Burnout in the staff of a chronic care hospital.
OBJECTIVE To estimate the prevalence of Burnout in a medium or long-stay hospital, to monitor its evolution and to highlight the importance of cut-off points used to avoid distortions in the interpretation of the results. METHODS Two cross-sectional studies (2013-2016) were carried out, applying the Spanish version of the Maslach Burnout Inventory to the staff of a chronic care hospital (n = 323). Result variables were: Burnout prevalence and a high degree of affectation of the subscales and predictor variables: sociodemographic characteristics and factors that trigger and modulate the syndrome. The association between variables was quantified using odds ratio. RESULTS The participation rate went from 31.5% to 39.3%. The professionals presented a mean level of Burnout in both moments, observing a lower degree of affectation of the depersonalization subscales and personal accomplishment in the 2016 cut-off. The average score of the subscales in 2016 was 21.5 for emotional fatigue, 4.7 for depersonalization and 41.7 for personal fulfillment, compared to the values of emotional fatigue = 21.6, depersonalization = 6.9 and personal fulfillment = 36.3 obtained in 2013. The emotional fatigue score was slightly higher than the mean value of the national studies (19.9), while the rest of the values were similar to the mean values of the studies considered. The prevalence of Burnout and the interpretation of the results varied significantly according to the cut-off points considered. In both studies, sociodemographic variables showed little significance, while social support and interpersonal relationships were associated with the degree of burnout among professionals. CONCLUSIONS Our prevalence of Burnout was similar to that of other studies consulted, although the emotional component is more marked in our environment. The interpretation of the results varied significantly according to the cut-off points applied, due to the cross-cultural differences.


Emergency service in an ambulatory outpatient women's health centre.
In order to optimise the service for patients who require an emergency service, and to meet patient needs, we conducted a study in Shillo ambulatory outpatient women's health centre, affiliated to Rabin Medical Center and Tel Aviv University. The study population consisted of 512 women, aged 25 - 55 years, attending the centre for emergency consultation and urgent obstetrics and gynaecological day care. Before the doctor's visit and at the end of the session, the women were asked to complete a 20-item questionnaire survey. The most common complaints were related to pregnancy complications (29%). Significant improvement in their problems was reported by almost 70% of these women; 20% thought that the information they received was inadequate or unsatisfactory. Less than 10% were referred to the hospital for further care such as surgery. Most of the women (96%) reported that they would continue to use these emergency services in the future if needed. There was a statistically significant difference between the doctors' opinion and the nurse regarding the urgency and severity of the patients' problems. The nurses graded them lower than did the doctors. There was also a statistically significant difference between patients' opinion and the nurses and the doctors regarding the urgency and severity of the patients' problems. The patients graded the problems as more urgent and more severe than the nurses or doctors. We concluded that an ambulatory emergency service is an essential part of an ideal ambulatory womens' health centre but it requires substantial progress to meet the patients' needs.


The efficacy of morphine, pregabalin, gabapentin, and duloxetine on mechanical allodynia is different from that on neuroma pain in the rat neuropathic pain model.
It has been reported that <50% of neuropathic pain patients are satisfactorily treated with drugs. It is possible that this lack of efficacy of drugs on neuropathic pain might be due to the drugs prescribed, regardless of the origin of pain. We compared the efficacy of orally administered morphine, pregabalin, gabapentin, and duloxetine on mechanical allodynia with that on neuroma pain using the tibial neuroma transposition (TNT) model. In the TNT model, the tibial nerve is transected, and the tibial nerve stump is transpositioned to the lateral aspect of the hindlimb. After TNT injury, mechanical allodynia and neuroma pain are observed. Morphine, pregabalin, gabapentin, and duloxetine were administered orally and were examined for the antiallodynic and antineuroma pain effects. Morphine, pregabalin, gabapentin, and duloxetine attenuated the level of mechanical allodynia in a dose-dependent manner. Morphine-but not pregabalin, gabapentin, and duloxetine-attenuated the neuroma pain. Morphine was less potent in neuroma pain than in mechanical allodynia. In the 2-drug-combination studies (morphine + pregabalin, morphine + duloxetine, and pregabalin + duloxetine), all drug combinations produced a synergistic effect on mechanical allodynia, but not on neuroma pain. These data indicate that the potency of morphine and the efficacy of pregabalin, gabapentin, and duloxetine on mechanical allodynia are different from those on neuroma pain and that combination therapy is one of different therapeutic choices for the treatment of neuropathic pain.


