-colored FISH demonstrated 90% sensitivity and 81% specificity in distinguishing AM in situ from AJN. There was a significant correlation between the FISH results and the unanimous diagnoses by pathologists alone (p = 0.03) in group III. However, FISH results were not significantly correlated with the unanimous diagnoses by dermatologists alone (p = 0.33) in group II. In conclusion, the four-colored FISH probe kit was useful in distinguishing between AM in situ and AJN and may be an ancillary method when pathologists who are not experts of dermatopathology diagnose melanocytic lesions.


Evaluation of computer aided detection of tuberculosis on chest radiography among people with diabetes in Karachi Pakistan.
Pakistan ranks fifth among high tuberculosis (TB) burden countries and also has seventh highest burden for diabetes mellitus (DM). DM increases the risk of developing TB and contributes to adverse TB treatment outcomes hence screening and integrated management for both diseases in high burden countries is suggested. Computer-Aided Detection for TB (CAD4TB) can potentially be used as triage tool in low resource settings to pre-screen individuals for Xpert MTB/RIF testing. The aim of this study was to evaluate the diagnostic accuracy and performance of CAD4TB software in people with diabetes (PWD) enrolled in a TB screening program in Karachi, Pakistan. A total of 694 individuals with a diagnosis of DM (of whom 31.1% were newly diagnosed) were screened with CAD4TB and simultaneously provided sputum for Xpert MTB/RIF testing. Of the 74 (10.7%) participants who had bacteriologically positive (MTB+) results on Xpert testing, 54 (73%) had a CAD4TB score >70; and 155 (25%) participants who tested MTB-negative had scores >70. The area under the receiver operator curve was 0.78 (95% CI: 0.77-0.80). Our study findings indicate that CAD4TB offers good diagnostic accuracy as a triage test for TB screening among PWD using Xpert MTB/RIF as the reference standard.


2D reconstruction of small intestine's interior wall.
Examining and interpreting of a large number of wireless endoscopic images from the gastrointestinal tract is a tiresome task for physicians. A practical solution is to automatically construct a two dimensional representation of the gastrointestinal tract for easy inspection. However, little has been done on wireless endoscopic image stitching, let alone systematic investigation. The proposed new wireless endoscopic image stitching method consists of two main steps to improve the accuracy and efficiency of image registration. First, the keypoints are extracted by Principle Component Analysis and Scale Invariant Feature Transform (PCA-SIFT) algorithm and refined with Maximum Likelihood Estimation SAmple Consensus (MLESAC) outlier removal to find the most reliable keypoints. Second, the optimal transformation parameters obtained from first step are fed to the Normalised Mutual Information (NMI) algorithm as an initial solution. With modified Marquardt-Levenberg search strategy in a multiscale framework, the NMI can find the optimal transformation parameters in the shortest time. The proposed methodology has been tested on two different datasets - one with real wireless endoscopic images and another with images obtained from Micro-Ball (a new wireless cubic endoscopy system with six image sensors). The results have demonstrated the accuracy and robustness of the proposed methodology both visually and quantitatively - registration residual error of 0.93±0.33 pixels on 2500 real endoscopy image pairs and residual error accumulation of 16.59 pixels and without affecting the visual registration quality on stitching 152 images of Micro-Ball.


[Fibrin adhesion of cartilage surfaces].
Basing on encouraging results with the fixation of pure articular cartilage with the fibrin sealant in animal experiments, pure cartilage fragments were replanted in human patients using fibrin sealant. From individual cases biopsies could be taken from macroscopically not well healed areas during arthroscopic examination. The histological results from these cases are presented together with overall clinical experiences. Six weeks after operation one side of the graft showed no union with the subchondral bone and was also separated from the cartilage bed. However, after three and six months, the grafted cartilage had fused with subchondral bone, but pannus-like tissue was covering the surface and filling the cleft at the border to the bed. After one and five years, complete fusion with the subchondral bone and the surrounding cartilage can be demonstrated. There is always covering pannus at the larger observation times. In the majority of the 73 cases treated so far excellent clinical results were obtained, enabling the patients to take up their sporting activities again.


Occupational and demographic factors associated with violence in the emergency department.
Violence against health care workers is a serious and growing problem. The objectives of this cross-sectional study were to (a) describe the frequency of workplace violence (WPV) against emergency department (ED) workers; (b) identify demographic and occupational characteristics related to WPV; and (c) identify demographic and occupational characteristics related to feelings of safety and level of confidence when dealing with WPV. Survey data were collected from 213 workers at 6 hospital EDs. Verbal and physical violence was prevalent in all 6 EDs. There were no statistically significant differences in the frequency of violence for age, job title, patient population, and hospital location. Sexual harassment was the only category of violence affected by gender with females having a greater frequency. Feelings of safety were positively related to the frequency of WPV. Females were significantly more likely to feel unsafe and have less confidence in dealing with WPV. The study findings indicate that all ED workers are at risk of violence, regardless of personal and occupational characteristics. Feelings of safety are related to job satisfaction and turnover. Violence has serious consequences for the employers, employees, and patients. It is recommended that administration, managers, and employees collaborate to develop and implement prevention strategies to reduce and manage the violence.


Increased running speed and previous cramps rather than dehydration or serum sodium changes predict exercise-associated muscle cramping: a prospective cohort study in 210 Ironman triathletes.
Despite the high prevalence of exercise-associated muscle cramping (EAMC) in endurance athletes, the aetiology and risk factors for this condition are not fully understood. The aim of this prospective cohort study was to identify risk factors associated with EAMC in endurance triathletes. 210 triathletes competing in an Ironman triathlon were recruited. Prior to the race, subjects completed a detailed validated questionnaire and blood samples were taken for serum electrolytes. Immediately before the race, pre-race body weight was obtained. Body weight and blood samples for serum electrolyte concentrations were obtained immediately after the race. Clinical data on EAMC experienced during or immediately after the race were also collected. 43 triathletes reported EAMC (cramping group) and were compared with the 166 who did not report EAMC (non-cramping group). There were no significant differences between groups in any pre-race-post-race serum electrolyte concentrations and body weight changes. The development of EAMC was associated with faster predicted race times and faster actual race times, despite similarly matched preparation and performance histories in subjects from both groups. A regression analysis identified faster overall race time (and cycling time) and a history of cramping (in the last 10 races) as the only two independent risk factors for EAMC. The results from this study add to the evidence that dehydration and altered serum electrolyte balance are not causes for EAMC. Rather, endurance runners competing at a fast pace, which suggests that they exercise at a high intensity, are at risk for EAMC.


Uncaria tomentosa.
Uncaria tomentosa (U. tomentosa) or uña de gato, a species of vine of Rubiaceae family, was used from centuries in various medical conditions. Although there are no randomized controlled trials or published human outcome studies, some conditions reportedly improved by U. tomentosa include osteoarthritis, rheumatoid arthritis, prostatitis, viral illnesses and cancer (acting as a non-specific immunomodulantign agent) and it may also have potential as an immunomodulating adaptogen in cellular aging. The understanding of some specific mechanisms of molecular action leads to the demonstration of various anti-inflammatory, immunostimulating and protective effects. These results bring the strong hypothesis that U. tomentosa could be effective in the topical treatment of dermatological manifestation, namely rosacea.


Lower prevalence of Chlamydia pneumoniae DNA compared with Chlamydia trachomatis DNA in synovial tissue of arthritis patients.
To assess the presence of Chlamydia pneumoniae DNA in the joints of patients with reactive arthritis (ReA) and other arthritides. DNA was prepared from synovial tissue (ST) and several synovial fluid (SF) samples from 188 patients with either ReA, undifferentiated oligoarthritis, or other forms of arthritis, and from 24 normal (non-arthritis) individuals. Preparations were screened using polymerase chain reaction (PCR) assays that independently targeted the C. pneumoniae 16S ribosomal RNA and major outer membrane protein genes. Twenty-seven of 212 ST samples (12.7%) were PCR positive for C. pneumoniae DNA; 10 SF samples from these 27 patients were similarly positive. Among the PCR-positive patients, 3 had ReA, 2 had Reiter's syndrome, 7 had undifferentiated oligoarthritis, 4 had undifferentiated monarthritis, 6 had rheumatoid arthritis, and 5 had other forms of arthritis. No samples from normal control individuals were PCR positive. DNA of C pneumoniae is present in synovial specimens from some arthritis patients. The prevalence of this organism in the joints was lower than that of C trachomatis, and synovial presence of the organism was not associated with any distinct clinical syndrome. Widely disseminated nucleic acids such as those of C. pneumoniae might have some role in the pathogenesis of several arthritides, since the organism was not found in the ST from normal control individuals.