Joint Modeling of Longitudinal Markers and Time-to-Event Outcomes: An Application and Tutorial in Patients After Surgical Repair of Transposition of the Great Arteries.
Most patients with congenital heart disease survive into adulthood; however, residual abnormalities remain and management of the patients is life-long and personalized. Patients with surgical repair of transposition of the great arteries, for example, face the risk to develop neoaortic valve regurgitation. Cardiologists update the prognosis of the patient intuitively with updated information of the cardiovascular status of the patient, for instance from echocardiographic imaging. Usually a time-dependent version of the Cox model is used to analyze repeated measurements with a time-to-event outcome. New statistical methods have been developed with multiple advantages, of which the most prominent one being the joint model for longitudinal and time-to-event outcome. In this tutorial, the joint modeling framework is introduced and applied to patients with transposition of the great arteries after surgery with a long-term follow-up, where repeated echocardiographic values of the neoaortic root are evaluated against the risk of neoaortic valve regurgitation. The data are analyzed with the time-dependent Cox model as benchmark method, and the results are compared with a joint model, leading to different conclusions. The flexibility of the joint model is shown by adding the growth rate of the neoaortic root to the model and adding repeated values of body surface area to obtain a multimarker model. Lastly, it is demonstrated how the joint model can be used to obtain personalized dynamic predictions of the event. The joint model for longitudinal and time-to-event data is an attractive method to analyze data in follow-up studies with repeated measurements. Benefits of the method include using the estimated natural trajectory of the longitudinal outcome, great flexibility through multiple extensions, and dynamic individualized predictions.


Freezing from the inside: Ice nucleation in Escherichia coli and Escherichia coli ghosts by inner membrane bound ice nucleation protein InaZ.
Ice nucleation (IN) active bacteria such as Pseudomonas syringae promote the growth of ice crystals more effectively than any material known. Using the specialized ice nucleation protein (INP) InaZ, P. syringae-the well studied epiphytic plant pathogen-attacks plants by frost damage and, likewise fascinating, drives ice nucleation within clouds when airborne in the atmosphere by linkage to the Earth's water cycle. While ice nucleation proteins play a tremendous role for life on the planet, the molecular details of their activity on the bacterial membrane surface are largely unknown. Bacterial ghosts (BGs) derived from Escherichia coli can be used as simplified model systems to study the mode of action of InaZ. In this work, the authors used BGs to study the role of InaZ localization on the luminal side of the bacterial inner membrane. Naturally, P. syringae INPs are displayed on the surface of the outer membrane; so in contrast, the authors engineered an N-terminal truncated form of inaZ lacking the transport sequence for anchoring of InaZ on the outer membrane. This construct was fused to N- and C-terminal inner membrane anchors and expressed in Escherichia coli C41. The IN activity of the corresponding living recombinant E. coli catalyzing interfacial ice formation of supercooled water at high subzero temperatures was tested by a droplet-freezing assay and surface spectroscopy. The median freezing temperature (T50) of the parental living E. coli C41 cells without INP was detected at -20.1 °C and with inner membrane anchored INPs at a T50 value between -7 and -9 °C, demonstrating that the induction of IN from the inside of the bacterium by inner membrane anchored INPs facing the luminal inner membrane side is very similar to IN induced by bacterial INPs located at the outer membrane. Bacterial ghosts derived from these different constructs showed first droplet freezing values between -6 and -8 °C, whereas E. coli C41 BGs alone without carrying inner membrane anchored INPs exhibit a T50 of -18.9 °C. Sum frequency generation spectroscopy showed structural ordered water at the BG/water interface, which increased close to the water melting point. Together, this indicates that the more efficient IN of INP-BGs compared to their living parental strains can be explained by the free access of inner membrane anchored INP constructs to ultrapure water filling the inner space of the BGs.