Mechanisms of resistance to EGFR targeted therapies.
EGFR is a validated therapeutic target in many human cancers. EGFR targeted therapies are in widespread clinical use in patients with non-small cell lung cancer and other tumor types. Despite the clinical success of EGFR targeted therapy, resistance to treatment is a significant barrier to the optimized use of EGFR inhibitors to cure patients with lung and other cancers. Here, we review established and emerging mechanisms of resistance to EGFR targeted therapy and highlight strategies that could overcome treatment resistance and therefore enhance clinical outcomes.


Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine.
Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants.


Impact of nutrition education on university students' fat consumption.
University science students who have taken a nutrition course possess greater knowledge of fats than do those who have not; whether students apply this knowledge to their diet is unknown. We measured and compared science students' total and saturated fat intake in the first and fourth years, and evaluated whether taking a nutrition course influenced fat consumption. A sample of 269 first- and fourth-year science students at a small undergraduate university completed a survey with both demographic questions and a semi-quantitative food frequency questionnaire about fats in the diet. Data were analyzed using chi-square tests and independent-sample t-tests. Fourth-year science students consumed fewer grams of total and saturated fat than did first-year science students (p<0.001). Science students who had taken a nutrition course consumed fewer grams of total and saturated fat than did those who had not (p<0.001). Taking a nutrition course may decrease first-year students' fat consumption, which may improve diet quality and decrease the risk of chronic disease related to fat consumption.


Central venous catheter placement: extending the role of the nurse.
To improve the quality of the percutaneous tunnelled central venous catheter placement service for patients being treated for malignant disease. A clinical nurse specialist was specially trained to insert percutaneous tunnelled central venous catheters according to predetermined guidelines. Catheters were inserted under local anaesthetic in the outpatient department or the ward. The quality of the service was analysed and compared with the pre-existing service provided by junior medical staff. Two hundred adult patients with malignant disease seen between January 1995 and January 1996 at the Christie Hospital Trust. Success of the procedure, insertion-related infection rates and waiting times compared to historical controls. The rate of failed insertions fell from 20% to 3% with a concomitant reduction in surgical referrals; for 97% of patients waiting time was reduced to less than one working day compared with 80% previously. Line-related infection rates in the first thirty days following insertion fell from 10 episodes per 72 lines inserted to two episodes per 200 lines inserted. Training and using a clinical nurse specialist has improved the quality of service and gives junior doctors more opportunity to become competent in the technique of central venous catheter placement. The introduction of guidelines has encouraged a standard approach that facilitates audit.


A Mechatronic Platform for Computer Aided Detection of Nodules in Anatomopathological Analyses via Stiffness and Ultrasound Measurements.
This study presents a platform for ex-vivo detection of cancer nodules, addressing automation of medical diagnoses in surgery and associated histological analyses. The proposed approach takes advantage of the property of cancer to alter the mechanical and acoustical properties of tissues, because of changes in stiffness and density. A force sensor and an ultrasound probe were combined to detect such alterations during force-regulated indentations. To explore the specimens, regardless of their orientation and shape, a scanned area of the test sample was defined using shape recognition applying optical background subtraction to the images captured by a camera. The motorized platform was validated using seven phantom tissues, simulating the mechanical and acoustical properties of ex-vivo diseased tissues, including stiffer nodules that can be encountered in pathological conditions during histological analyses. Results demonstrated the platform's ability to automatically explore and identify the inclusions in the phantom. Overall, the system was able to correctly identify up to 90.3% of the inclusions by means of stiffness in combination with ultrasound measurements, paving pathways towards robotic palpation during intraoperative examinations.


Idiopathic Intracranial Hypertension After Surgical Treatment of Cushing Disease: Case Report and Review of Management Strategies.
Idiopathic intracranial hypertension (IIH) in patients with Cushing disease (CD), after treatment, is rarely described, in adults. The cause is believed to be multifactorial, potentially related to a relative decrease in cortisol after surgical resection or medical treatment of a corticotroph pituitary adenoma. We investigate our center's CD database (140 surgically and 60 medically [primary or adjunct] treated patients) for cases of IIH, describe our center's experience with symptomatic IIH, and review treatment strategies in adults with CD after transsphenoidal resection. We present the case of a 22-year-old woman who presented with worsening headache, nausea, vomiting, blurry vision, diplopia, visual loss, and facial numbness 14 weeks after surgical resection of adrenocorticotropic hormone-positive pituitary adenoma. Her CD had been in remission since surgery, with subsequent adrenal insufficiency (AI), which was initially treated with supraphysiologic glucocorticoid replacement, tapered down to physiologic doses at the time the IIH symptoms developed. Symptomatic IIH is rare in adult patients but can be severe and result in permanent vision loss. A high index of suspicion should be maintained and a fundus examination is necessary to exclude papilledema, whenever there are suggestive symptoms that initially may overlap with AI. It is possible that some cases of mild IIH are misdiagnosed as GC withdrawal or AI; however, further studies are needed. Treatment consists of reinitiation of higher steroid doses together with acetazolamide with or without cerebrospinal fluid diversion and the priority is to preserve vision and reverse any visual loss.


[Approach to open treatment of osteochondral lesions of the talus].
Arthroscopic techniques still represent the treatment of choice in osteochondral lesions of the talus (OLT). Open techniques may be used as an alternative or may be complementary to arthroscopic treatments. They are especially indicated in cases of large osteochondral lesions, difficult localisations and in cases of recurrent interventions. In addition to the type of treatment for the lesion itself, the choice of an ideal surgical approach is of paramount importance. Indications, operative technique, possible complications and rehabilitation are described in detail for each approach. Anterolateral, anteromedial, posterolateral and posteromedial soft-tissue approaches as well as medial and lateral malleolar osteotomies are discussed. If a distraction is not desired with arthroscopy, posteromedial and posterolateral soft-tissue approaches offer a good alternative for the treatment of posterior OLT. Osteotomy of the (medial) malleolus offers good visualisation of the medial talar dome. With the introduction of new techniques of osteochondral transplantations, the use of this approach is becoming more popular. However, it is an invasive technique and the risk of secondary osteoarthritis after malleolar osteotomy still needs to be determined.


Opsonophagocytosis of Campylobacter pylori.
The opsonic activity of human serum from various sources against Campylobacter pylori was compared. All sera, whether from control subjects with no symptoms of gastritis or peptic ulceration, or from symptomatic patients from whom C. pylori had or had not been isolated, opsonised C. pylori equally well. Opsonisation depended on the alternative pathway of complement activation but not on antibody. These findings suggest that antibody plays no role in protection against C. pylori and that the presence of antibody in patients' sera is mainly of diagnostic value.


Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1.
Murine IgM monoclonal antibody STRO-1 identifies a cell surface antigen expressed by stromal elements in human bone marrow (BM). STRO-1 binds to approximately 10% of BM mononuclear cells, greater than 95% of which are nucleated erythroid precursors, but does not react with committed progenitor cells (colony-forming unit granulocyte-macrophage [CFU-GM], erythroid bursts [BFU-E], and mixed colonies [CFU-Mix]). Fibroblast colony-forming cells (CFU-F) are present exclusively in the STRO-1+ population. Dual-color cell sorting using STRO-1 in combination with antibody to glycophorin A yields a population approximately 100-fold enriched in CFU-F in the STRO-1+/glycophorin A- population. When plated under long-term BM culture (LTBMC) conditions, STRO-1+ cells generate adherent cell layers containing multiple stromal cell types, including adipocytes, smooth muscle cells, and fibroblastic elements. STRO-1+ cells isolated from LTBMC at later times retain the capacity to generate adherent layers with a cellular composition identical to that of the parent cultures. The STRO-1-selected adherent layers are able to support the generation of clonogenic cells and mature hematopoietic cells from a population of CD34+ cells highly enriched in so-called long-term culture-initiating cells. We conclude that antibody STRO-1 binds to BM stromal elements with the capacity to transfer the hematopoietic microenvironment in vitro.


Inclusive education: A transformation and human rights agenda under spotlight in South Africa.
This study investigated the progress made in the implementation of inclusive education as a transformation and human rights tool since its inception in 2001. The study was conducted upon realising that most people underestimate the transformation and human rights value that inclusive education strives to maintain. The total number of participants interviewed was 84. Data was collected using semi-structured interview schedules for the teachers and community members, whereafter it was presented in thematic sections and qualitatively examined for meaning. The results showed that participants comprising teachers and community members do not know or understand the transformational and human rights value of inclusive education. The participants seemed to be equally aware of inclusive education, but they rated its success and value differently. The participants concurred that the philosophy of inclusive education was noble, but they differed regarding the extent to which it had transformed, added value or played an advocacy role in the lives of learners and the community at large over the years.