Bronchoscopy for foreign body removal: where is the delay?
This was a retrospective analysis of the medical charts of 145 patients treated at the Bronchoscopy and Thoracic Surgery Clinic of the Hospital das Clínicas da Universidade Estadual de Campinas (HC-Unicamp, State University of Campinas Hospital das Clínicas) over a period of 10 years. There was a significant difference related to the site of first medical visit (Unicamp-HC versus other institutions) in terms of the time elapsed between the suspicion of bronchial aspiration and the actual respiratory endoscopic examination. However, no significant difference was found in the rate of positive results. The low number of referral centers that provide emergency respiratory endoscopy can negatively influence the treatment of patients under suspicion of bronchial aspiration, jeopardizing the overall recovery in the mid- and long-term.


Sensory Improvement of a Pea Protein-Based Product Using Microbial Co-Cultures of Lactic Acid Bacteria and Yeasts.
Consumer demands for plant-based products have increased in recent years. However, their consumption is still limited due to the presence of off-flavor compounds, primarily beany and green notes, which are mainly associated with the presence of aldehydes, ketones, furans, and alcohols. To overcome this problem, fermentation is used as a lever to reduce off-flavors. A starter culture of lactic acid bacteria (LAB) was tested in a 4% pea protein solution with one of the following yeasts: Kluyveromyces lactis, Kluyveromyces marxianus, or Torulaspora delbrueckii. The fermented samples were evaluated by a sensory panel. Non-fermented and fermented matrices were analyzed by gas chromatography coupled with mass spectrometry to identify and quantify the volatile compounds. The sensory evaluation showed a significant reduction in the green/leguminous attributes of pea proteins and the generation of new descriptors in the presence of yeasts. Compared to the non-fermented matrix, fermentations with LAB or LAB and yeasts led to the degradation of many off-flavor compounds. Moreover, the presence of yeasts triggered the generation of esters. Thus, fermentation by a co-culture of LAB and yeasts can be used as a powerful tool for the improvement of the sensory perception of a pea protein-based product.


GW190521 Mass Gap Event and the Primordial Black Hole Scenario.
The LIGO/Virgo Collaboration has recently observed GW190521, the first binary black hole merger with at least the primary component mass in the mass gap predicted by the pair-instability supernova theory. This observation disfavors the standard stellar-origin formation scenario for the heavier black hole, motivating alternative hypotheses. We show that GW190521 cannot be explained within the primordial black hole (PBH) scenario if PBHs do not accrete during their cosmological evolution, since this would require an abundance which is already in tension with current constraints. On the other hand, GW190521 may have a primordial origin if PBHs accrete efficiently before the reionization epoch.


Expression of FTZ-F1alpha in frog testicular cells.
Fushi tarazu transcription factor-1 (FTZ-F1), a member of a nuclear hormone receptor superfamily, is a transcriptional regulator for fushi tarazu gene expression in Drosophila (Ueda et al., '90). We have cloned a homologue (rrFTZ-F1alpha) of the FTZ-F1 gene of the frog Rana rugosa. The gene, in frogs, has been shown to have high expression level in the testis (Nakajima et al., 2000). In this study, the RT-PCR analysis showed that the FTZ-F1alpha mRNA level in adult frogs did not change throughout the year, even during hibernation. However, when immunohistological studies using the anti-rrFTZ-F1alpha antibody were employed to examine which testicular cells expressed this gene, Sertoli cells were found to produce rrFTZ-F1alpha in the two seasons: the breeding season (from March through May) and the pre-hibernating season (from October through November). Interstitial cells, however, did it in only the breeding season (from April through May). Taken together, the results suggest that the rrFTZ-F1alpha expression is regulated at the post-transcriptional step, and that the rrFTZ-F1alpha may play an important role(s) in the seasonal activities of Sertoli and interstitial cells in the frog testis. J. Exp. Zool. 290:182-189, 2001.


Why kidneys fail post-partum: a tubulocentric viewpoint.
Kidneys may fail post-partum in a number of circumstances due, for example, to post-partum haemorrhage, preeclampsia, amniotic fluid embolism or septic abortion. All these conditions in pregnancy and post partum represent a threat not only to the endothelium but also to the renal tubular epithelium, and as such may lead to rapid and also irreversible impairment of the renal function. This paper is a non-systematic review of the literature and of our experience, in which we discuss the main open issues on kidney disease in pregnancy and following delivery, in particular as regards tubular damage, with the aim to help reasoning on acute kidney injury (AKI) following delivery. The review will emphasize the often under-estimated importance of the tubular epithelium in the peri-partum period and will: (1) describe the main characteristics of the renal tissues around delivery; (2) define pregnancy-related AKI according to recent Kidney Disease/Improving Global Outcome (KDIGO) guidelines; (3) discuss the most common circumstances of post-partum AKI; and (4) describe the input expected from urinalysis, renal imaging and kidney biopsy.