Ki-4(scFv)-ETA', a new recombinant anti-CD30 immunotoxin with highly specific cytotoxic activity against disseminated Hodgkin tumors in SCID mice.
The human lymphocyte activation marker CD30 is highly overexpressed on Hodgkin/Reed-Sternberg cells and represents an ideal target for selective immunotherapy. We used the murine anti-CD30 hybridoma Ki-4 to construct a new recombinant immunotoxin (rIT) for possible clinical use in patients with CD30(+) lymphoma. Hybridoma V genes were polymerase chain reaction-amplified, assembled, cloned, and expressed as a mini-library for display on filamentous phage. Functional Ki-4 scFv obtained by selection of binding phage on the CD30-expressing Hodgkin lymphoma cell line L540cy was inserted into the bacterial expression vector pBM1.1 and fused to a deletion mutant of Pseudomonas exotoxin A (ETA'). Periplasmically expressed Ki-4(scFv)-ETA' demonstrated specific activity against a variety of CD30(+) lymphoma cells as assessed by different in vitro assays. To evaluate in vivo antitumor activity, severe combined immunodeficient mice challenged with human lymphoma cell lines were treated with the immunotoxin. The blood distribution time t(1/2)alpha of Ki-4(scFv)-ETA' was 19 minutes, and its serum elimination time t(1/2)alpha was 193 minutes. A single intravenous injection of 40 microg rIT 1 day after tumor inoculation rendered 90% of the mice tumor free, extending the mean survival time to more than 200 days compared with 38.1 days in the phosphate-buffered saline control group (P <.001). This new rIT is a promising candidate for further clinical evaluation in patients with Hodgkin lymphoma or other CD30(+) malignancies. (Blood. 2000;95:3909-3914)


Medulloblastoma in children: a 32-year experience from a single institution.
We retrospectively evaluated 203 patients newly diagnosed with medulloblastoma between 1975 and 2006. All patients underwent surgical resection and after surgery were treated with a combination of radiotherapy and chemotherapy. CCNU-based protocols were used in the early years, with CDDP+VP16 being used more recently. Radiotherapy was used in patients older than three years of age according to the protocols. One hundred fifteen patients had total surgical resection, 78 had subtotal resection, and 4 patients had only a biopsy. Every patient received chemotherapy: 124 with the CCNU-based protocol, 75 with CDDP+VP16, and 4 with other protocols. Overall (OS) and event free-survival (EFS) rates were 43.1 and 41.9% in the whole group, with a median follow-up time of 8 years. OS rates for patients with and without spinal seeding were 30 and 63.1% (P = 0.0002). OS rates for males and females were 36.2 and 54.7% (P = 0.03). OS rates for patients receiving the CCNU and CDDP+VP16 protocols were 41.1 and 45%.


Transient activation of superior prefrontal cortex during inhibition of cognitive set.
The prefrontal cortex implements a set-shifting function that includes inhibition of a previously acquired cognitive set. The impairment of the inhibitory function results in perseverative behavior that forms one characteristic feature of frontal lobe dysfunction. Previous neuroimaging studies have revealed inhibitory mechanisms in the inferior prefrontal cortex. The present functional magnetic resonance imaging study devised "dual-match" stimuli in a set-shifting paradigm that allowed us to temporally isolate the inhibitory processes recruited during exposure to a previously acquired set. Transient activation time-locked to the isolated inhibition was revealed in the left middle frontal gyrus near the superior frontal sulcus. In a control experiment conducted after subjects had been informed and made aware of the exposure, however, the superior prefrontal activation disappeared, and prominent activation was revealed in a set of brain regions that included the left posterior inferior frontal sulcus. These double dissociation results indicate inhibitory mechanisms in the superior prefrontal cortex, alternative to the inferior prefrontal ones, that are activated depending on the subjects' strategy for inhibition of cognitive set.


Home administration of maintenance pemetrexed for patients with advanced non-squamous non-small cell lung cancer: rationale, practicalities and phase II feasibility study design.
Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting. Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0-1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m(2) every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients' quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011. This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home-based chemotherapy. The study design requires unusual methodology and specific logistics to address outcomes relevant to the home-delivery approach. This article presents a study design that offers a novel and reproducible model for home-based chemotherapy, and provides an up-to-date overview of the literature regarding this type of treatment. ClinicalTrials.gov: NCT01473563.


[Regulation of glucose-6-phosphate dehydrogenase activity in rat liver by insulin and hydrocortisone].
Activity of glucose-6-phosphate dehydrogenase (G6PD), its isoenzyme spectrum and kinetic properties of the partially purified enzyme were studied in liver tissue of intact rats as well as in animals treated with insulin and hydrocortisone. The data obtained suggest that the activation and inhibition of G6PD by insulin and hydrocortisone, respectively, are due most likely not to alterations in conformation of the enzymatic molecules, but to the opposite influence of these hormones on the content of the main fraction of the isoenzyme spectrum of G6PD, which accounts for 78-90% of its total activity.


Assessment of patient perception of glaucomatous visual field loss and its association with disease severity using Amsler grid.
To investigate patients' perception of glaucomatous VF loss and its association with glaucoma severity using the Amsler grid test. In this prospective cross-sectional study, glaucoma patients with abnormal 10-2 Humphrey Swedish Interactive Threshold Algorithm-standard VF tests were enrolled consecutively. All patients underwent a black-on-white Amsler grid test for each eligible eye. They were asked to outline any perceived scotomas (areas with abnormal grid lines) on the grid and then describe verbally their perception of the scotomas. Examiners asked patients to clarify their descriptions. All descriptions used by patients were recorded in their own words, which were then sorted into descriptor categories according to similar themes. The number of descriptor categories was counted for each eye. 10-2 VF mean deviation (MD) was compared among eyes that reported different number of descriptor categories. The mean 10-2 VF MD values were compared among different descriptor categories. Fifty glaucoma patients (88 eyes) were included. Patients used a total of 44 different descriptors for their scotomas. Patients' descriptors were classified into categories that incorporated similar themes, resulting in 4 overarching descriptor categories: Missing/White, Blurry/Gray, Black, and Not Aware. Fifty-two eyes reported one descriptor category and 19 eyes reported two descriptor categories (mean number of descriptor categories = 1.27±0.45). Eyes that reported two descriptor categories had worse VF MD than those that reported one (-17.86±10.31 dB vs. -12.08±7.53 dB; p = 0.012). When eyes were organized according to its combination of descriptor categories, each eye naturally sorted into one of the following 5 groups, in frequency order: Missing/White (27 eyes; 31%), Blurry/Gray (21 eyes; 24%), combined Missing/White and Blurry/Gray (19 eyes; 21%), Not Aware (17 eyes; 19%), and Black (4 eyes; 5%). The mean 10-2 VF MD severity order was Black (-21.18±10.59 dB), combined Missing/White and Blurry/Gray (-17.86±10.31 dB), Missing/White (-11.92±6.76 dB), Blurry/Gray (-10.55±7.03 dB), and Not Aware (-3.91±4.05 dB) (p<0.001). Paracentral vision loss in glaucoma is perceived by patients. As the perception of scotomas and the variety of terms to describe scotomas are related to glaucoma severity, clinicians should pay attention to patients' subjective descriptions of their glaucomatous VF loss. The historical notion that glaucoma patients lose their peripheral vision first and eventually look through a black tunnel needs to be updated to reflect the true perception of glaucoma.


Optimizing cell arrays for accurate functional genomics.
Cellular responses emerge from a complex network of dynamic biochemical reactions. In order to investigate them is necessary to develop methods that allow perturbing a high number of gene products in a flexible and fast way. Cell arrays (CA) enable such experiments on microscope slides via reverse transfection of cellular colonies growing on spotted genetic material. In contrast to multi-well plates, CA are susceptible to contamination among neighboring spots hindering accurate quantification in cell-based screening projects. Here we have developed a quality control protocol for quantifying and minimizing contamination in CA. We imaged checkered CA that express two distinct fluorescent proteins and segmented images into single cells to quantify the transfection efficiency and interspot contamination. Compared with standard procedures, we measured a 3-fold reduction of contaminants when arrays containing HeLa cells were washed shortly after cell seeding. We proved that nucleic acid uptake during cell seeding rather than migration among neighboring spots was the major source of contamination. Arrays of MCF7 cells developed without the washing step showed 7-fold lower percentage of contaminant cells, demonstrating that contamination is dependent on specific cell properties. Previously published methodological works have focused on achieving high transfection rate in densely packed CA. Here, we focused in an equally important parameter: The interspot contamination. The presented quality control is essential for estimating the rate of contamination, a major source of false positives and negatives in current microscopy based functional genomics screenings. We have demonstrated that a washing step after seeding enhances CA quality for HeLA but is not necessary for MCF7. The described method provides a way to find optimal seeding protocols for cell lines intended to be used for the first time in CA.


Vibrio parahaemolyticus serotypes in Calcutta, India.
A study of V. parahaemolyticus strains isolated from different sources in Calcutta showed that the serotypes associated with human gastroenteritis do not frequently coincide with those of marine and non-marine isolates. Some atypical, complex, and new serotypes are reported.