Magnetic Resonance Imaging Artifact Associated With Transcutaneous Bone Conduction Implants: Cholesteatoma and Vestibular Schwannoma Surveillance.
To evaluate the magnetic resonance (MR) image artifact and image distortion associated with the two transcutaneous bone conduction implants currently available in the United States. Cadaveric study. Two cadaveric head specimens (1 male, 1 female) were unilaterally implanted according to manufacturer guidelines and underwent MR imaging (General Electric and Siemens 1.5 T scanners) under the following device conditions: (1) no device, (2) Cochlear Osia with magnet and headwrap, (3) Cochlear Osia without magnet, and (4) MED-EL Bonebridge with magnet. Maximum metal mitigation techniques were employed in all conditions, and identical sequences were obtained. Blinded image scoring (diagnostic vs nondiagnostic image) was performed by experienced neuroradiologists according to anatomical subsites. All device conditions produced artifact and image distortion. The Osia with magnet produced diagnostic T1- and T2-weighted images of the ipsilateral temporal bone, however, non-echo planar imaging diffusion-weighted imaging (DWI) was nondiagnostic. The Osia without magnet scanned on the Siemens MR imaging demonstrated the least amount of artifact and was the only condition that allowed for diagnostic imaging of the ipsilateral temporal bone on DWI. The Bonebridge produced a large area of artifact and distortion with the involvement of the ipsilateral and contralateral temporal bones. In summary, of the three device conditions (Osia with magnet, Osia without magnet, and Bonebridge), Osia without magnet offered the least amount of artifact and distortion and was the only condition in which diagnostic DWI was available for the middle ear and mastoid regions on the Siemens MR imaging scanner.


Desaspidin: a nonspecific uncoupler of photophosphorylation.
The inhibitory effect of desaspidin is shown to depend on the oxidation-reduction state of the system investigated. The more reducing the conditions, the more desaspidin-inhibited the system and vice versa.The effect of desaspidin on noncyclic photophosphorylation induced by TPN(+), ferricyanide or DPIP is shown to be due to an uncoupling action.The decrease in effectiveness of desaspidin under oxidizing condition is shown to depend upon a photooxidation catalyzed by photosystem I of chloroplasts, which is prevented, but not reversed, by the presence of reducing agents, such as ascorbate + DPIP.These results are interpreted as indicating that, contrary to previous suggestions, desaspidin is a nonspecific uncoupler of all types of photophosphorylation.


Hyperinsulinemia induces hypertension associated with neurogenic vascular dysfunction resulting from abnormal perivascular innervations in rat mesenteric resistance arteries.
We previously reported that chronic hyperinsulinemia and insulin resistance induced by fructose-drinking loading elicited hypertension associated with abnormal neuronal regulation of vascular tone in an in vivo study using pithed rats. Therefore, to further clarify the detailed mechanisms of perivascular nervous system malfunction induced by chronic hyperinsulinemia, we investigated the neurogenic vascular responses and distribution of perivascular nerves using mesenteric vascular beds isolated from fructose-loaded rats with hyperinsulinemia. Male Wistar rats (6 weeks old) received 15% fructose solution as drinking fluid for 10 weeks (fructose-drinking rats, FDR), which resulted in significant increases in plasma levels of insulin, the glucose-insulin index, blood norepinephrine (NE) levels and systolic blood pressure, but not blood glucose levels, when compared with normal water-drinking rats (control rats). In perfused mesenteric vascular beds of FDR, enhanced adrenergic nerve-mediated vasoconstriction with no effect on NE-induced vasoconstriction and decreased calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation with no effect on CGRP-induced vasodilation were observed. Immunohistochemistry studies showed increased density of neuropeptide Y immunopositive adrenergic fibers and reduced density of CGRP immunopositive fibers in mesenteric arteries of FDR. Furthermore, FDR showed decreased CGRP content in dorsal root ganglia. These findings suggest that dysfunction of the neuronal vascular control system resulting from abnormal innervation of mesenteric perivascular nerves induced by the hyperinsulinemic state is responsible for the development of hypertension in FDR.


Microfluidic electrochemical sensor for on-line monitoring of aerosol oxidative activity.
Particulate matter (PM) air pollution has a significant impact on human morbidity and mortality; however, the mechanisms of PM-induced toxicity are poorly defined. A leading hypothesis states that airborne PM induces harm by generating reactive oxygen species in and around human tissues, leading to oxidative stress. We report here a system employing a microfluidic electrochemical sensor coupled directly to a particle-into-liquid sampler (PILS) system to measure aerosol oxidative activity in an on-line format. The oxidative activity measurement is based on the dithiothreitol (DTT) assay, where, after being oxidized by PM, the remaining reduced DTT is analyzed by the microfluidic sensor. The sensor consists of an array of working, reference, and auxiliary electrodes fabricated in a poly(dimethylsiloxane)-based microfluidic device. Cobalt(II) phthalocyanine-modified carbon paste was used as the working electrode material, allowing selective detection of reduced DTT. The electrochemical sensor was validated off-line against the traditional DTT assay using filter samples taken from urban environments and biomass burning events. After off-line characterization, the sensor was coupled to a PILS to enable on-line sampling/analysis of aerosol oxidative activity. Urban dust and industrial incinerator ash samples were aerosolized in an aerosol chamber and analyzed for their oxidative activity. The on-line sensor reported DTT consumption rates (oxidative activity) in good correlation with aerosol concentration (R(2) from 0.86 to 0.97) with a time resolution of approximately 3 min.


Highly conductive, stretchable, and breathable epidermal electrode based on hierarchically interactive nano-network.
Stretchable electrodes have a crucial impact on the development of flexible electronic systems. Most conventionally blended nanocomposite electrodes are incapable of achieving high stretchability, breathability, or durability. In this work, a highly conductive, breathable, and stretchable epidermal electrode (SEE) is demonstrated by designing a hierarchically interactive nano-network that is composed of elastic polymer nano-fibers and multi-level silver nano-wires (AgNWs). The elastic polymer nano-fibers act as a continuous scaffold, and multi-level AgNWs embedded in the nano-fibers form branched conductive pathways. This structure enables high conductivity of the SEE at 4800 S cm-1 (at a significantly low AgNW content of 1.59 vt%), with high stretchability and excellent durability. For example, the SEE remained conductive even at a high strain of 500%, and it also maintained its initial resistance even after 30 000 cycles of strain at 50% or being washed with water for 100 000 cycles. The SEE was prepared by a facile in situ nonequilibrium fabrication process, and can easily be produced into an elastic circuit on a large scale, which provides a foundation for integrated and multifunctional electronic skins. The SEE possesses superior mechanical conformability and permeability of gas and liquid, and therefore, it was successfully applied in measuring electrocardiogram signals and thermal therapy, and exhibited highly robust and comfortable performances even while being washed with water or undergoing complex deformations.


Characteristics of salivary profiles of oestradiol and progesterone in premenopausal women.
The objective of the study was to characterize salivary sex steroid levels in 56 women undergoing annual mammography who were participating in a breast density study at the Lynn Sage Breast Center of Northwestern Memorial Hospital, and to determine the predictability of the patterns within women. Saliva was collected daily by the women at home for one complete menstrual cycle and then again at approximately 6-month intervals. The occurrence of sporadic anovulatory cycles was identified in 12 subjects, and persistent oestradiol (OE2) elevation in all three cycles without significant progesterone levels occurred in another five subjects. In addition, both OE2 and progesterone were significantly lower in initial menstrual cycles than in subsequent cycles, suggestive of an effect of participation in the study on hormone levels. Initial salivary OE2 levels were not good predictors of corresponding levels in either follicular or luteal phases of the menstrual cycles at the 6-month intervals. However, after the initial cycle, progesterone levels were highly predictable within individuals over a period of 6 months (r=0.78, P<0.001). The study emphasizes the natural variation among and within women in the absence of any intervention, and indicates the need for properly controlled studies before attributing changes in hormonal levels to therapy. In addition, it emphasizes the importance of sampling at multiple time points when examining the relationship between hormones and risk.