The influence of context on pain practices in the NICU: perceptions of health care professionals.
In this qualitative descriptive study, we explored health care professionals' perceptions of the influence of context (i.e., organizational culture, structure, resources, capabilities/competencies, and politics) on evidence-based pain practices. A total of 16 focus groups with 147 health care professionals were conducted in three neonatal intensive care units (NICUs) in central and eastern Canada. Three overarching themes emerged from the data, which captured influences on optimal pain practices in the NICU, including (a) a culture of collaboration and support for evidence-based practice, (b) threats to autonomous decision making, and (c) complexities in care delivery. These results were consistent with theoretical conceptualizations of how context influences practice, as well as recent empirical research findings. This study supports the importance of context in shaping evidence-based practices by health care professionals in the management of pain in the NICU.


[Irreversible generalized pulmonary emphysema resulting from destructive bronchitis and bronchiolitis following adenovirus infection].
Report of an 1 1/2 year old boy with the typical features of Williams-Campbell syndrome: chest deformity (thorax piriformis), pulmonary hyperinflation, ballooning of the segmental and subsegmental bronchi during inspiration and collapse with expiration. Atelectasis of the left upper lobe after bronchiolitis obliterans. The literature reports 23 patients with Williams-Campbell syndrome. There is every reason to believe that the extensive bronchiectasis are not due primarily to developmental deficiency of the bronchial cartilage, as the most authors assume, but result from destructive changes after inflammation. In our case very likely an adenovirus infection was the cause. The clinical features of the syndrome look like a severe therapy resistant asthma bronchiale.


Rapid Increase in Carriage Rates of Enterobacteriaceae Producing Extended-Spectrum β-Lactamases in Healthy Preschool Children, Sweden.
By collecting and analyzing diapers, we identified a >6-fold increase in carriage of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae for healthy preschool children in Sweden (p<0.0001). For 6 of the 50 participating preschools, the carriage rate was >40%. We analyzed samples from 334 children and found 56 containing >1 ESBL producer. The prevalence in the study population increased from 2.6% in 2010 to 16.8% in 2016 (p<0.0001), and for 6 of the 50 participating preschools, the carriage rate was >40%. Furthermore, 58% of the ESBL producers were multidrug resistant, and transmission of ESBL-producing and non-ESBL-producing strains was observed at several of the preschools. Toddlers appear to be major carriers of ESBL producers in Sweden.


Photoswitchable hydrogel surface topographies by polymerisation-induced diffusion.
Herein, we describe the preparation of patterned photoresponsive hydrogels by using a facile method. This polymer-network hydrogel coating consists of N-isopropylacrylamide (NIPAAM), cross-linking agent tripropylene glycol diacrylate (TPGDA), and a new photochromic spiropyran monoacrylate. In a pre-study, a linear NIPAAM copolymer (without TPGDA) that contained the spiropyran dye was synthesised, which showed relatively fast photoswitching behaviour. Subsequently, the photopolymerisation of a similar monomer mixture that included TPGDA afforded freestanding hydrogel polymer networks. The light-induced isomerisation of protonated merocyanine into neutral spiropyran under slightly acidic conditions resulted in macroscopic changes in the hydrophilicity of the entire polymer film, that is, shrinkage of the hydrogel. The degree of shrinkage could be controlled by changing the chemical composition of the acrylate mixture. After these pre-studies, a hydrogel film with spatially modulated cross-link density was fabricated through polymerisation-induced diffusion, by using a patterned photomask. The resulting smooth patterned hydrogel coating swelled in slightly acidic media and the swelling was higher in the regions with lower cross-linking densities, thus yielding a corrugated surface. Upon exposure to visible light, the surface topography flattened again, thus showing that a hydrogel coating could be created, the topography of which could be controlled by light irradiation.


Effects of carbohydrate meals of varying consistency on gastric myoelectrical activity.
There is at present no agreement on the type of test meal to be used when performing EGG. To our knowledge the response of the stomach to high carbohydrate isocaloric meals of different consistencies has not been formally assessed. To study 1) the effects of high carbohydrate meals of varying consistency on EGG activity; and 2) the effects of increasing the calorie content of a meal without changing its consistency and composition on the postprandial EGG. Eighteen healthy volunteers, six males (age: 21-35 year, weight: 45-60 kg) and 12 females in the follicular phase of the menstrual cycle (age: 24-30 years, weight: 45-55 kg). Following an overnight fast subjects were given three high carbohydrate, low fat, isocaloric meals (165-170 kcal) of different consistencies (solid, semisolid, liquid), on three separate days in a random order. The liquid and semisolid meals were equal in volume (200 ml) while the volume of the solid meal was smaller. One hour EGG recordings were done in the fasting and fed states in each subject. As a second step, ten of the above volunteers (taken randomly) were given the solid test meal on a separate day after increasing the calorie content of the meal to 350 kcal. The power of the EGG at the dominant frequency significantly increased after solid (175 kcal meal: fasting 49 +/- 12 dB vs. fed 57 +/- 13 dB; p < 0.05, 375 kcal meal: fasting 48.5 +/- 12.9 dB vs fed 58.1 +/- 11.7 dB) and semisolid (fasting 50 +/- 12 dB vs. fed 55 +/- 13; P < 0.05). The increase in power was not significantly different when fed with solids and semisolids. There was no statistically significant change in EGG power during the first 15 or 60 minutes after the liquid meal. Feeding showed no significant effect on the dominant frequency and the percentage of 2-4 cpm waves of the EGG with any of the three types of test meals. Solid and semisolid meals high in carbohydrate and low in fat are capable of inducing a significant increase in the EGG power in normal subjects. Isocaloric solid and semisolid meals have similar effects on gastric slow wave activity. EGG appears unaffected by the liquid meal. Therefore only an increase in the power of the EGG can be regarded as normal if a high carbohydrate solid or a semisolid meal is given as the test meal when performing an EGG.


Ectomycorrhizal lifestyle in fungi: global diversity, distribution, and evolution of phylogenetic lineages.
The ectomycorrhizal (EcM) symbiosis involves a large number of plant and fungal taxa worldwide. During studies on EcM diversity, numerous misidentifications, and contradictory reports on EcM status have been published. This review aims to: (1) critically assess the current knowledge of the fungi involved in the EcM by integrating data from axenic synthesis trials, anatomical, molecular, and isotope studies; (2) group these taxa into monophyletic lineages based on molecular sequence data and published phylogenies; (3) investigate the trophic status of sister taxa to EcM lineages; (4) highlight other potentially EcM taxa that lack both information on EcM status and DNA sequence data; (5) recover the main distribution patterns of the EcM fungal lineages in the world. Based on critically examining original reports, EcM lifestyle is proven in 162 fungal genera that are supplemented by two genera based on isotopic evidence and 52 genera based on phylogenetic data. Additionally, 33 genera are highlighted as potentially EcM based on habitat, although their EcM records and DNA sequence data are lacking. Molecular phylogenetic and identification studies suggest that EcM symbiosis has arisen independently and persisted at least 66 times in fungi, in the Basidiomycota, Ascomycota, and Zygomycota. The orders Pezizales, Agaricales, Helotiales, Boletales, and Cantharellales include the largest number of EcM fungal lineages. Regular updates of the EcM lineages and genera therein can be found at the UNITE homepage http://unite.ut.ee/EcM_lineages . The vast majority of EcM fungi evolved from humus and wood saprotrophic ancestors without any obvious reversals. Herbarium records from 11 major biogeographic regions revealed three main patterns in distribution of EcM lineages: (1) Austral; (2) Panglobal; (3) Holarctic (with or without some reports from the Austral or tropical realms). The holarctic regions host the largest number of EcM lineages; none are restricted to a tropical distribution with Dipterocarpaceae and Caesalpiniaceae hosts. We caution that EcM-dominated habitats and hosts in South America, Southeast Asia, Africa, and Australia remain undersampled relative to the north temperate regions. In conclusion, EcM fungi are phylogenetically highly diverse, and molecular surveys particularly in tropical and south temperate habitats are likely to supplement to the present figures. Due to great risk of contamination, future reports on EcM status of previously unstudied taxa should integrate molecular identification tools with axenic synthesis experiments, detailed morphological descriptions, and/or stable isotope investigations. We believe that the introduced lineage concept facilitates design of biogeographical studies and improves our understanding about phylogenetic structure of EcM fungal communities.


Ginkgo biloba extract protects human melanocytes from H2 O2 -induced oxidative stress by activating Nrf2.
Vitiligo is a common skin depigmenting disorder characterized by the loss of functional melanocytes. Its pathogenesis is complicated and oxidative stress plays a critical role in the development of vitiligo. Thus, antioxidant therapy is a promising therapeutic strategy to prevent or even reverse the progression of depigmentation. Ginkgo biloba extract EGb761 has been confirmed to have protective effects on neurons against oxidative stress. Notably, several clinical trials have shown that patients with stable vitiligo achieved repigmentation after taking EGb761. However, the exact mechanism underlying the protective effects of EGb761 on melanocytes against oxidative stress has not been fully elucidated. In the present study, we found that EGb761 effectively protected melanocytes against oxidative stress-induced apoptosis and alleviated the excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation by enhancing the activity of antioxidative enzymes. Furthermore, the antioxidative effect of EGb761 was achieved by activating Nrf2 and its downstream antioxidative genes. In addition, interfering Nrf2 with siRNA abolished the protective effects of EGb761 on melanocytes against oxidative damage. In conclusion, our study proves that EGb761 could protect melanocytes from H2 O2 -induced oxidative stress by activating Nrf2. Therefore, EGb761 is supposed to be a potential therapeutic agent for vitiligo.


Fetal phenotype of Rubinstein-Taybi syndrome caused by CREBBP mutations.
Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.


Jacquet erosive diaper dermatitis after surgery for Hirschsprung disease.
We report a case of Jacquet erosive diaper dermatitis that occurred as a consequence of severe diarrhea following extensive colectomy and coloanal anastomosis for Hirschsprung disease. Perianal pseudoverrucous papules and nodules and granuloma gluteal infantum have also been seen following this kind of surgery. We propose that these three entities represent variants in a spectrum of skin lesions associated with severe diaper dermatitis.


Amino acid uptake by liver of genetically obese Zucker rats.
Alanine and glutamine uptake by the liver of 50-52-day-old genetically obese Zucker rats and their lean littermates has been studied. The net uptake in vivo of L-alanine is 2-fold higher in the obese animals. No significant change in L-glutamine net balance was found. We also studied the Na(+)-dependent uptake of L-alanine and L-glutamine into plasma-membrane vesicles isolated from either obese- or lean-rat livers. Vmax. values of both L-alanine and L-glutamine transport were 2-fold higher in those preparations from obese rats. No change in Km was observed. As suggested by inhibition studies, this seemed to be mediated by an enhancement of the activities of systems A, ASC and N. We conclude that the liver of the obese Zucker rat is extremely efficient in taking up neutral amino acids from the afferent blood, which results in an enhanced net uptake of L-alanine in vivo. The changes in transport activities at the plasma-membrane level might contribute to increase amino acid disposal by liver, probably for lipogenic purposes, as recently reported by Terrettaz & Jeanrenaud [Biochem. J. (1990) 270, 803-807].


The mechanism of tautomerisation and geometric isomerisation in thioformic acid and its water complexes: exploring chemical pathways for water migration.
A systematic and automated search for chemical pathways of isomerisation between geometric and tautomeric forms of gas-phase thioformic acid (TFA) and its water complexes is performed using a global reaction route mapping (GRRM) method, and an uncovered pathway for cis-trans isomerisation in the thiol form of TFA has been explored through computations performed at CCSD(T)/6-311++G(2d,2p)//B3LYP/6-311++G(2d,2p) level of the coupled cluster and density functional theories. To explore the routes for water migration, a detailed analysis of complexes of TFA with a single-water molecule is presented. Notably, during the isomerisation process in TFA, a positive catalytic effect of water was observed that can arise either by the stabilization of the reactant and/or of the transition state through extensive hydrogen bonding. Interesting behavior of isomeric forms of TFA along the pathways analysed is revealed through the Gibbs free-energy change and its temperature-dependence. The cis form of TFA(thiol) in the complexes of TFA with a single-water molecule is found to be thermodynamically equally feasible as the trans form which though is known to be the most dominating among the isomeric forms of TFA. Besides these, various complexes of TFA with two-water molecules have also been explored to study the hydrogen-bonding interaction through natural bond-orbital (NBO) analysis. The complexes of TFA with two-water molecules have also been characterized using spectral features including vibrational frequency analysis, and the effect of complexation has been observed by noting frequency shift.


Design of the oxygen and substrate pathways. I. Model and strategy to test symmorphosis in a network structure.
This first paper in a series develops a model of structure-function relationships for the oxygen and substrate pathways of oxidative metabolism in working muscle. This will be used in the subsequent experimental papers in asking how biological structures are designed if they serve more than one function and whether one function can be served by more than one structural pathway. We have used the concept of symmorphosis to address this question; in its original form, it postulates that no more structure is built and maintained at each step in a pathway than is required to meet functional demands. The concept of symmorphosis was developed to deal with the problem of modelling the pathway for oxygen from the environment to mitochondria, essentially a single series of interconnected transfer steps. In the present context, the application of this concept is more complex. Both oxygen and substrates are transported directly from the blood to the mitochondria in what appear to be shared steps. The flows along this direct pathway are adjusted during muscular work. However, substrates have an additional option. They can be stored intracellularly as lipid droplets or glycogen, and thus their supply to mitochondria can occur in two steps separated in time: from capillaries to stores during rest, and from stores to mitochondria during work. The integrated pathways have a network structure and the functional flows are partitioned to different branches of the network, and we must ask whether the partitioning of fluxes is related to design constraints. The principle of symmorphosis predicts that the best use is made of the available options and that the design of each step is matched to the specific functional demand in view of a balance to be achieved over the entire network. This will be tested in subsequent papers by determining maximal flows for oxygen, carbohydrates and lipids through each of the transport steps and their respective structural capacities, comparing dogs and goats, animals of the same size whose maximal oxidative capacities differ by more than twofold. Finally, we will ask whether the principle of symmorphosis can be extended to apply to network systems.


[The antiheparin thrombocyte factor 4 and its interaction with heparin].
A rat platelet factor has a high antiheparin activity. It also decreases nonenzymatic fibrinolytic activity of normal rat plasma and antithrombin III-heparin complex. The platelet factor 4 formed inactive complexes with heparin in molar ratios of 1:1 and 2:1. Intravenous injection of the platelet factor 4 before injection of albino rats with tissue thromboplastin prevented the reaction of anticoagulation system inactivated the synthesis of endogenous thrombin. This effect is accompanied by high hypercoagulation and depression of nonenzymatic fibrinolysis in blood.


Simultaneous tracing of carbon and nitrogen isotopes in human cells.
Stable isotope tracing is a powerful method for interrogating metabolic enzyme activities across the metabolic network of living cells. However, most studies of mammalian cells have used (13)C-labeled tracers only and focused on reactions in central carbon metabolism. Cellular metabolism, however, involves other biologically important elements, including nitrogen, hydrogen, oxygen, phosphate and sulfur. Tracing stable isotopes of such elements may help shed light on poorly understood metabolic pathways. Here, we demonstrate the use of high-resolution mass spectrometry to simultaneously trace carbon and nitrogen metabolism in human cells cultured with (13)C- and (15)N-labeled glucose and glutamine. To facilitate interpretation of the complex isotopomer data generated, we extend current methods for metabolic flux analysis to handle multivariate mass isotopomer distributions (MMIDs). We find that observed MMIDs are broadly consistent with known biochemical pathways. Whereas measured (13)C MIDs were informative for central carbon metabolism, (15)N isotopes provided evidence for nitrogen-carrying reactions in amino acid and nucleotide metabolism. This computational and experimental methodology expands the scope of metabolic flux analysis beyond carbon metabolism, and may prove important to understanding metabolic phenotypes in health and disease.


Antidepressants and antiepileptic drugs for chronic non-cancer pain.
The development of newer classes of antidepressants and second-generation antiepileptic drugs has created unprecedented opportunities for the treatment of chronic pain. These drugs modulate pain transmission by interacting with specific neurotransmitters and ion channels. The actions of antidepressants and antiepileptic drugs differ in neuropathic and non-neuropathic pain, and agents within each medication class have varying degrees of efficacy. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) and certain novel antidepressants (i.e., bupropion, venlafaxine, duloxetine) are effective in the treatment of neuropathic pain. The analgesic effect of these drugs is independent of their antidepressant effect and appears strongest in agents with mixed-receptor or predominantly noradrenergic activity, rather than serotoninergic activity. First-generation antiepileptic drugs (i.e., carbamazepine, phenytoin) and second-generation antiepileptic drugs (e.g., gabapentin, pregabalin) are effective in the treatment of neuropathic pain. The efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain is comparable; tolerability also is comparable, but safety and side effect profiles differ. Tricyclic antidepressants are the most cost-effective agents, but second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients. Tricyclic antidepressants have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain. Recent evidence suggests that duloxetine and pregabalin have modest efficacy in patients with fibromyalgia.


Nutrition and exercise in Pompe disease.
The current standard of care for Pompe disease (PD) is the administration of enzyme replacement therapy (ERT). Exercise and nutrition are often considered as complementary strategies rather than "treatments" per se. Nutritional assessment is important in patients with locomotor disability because the relative hypodynamia limits energy expenditure and thus the total amount of energy must be reduced to avoid obesity. A lower total energy intake often leads to lower protein and micronutrient intake. Consequently, ensuring that Pompe patients are tested for and replaced for deficiencies (protein, vitamin D, vitamin B12, etc.) is an important aspect of care. Furthermore, given the role of autophagy in the pathophysiology of PD and the fact that fasting induces autophagy, it is important that strategies such as nutritional timing and amino acid intake (L-arginine, L-leucine) be evaluated as therapies. Exercise interventions have been shown to improve six-minute walk testing distance by more than what was seen in the seminal ERT study in late-onset PD. Exercise therapy can also activate autophagy, and this is likely another component of its efficacy. The current review will evaluate the theoretical and practical aspects of nutrition and exercise as therapies for patients with PD.


Development and Validation of the Self-Compassion Scale for Youth.
We present a series of studies on the development and validation of the Self-Compassion Scale-Youth version (SCS-Y), which is intended for use with early adolescents in middle school. Study 1 (N = 279, Mage = 12.17) describes the selection of 17 items out of a pool of 36 potential items, with three items each representing the subscales of self-kindness, mindfulness, common humanity, self-judgment, isolation, and two items representing over-identification. Using state-of-the-art psychometric analyses ideal for examining multidimensional constructs like self-compassion-bifactor exploratory structural equation modeling (bifactor-ESEM)-findings supported the use of a general self-compassion score and six subscale scores. Study 2 cross-validated the factor structure of the SCS-Y with a second sample of youths (N = 402, Mage = 12.43). Study 3 found support for the test-retest reliability of the SCS-Y (N = 102, Mage = 12.52). Study 4 (N = 212, Mage = 12.18) established construct validity for the SCS-Y by demonstrating that SCS-Y scores were significantly associated with mindfulness, happiness, life-satisfaction, depression, resilience, and achievement goal orientation in expected directions. Overall, findings suggest that the SCS-Y is a reliable and valid measure of self-compassion for use with youths.


Maximizing teaching on the wards: review and application of the One-Minute Preceptor and SNAPPS models.
Hospitalist educators face a number of challenges in teaching clinical reasoning to residents and medical students. Helping to develop trainees' clinical acumen is an essential and highly nuanced process, yet complex patients, documentation requirements, and productivity goals compete with teaching time. Workplace-based assessment is particularly important for residents with the institution of the developmental milestones for meeting Accreditation Council for Graduate Medical Education competencies. Two frameworks for facilitating the clinical reasoning discussion-the One-Minute Preceptor preceptor and SNAPPS-have been well studied in the outpatient setting with positive results. Both models show promise for use in the inpatient teaching environment with little modification. This narrative review compares and contrasts these 2 teaching frameworks and discusses their application to the inpatient teaching environment. These models can provide opportunities for hospitalist educators to better assess trainees, integrate regular feedback, and encourage self-directed learning. These teaching frameworks can also allow hospitalists to provide more focused education to trainees without taking additional valuable time.


Eight-year follow up result of the OTOASOR trial: The Optimal Treatment Of the Axilla - Surgery Or Radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: A randomized, single centre, phase III, non-inferiority trial.
The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy) trial compares completion of axillary lymph node dissection (cALND) to regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in stage I-II breast cancer. Patients with primary invasive breast cancer (cN0 and cT ≤ 3 cm) were randomized before surgery for cALND (standard treatment) or RNI (investigational treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm levels by hematoxylin-eosin staining. Investigational treatment arm patients received 50 Gy RNI instead of cALND. Adjuvant treatment and follow up were performed according to the actual guidelines. Between August 2002 and June 2009, 1054 patients were randomized for cALND and 1052 patients for RNI. SN was evaluated in 2073 patients and was positive in 526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm), and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary surgery has additional positive nodes. The two arms were well balanced according to the majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary endpoints were overall survival (OS) and disease-free survival (DFS). Mean follow-up was 97 months (Q1-Q3: 80-120). Axillary recurrence was 2.0% in cALND arm vs. 1.7% in RNI arm (p = 1.00). OS at 8 years was 77.9% vs. 84.8% (p = 0.060), and DFS was 72.1% in cALND arm and 77.4% after RNI (p = 0.51). The results show that RNI is statistically not inferior to cALND treatment. The long term follow-up results of this prospective-randomized trial suggest that RNI without cALND does not increase the risk of axillary failure in selected patients with early-stage invasive breast cancer (cT ≤ 3 cm, cN0) and pN1(sn). Axillary radiotherapy should be an alternative treatment for selected patients with sentinel lymph node metastases.


Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins.
Recent studies have implicated the Tie2 tyrosine-kinase receptor and its main ligands--angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)--as crucial regulators of mural cell recruitment during angiogenesis. Angiopoietin-mediated activation of Tie2 promotes perivascular mural cell assembly, but the mechanisms regulating this process are poorly understood because differentiated mural cells do not have the Tie2 receptor, which is reportedly expressed only in endothelial cells. There is also no direct evidence that Tie2 activation results in production of mural cell chemoattractants by the endothelium. In the rat aorta model of angiogenesis, developing microvessels recruit mural cells from the intimal/subintimal layers of the aortic wall. Ang-1 and Ang-2 promote angiogenesis in this system, stimulating branching morphogenesis and mural cell assembly. Mural precursor cells (MPCs) isolated with a nonenzymatic method from the intimal aspect of the rat aorta were positive for smooth muscle cell markers (alpha-smooth muscle actin and calponin) and negative for endothelial markers (factor-VIII-related antigen and CD31). These cells responded chemotactically to Ang-1 and Ang-2, and secreted MMP-2 when treated with these factors. Western-blot analysis, immunocytochemistry and RT-PCR demonstrated that MPCs express the Tie2 receptor. Immunoprecipitation showed phosphorylation of MPC Tie2 on tyrosine residues upon stimulation with Ang-1 or Ang-2. Surface expression of Tie2 was further demonstrated by isolating Tie2+/alpha-smooth muscle actin+ MPCs from primary aortic outgrowths with anti-Tie2-IgG-coated magnetic beads. Immunostaining of the rat aorta confirmed expression of Tie2 not only in endothelial cells but also in nonendothelial mesenchymal cells located in the aortic intimal/subintimal layers, which are the source of MPCs. These data indicate that the aortic wall contains Tie2+ nonendothelial mesenchymal cells and suggest that Tie2-related recruitment of mural cells during angiogenesis may occur through angiopoietin-mediated direct stimulation of these cells.


Medicare Part D Spending on Drugs Prescribed by Oncologists: Temporal Trends and Regional Variation.
Drug cost is a significant factor in the ever-increasing expenditures for cancer health care. We used Medicare Part D administrative data to explore prescribing patterns and attributed drug costs of oncologists from 2013 to 2017. We highlighted regional variation in spending and potential associations. We used the location quotient (LQ) to measure the relative concentration of oncologists compared with the national average by hospital referral regions. Costs were reported in 2017 US dollars (inflation adjusted) for cross-year comparisons. Oncology's share in Part D spending showed an uninterrupted increasing trend. In 2017, oncologists prescribed medicines with $12.8 billion in Part D costs (8.3% of all Part D payments), which exceeded 2013 costs by $7.3 billion, when their claim payments were $5.5 billion (5.0% of all Part D payments). Oncology contributed a higher annual growth in Part D drug costs compared with all other providers (15.1% and 3.1%, respectively, for 2017). The top 3 drugs increased cost by approximately $3.5 billion from 2013 to 2017. Across hospital referral regions, the oncologists' Part D share varied (median in 2017, 7.7%; interquartile range, 6.2%-9.3%) and was higher across regions where oncologists had an LQ significantly > 1 (mostly in areas with centers that excel in cancer care) and lower for an LQ significantly < 1 (median, 9.7% v 6.2%, respectively; P < .001). Oncology increased its share in Part D drug spending, disproportionately to all other providers, with regional differences partially moderated by the oncology workforce and quality of cancer care.


Targeted Imaging of Endometriosis and Image-Guided Resection of Lesions Using Gonadotropin-Releasing Hormone Analogue-Modified Indocyanine Green.
In this study, we utilized gonadotropin-releasing hormone analogue-modified indocyanine green (GnRHa-ICG) to improve the accuracy of intraoperative recognition and resection of endometriotic lesions. Gonadotropin-releasing hormone receptor (GnRHR) expression was detected in endometriosis tissues and cell lines via immunohistochemistry and western blotting. The in vitro binding capacities of GnRHa, GnRHa-ICG, and ICG were determined using fluorescence microscopy and flow cytometry. In vivo imaging was performed in mouse models of endometriosis using a near-infrared fluorescence (NIRF) imaging system and fluorescence navigation system. The ex vivo binding capacity was determined using confocal fluorescence microscopy. GnRHa-ICG exhibited a significantly stronger binding capacity to endometriotic cells and tissues than ICG. In mice with endometriosis, GnRHa-ICG specifically imaged endometriotic tissues (EMTs) after intraperitoneal administration, whereas ICG exhibited signals in the intestine. GnRHa-ICG showed the highest fluorescence signals in the EMTs at 2 h and a good signal-to-noise ratio at 48 h postadministration. Compared with traditional surgery under white light, targeted NIRF imaging-guided surgery completely resected endometriotic lesions with a sensitivity of 97.3% and specificity of 77.8%. No obvious toxicity was observed in routine blood tests, serum biochemicals, or histopathology in mice. GnRHa-ICG specifically recognized and localized endometriotic lesions and guided complete resection of lesions with high accuracy.


Use of Artificial Intelligence in the Prediction of Malignant Potential of Gastric Gastrointestinal Stromal Tumors.
This study aimed to investigate whether AI via a deep learning algorithm using endoscopic ultrasonography (EUS) images could predict the malignant potential of gastric gastrointestinal stromal tumors (GISTs). A series of patients who underwent EUS before surgical resection for gastric GISTs were included. A total of 685 images of GISTs from 55 retrospectively included patients were used as the training data set for the AI system. Convolutional neural networks were constructed to build a deep learning model. After applying the synthetic minority oversampling technique, 70% of the generated images were used for AI training and 30% were used to test AI diagnoses. Next, validation was performed using 153 EUS images of 15 patients with GISTs. In addition, conventional EUS features of 55 patients in the training cohort were evaluated to predict the malignant potential of GISTs and mitotic index. The overall sensitivity, specificity, and accuracy of the AI system for predicting malignancy risk were 83%, 94%, and 82% in the training dataset, and 75%, 73%, and 66% in the validation cohort, respectively. When patients were divided into low-risk and high-risk groups, sensitivity, specificity, and accuracy increased to 99% in the training dataset and 99.7%, 99.7%, and 99.6%, respectively, in the validation cohort. No conventional EUS features were found to be associated with either malignant potential or mitotic index (P > 0.05). AI via a deep learning algorithm using EUS images could predict the malignant potential of gastric GISTs with high accuracy.


Anticipated Ethics and Regulatory Challenges in PCORnet: The National Patient-Centered Clinical Research Network.
PCORnet, the National Patient-Centered Clinical Research Network, seeks to establish a robust national health data network for patient-centered comparative effectiveness research. This article reports the results of a PCORnet survey designed to identify the ethics and regulatory challenges anticipated in network implementation. A 12-item online survey was developed by leadership of the PCORnet Ethics and Regulatory Task Force; responses were collected from the 29 PCORnet networks. The most pressing ethics issues identified related to informed consent, patient engagement, privacy and confidentiality, and data sharing. High priority regulatory issues included IRB coordination, privacy and confidentiality, informed consent, and data sharing. Over 150 IRBs and five different approaches to managing multisite IRB review were identified within PCORnet. Further empirical and scholarly work, as well as practical and policy guidance, is essential if important initiatives that rely on comparative effectiveness research are to move forward.


Examination of the mitochondrial genome of revertant progeny from S cms maize with cloned S-1 and S-2 hybridization probes.
We have examined the molecular rearrangement of mitochondrial DNAs in each of several fertile revertants that arose spontaneously from S-type cytoplasmically male-sterile maize. Cloned segments of S-1 and S-2 DNAs (plasmid-like DNAs characteristic of the mitochondrial DNAs of S-type lines) were hybridized to untreated and restriction endonuclease-treated mitochondrial DNAs from fertile plants carrying normal cytoplasm, from cytoplasmically male-sterile plants, and from plants that had cytoplasmically reverted to fertility. The relative intensity of hybridization with S-1 and S-2 probes was different among the fertile, sterile, and revertant lines. The sizes of some restriction endonuclease fragments from the fertile revertant lines that hybridize with the S-2 probe differ from those of the sterile parental lines. Preferential synthesis of high molecular weight components of the mitochondrial genome carrying S-1 and S-2 sequences, concomitant with cessation in apparent autonomous replication of discrete S-1 and S-2 DNAs and their replicative intermediates (described here), could accommodate the hybridization data. The results suggest but do not prove that S-2 sequences are transposed coincident with the sterile plant's reversion to fertility. The inserted segments could arise from sequences already present in the high molecular weight DNA or from the lower molecular weight linear components of the mitochondrial genome. Putative target sites of insertion of S-1 and S-2 sequences would be multiple and separate for each. Reversion of S-type cytoplasmically male-sterile plants to fertility does not restore the organization of the mitochondrial genome to that of a normal fertile plant.


Acute bioprosthetic thrombosis immediately after aortic valve replacement.
We present the case of a 72-year-old woman referred for dyspnea and vertigo when admitted to the hospital with a diagnosis of aortic stenosis. She had hypertension with previous deep venous thrombosis with no known hypercoagulable diathesis. She underwent aortic valve replacement with a Carpentier-Magna bioprosthesis without intraoperative complications; selective cardioplegia before aortic wall suture confirmed that coronary ostia were free. After extracorporeal circulation weaning, an episode of ventricular fibrillation occurred; sinus rhythm was restored using 20 J shock. Considering new episodes of ventricular fibrillation, the increasing number of polymorph ectopic ventricular systoles and the worsening of patient condition despite the use of high doses of inotropes, an intra-aortic balloon pump 1: 1 was inserted via the right femoral artery. Echocardiography (ECG) did not show alteration of the bioprosthesis in the presence of severe left ventricular impairment (ejection fraction <30%) with ipokinesia of the anterior-lateral wall and moderate-severe mitral regurgitation. Considering the rapid decline of the patient's condition despite the use of high doses of inotropes and an intra-aortic balloon pump, the aortic wall was reopened to control bioprosthesis. The intraoperative finding was unexpected; a thrombus of length 3-4 cm was found, attached to the prosthetic annulus and protruding into the left main trunk. The thrombus was immediately sucked up to avoid coronary embolization and, after that, the prosthesis was replaced with a Mitroflow 19 (Sorin Group Inc, Mitroflow Division, Vancouver, Canada) bioprosthesis. Probably, an association between factors could induce thrombosis-like aortic sinuses: annulus dimensions, endothelium damage caused during decalcification, tears in the bioprosthetic sewing ring, unknown coagulation diathesis and the structure of the Carpentier-Magna support may have induced this very unusual complication. However, we do not have enough information to establish with certainty the causes of this complication, but discussion of this topic may be useful.


Optimal design of photoreceptor mosaics: why we do not see color at night.
While color vision mediated by rod photoreceptors in dim light is possible (Kelber & Roth, 2006), most animals, including humans, do not see in color at night. This is because their retinas contain only a single class of rod photoreceptors. Many of these same animals have daylight color vision, mediated by multiple classes of cone photoreceptors. We develop a general formulation, based on Bayesian decision theory, to evaluate the efficacy of various retinal photoreceptor mosaics. The formulation evaluates each mosaic under the assumption that its output is processed to optimally estimate the image. It also explicitly takes into account the statistics of the environmental image ensemble. Using the general formulation, we consider the trade-off between monochromatic and dichromatic retinal designs as a function of overall illuminant intensity. We are able to demonstrate a set of assumptions under which the prevalent biological pattern represents optimal processing. These assumptions include an image ensemble characterized by high correlations between image intensities at nearby locations, as well as high correlations between intensities in different wavelength bands. They also include a constraint on receptor photopigment biophysics and/or the information carried by different wavelengths that produces an asymmetry in the signal-to-noise ratio of the output of different receptor classes. Our results thus provide an optimality explanation for the evolution of color vision for daylight conditions and monochromatic vision for nighttime conditions. An additional result from our calculations is that regular spatial interleaving of two receptor classes in a dichromatic retina yields performance superior to that of a retina where receptors of the same class are clumped together.


Two types of peak emotional responses to music: The psychophysiology of chills and tears.
People sometimes experience a strong emotional response to artworks. Previous studies have demonstrated that the peak emotional experience of chills (goose bumps or shivers) when listening to music involves psychophysiological arousal and a rewarding effect. However, many aspects of peak emotion are still not understood. The current research takes a new perspective of peak emotional response of tears (weeping, lump in the throat). A psychophysiological experiment showed that self-reported chills increased electrodermal activity and subjective arousal whereas tears produced slow respiration during heartbeat acceleration, although both chills and tears induced pleasure and deep breathing. A song that induced chills was perceived as being both happy and sad whereas a song that induced tears was perceived as sad. A tear-eliciting song was perceived as calmer than a chill-eliciting song. These results show that tears involve pleasure from sadness and that they are psychophysiologically calming; thus, psychophysiological responses permit the distinction between chills and tears. Because tears may have a cathartic effect, the functional significance of chills and tears seems to be different. We believe that the distinction of two types of peak emotions is theoretically relevant and further study of tears would contribute to more understanding of human peak emotional response.


Endothelial effects of leptin: implications in health and diseases.
Leptin is an adipocyte-derived hormone that plays a major role in the regulation of energy homeostasis through its action in the central nervous system. Leptin also acts on several peripheral tissues, including the vascular endothelium. The leptin receptor has been identified in endothelial cells. Leptin action on the endothelium modulates several physiologic processes, with potential implications in pathophysiologic diseases associated with obesity. Leptin stimulation of angiogenesis has attracted attention because of its potential involvement in retinopathy and atherosclerosis. Leptin activation of endothelial oxidative stress also has implications in atherosclerosis and inflammation. However, data on the impact of the endothelial effect of leptin on arterial pressure are contrasting. Although some investigators have shown that leptin action on the endothelial nitric oxide system tends to decrease arterial pressure, others have shown no contribution from the endothelial effect of leptin to the control of arterial pressure. Further characterization of the endothelial effects of leptin will, it is hoped, help in the understanding of the different pathophysiologic diseases associated with obesity.


Oxidative Stress Mediates Associations Between Preoperative Psychosocial Phenotype and Pain-Related Outcomes at 6 Months Following Total Knee Arthroplasty: A Longitudinal Cohort Study.
Greater preoperative depression, anxiety, and pain catastrophizing are associated with more severe long-term pain following total knee arthroplasty (TKA). In a secondary analysis of previously reported data, we tested the hypothesis that these associations are mediated by oxidative stress (OS). A mixed between/within-subjects longitudinal cohort design. A single academic medical center. Osteoarthritis patients (n = 91; 62.6% female) undergoing unilateral TKA. We assessed depression, anxiety, and catastrophizing, as well as markers of central sensitization (widespread pain, temporal summation of pain) preoperatively. Blood samples were then obtained immediately prior to intraoperative tourniquet placement for quantification of in vivo biomarkers of systemic OS, F2-isoprostanes and isofurans. Post-TKA pain intensity (numeric rating scale worst pain [NRS], McGill Pain Questionnaire-2 [MPQ-2]) and function (PROMIS Pain Interference) were assessed at 6 months following TKA. Greater preoperative depression, catastrophizing, and widespread pain were associated with higher intraoperative combined OS (F2-isoprostanes+isofurans/2), which was in turn associated with higher post-TKA pain intensity and worse function (p's<0.05). All preoperative phenotype predictors except anxiety were correlated positively with post-TKA pain and/or function (p's<0.05). Bootstrapped mediation analyses revealed significant (p's<0.05) indirect (mediated) effects of depression (NRS Worst Pain, MPQ-2, PROMIS Pain Interference), anxiety (MPQ-2, PROMIS Pain Interference), and catastrophizing (PROMIS Pain Interference) on adverse long-term post-TKA outcomes via elevated OS. Central sensitization-related predictors demonstrated only direct effects (p's<0.05) on post-TKA outcomes that were independent of OS mechanisms. Results suggest that the adverse impact of depression, anxiety, and pain catastrophizing on post-TKA pain and functional outcomes are mediated in part by elevated OS.


Development of a survey of asthma knowledge, attitudes, and perceptions: the Chicago Community Asthma Survey. Chicago Asthma Surveillance Initiative Project Team.
Little is known about the general public's perception of the diagnosis of asthma and the impact of asthma on individuals, their families, and their communities. In addition, there appear to be no published survey instruments specifically designed to gain insights into how the general public perceives asthma. The purpose of this paper is to describe the development of such an instrument, the Chicago Community Asthma Survey (CCAS)-32. Development began with two qualitative steps. First, a review of the published literature guided the initial instrument construction (Step 1). Content domains were chosen based on clinical input and the Health Belief Model. Most items were derived from existing instruments. To assess content validity, cognitive interviews and expert reviews were conducted (Step 2). Items were added, modified, and deleted based on the information gathered at each of these steps. In the next step, item performance measurement (Step 3), testing of two samples provided quantitative data to further inform item reduction. Items with uniform correct responses or responses lacking in variability were excluded. The result of this three-step process was a 32-item survey of asthma knowledge, attitudes and perceptions, the CCAS-32. The introduction to the survey was subsequently modified to minimize respondent bias (Step 4). In conclusion, the CCAS-32 was constructed with input from experts in asthma and individuals from the Chicago area. The items in the CCAS-32 appear to have both face validity and acceptable performance characteristics.


Removal of foreign bodies from subsegmental bronchi with the fiberbronchoscope.
Though the fiberbronchoscope has been designed for diagnostic purposes, it can be used, as well, for the removal of small foreign bodies from segmental and subsegmental bronchi; In this paper we report two cases in which we successfully removed from subsegmental bronchi a pulp-canal reamer and a melon seed. This fact proves that in some of these cases we can avoid thoracotomies.


Trends and predictors of multidimensional health-related quality of life after living donor kidney transplantation.
Living donor kidney transplant (LDKT) imparts the best graft and patient survival for most end-stage kidney disease (ESKD) patients. Yet, there remains variation in post-LDKT health-related quality of life (HRQOL). Improved understanding of post-LDKT HRQOL can help identify patients for interventions to maximize the benefit of LDKT. For 477 LDKT recipients transplanted between 11/2007 and 08/2016, we assessed physical, mental, social, and kidney-targeted HRQOL pre-LDKT, as well as 3 and 12 months post-operatively using the SF-36, Kidney Disease Quality of Life-Short Form (KDQOL-SF), and the Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 item version (FKSI-19). We then examined trajectories of each HRQOL domain using latent growth curve models (LGCMs). We also examined associations between decline in HRQOL from 3 months to 12 months post-LDKT and death censored graft failure (DCGF) using Cox regression. Large magnitude effects (d > 0.80) were observed from pre- to post-LDKT change on the SF-36 Vitality scale (d = 0.81) and the KDQOL-SF Burden of Kidney Disease (d = 1.05). Older age and smaller pre- to post-LDKT decreases in serum creatinine were associated with smaller improvements on many HRQOL scales across all domains in LGCMs. Higher DCGF rates were associated with worse physical [e.g., SF-36 PCSoblique hazard ratio (HR) 1.18; 95% CI 1.01-1.38], mental (KDQOL-SF Cognitive Function HR 1.27; 95% CI 1.00-1.62), and kidney-targeted (FKSI-19 HR: 1.18; 95% CI 1.00-1.38) HRQOL domains. Clinical HRQOL monitoring may help identify patients who are most likely to have failing grafts and who would benefit from post-LDKT intervention.


Engaging primary care professionals in suicide prevention: A qualitative study.
In health systems with strongly developed primary care, such as in the Netherlands, effectively engaging primary care professionals (PCPs) in suicide prevention is a key strategy. As part of the national Suicide Prevention Action Network (SUPRANET), a program was offered to PCPs in six regions in the Netherlands in 2017-2018 to more effectively engage them in suicide prevention. This implementation study aimed to evaluate to what extent SUPRANET was helpful in supporting PCPs to apply suicide prevention practices. From March to May 2018, 21 semi-structured interviews have been carried out with PCPs and other non-clinical professionals from SUPRANET regions in the Netherlands. Verbatim transcripts were analysed using the grounded theory approach. Data was structured using the Consolidated Framework for Implementation Research, which enabled identifying facilitating and challenging factors for PCPs to carry out suicide prevention practices. An important challenge included difficulties in assessing suicide risk (intervention characteristics) due to PCPs' self-perceived incompetence, burdensomeness of suicide and limited time and heavy workload of PCPs. Another important limitation was collaboration with mental health care (outer setting), whereas mental health nurses (inner setting) and SUPRANET (implementation process) were facilitating factors for applying suicide prevention practices. With regard to SUPRANET, especially the training was positively evaluated by PCPs. PCPs expressed a strong need for improving collaboration with specialized mental health care, which was not provided by SUPRANET. Educating PCPs on suicide prevention seems beneficial, but is not sufficient to improve care for suicidal patients. Effective suicide prevention also requires improved liaison between mental health services and primary care, and should therefore be the focus of future suicide prevention strategies aimed at primary care.


Effect of pill mill laws on opioid overdose deaths in Ohio & Tennessee: A mixed-methods case study.
Pill mill laws impose strict regulations on pain management clinics to prevent them from issuing opioid prescriptions without medical indication. To date, little is known about the implementation or effects of these laws on opioid overdose deaths. A previously untested concern is that by restricting access to prescription opioids, pill mill laws could increase overdose from heroin and synthetic opioids, like illicitly produced fentanyl. We evaluated the effects of pill mill laws on opioid overdose deaths in Ohio and Tennessee. Of the 11 total U.S. states with pill mill laws, Ohio and Tennessee were the only two where: (1) the pill mill law was the only state law designed to curb opioid prescribing implemented in a two-year period, one-year pre/post law; and (2) high-quality drug-specific overdose death data were available from CDC. We conducted synthetic control analyses examining differences in post-pill mill law trends in overdose deaths in Ohio and Tennessee compared to weighted combinations of comparison states. We also conducted qualitative interviews with 11 leaders responsible for pill mill law implementation and enforcement in Ohio and Tennessee. Pill mill law enactment had no effects on overall, prescription opioid, heroin, or synthetic opioid overdose deaths in Ohio or Tennessee. Interview results suggest that both states engaged in robust enforcement and implementation of the law. A multi-pronged policy approach, including but not limited to pill mill laws, may be required to effectively address opioid overdose deaths.