SPECTRUM - A MATLAB Toolbox for Proteoform Identification from Top-Down Proteomics Data.
Top-Down Proteomics (TDP) is an emerging proteomics protocol that involves identification, characterization, and quantitation of intact proteins using high-resolution mass spectrometry. TDP has an edge over other proteomics protocols in that it allows for: (i) accurate measurement of intact protein mass, (ii) high sequence coverage, and (iii) enhanced identification of post-translational modifications (PTMs). However, the complexity of TDP spectra poses a significant impediment to protein search and PTM characterization. Furthermore, limited software support is currently available in the form of search algorithms and pipelines. To address this need, we propose 'SPECTRUM', an open-architecture and open-source toolbox for TDP data analysis. Its salient features include: (i) MS2-based intact protein mass tuning, (ii) de novo peptide sequence tag analysis, (iii) propensity-driven PTM characterization, (iv) blind PTM search, (v) spectral comparison, (vi) identification of truncated proteins, (vii) multifactorial coefficient-weighted scoring, and (viii) intuitive graphical user interfaces to access the aforementioned functionalities and visualization of results. We have validated SPECTRUM using published datasets and benchmarked it against salient TDP tools. SPECTRUM provides significantly enhanced protein identification rates (91% to 177%) over its contemporaries. SPECTRUM has been implemented in MATLAB, and is freely available along with its source code and documentation at https://github.com/BIRL/SPECTRUM/.


Overweight in adolescence is related to increased risk of future urothelial cancer.
Obesity has been linked to various malignancies, but a clear relation of overweight with urothelial cancer has not been established. We assessed the association between adolescent obesity and future risk for urothelial cancer. Medical data on 1,110,835 Israeli adolescents examined for fitness for military duty between 1967 and 2005 were linked to the National Cancer Registry in this nationwide population-based cohort study. We used Cox proportional hazards modeling to estimate the covariate-adjusted hazard ratio (HR) for urothelial cancer associated with BMI measured at age 17. The mean follow-up of 17.6 ± 10.8 years reflected 19,576,635 person years, during which 661 examinees developed urothelial cancer of the bladder, ureter, or renal pelvis. BMI ≥ 85 th standard percentile in adolescence significantly predicted increased risk of urothelial cancer with a HR (adjusted for year of birth, education and religiosity) of 1.42 (95% confidence interval (CI), 1.13-1.77, P = 0.002). Similar results were observed using the ≥ 25 kg/m(2) definition of overweight (HR = 1.36 (95% CI, 1.08-1.72), P = 0.008). Incidence of urothelial cancer was significantly lower in the more educated and among those who attended religious schools. Overweight in adolescence is related to increased risk of future urothelial cancer. In view of the growing incidence of both urothelial cancer and adolescent obesity, our study suggests an avenue for possible prevention of urothelial cancer.


First Report of Fusarium proliferatum Causing Dry Rot in Michigan Commercial Potato (Solanum tuberosum) Production.
Fusarium dry rot of potato (Solanum tuberosum L.) is a postharvest disease caused by several Fusarium spp. Thirteen Fusarium spp. have been implicated in dry rot of potatoes worldwide. Among them, 11 species have been reported causing potato dry rot of seed tubers in the northern United States (1). Historically, Fusarium sambucinum was the predominant species in Michigan potato production (3). Dry rot symptomatic tubers (n = 972) were collected from Michigan commercial potato storage facilities in 2011 and 2012 to determine the composition of Fusarium spp. Sections were cut from the margins of necrotic tissue with a sterile scalpel and surface disinfested in 0.6% sodium hypochlorite for 10 s, rinsed twice in sterile distilled water, and dried on sterile filter paper. The tissue sections were plated on half-strength potato dextrose agar (PDA) amended with 0.5 g/liter of streptomycin sulfate. Dishes were incubated at 23°C in the dark for 7 days. Putative Fusarium isolates were transferred onto water agar and hyphal tips from the margin of actively growing cultures were removed with a sterile scalpel and plated to carnation leaf agar (CLA) and half-strength PDA to generate pure cultures. Seven hundred and thirty Fusarium isolates were collected using these techniques. Preliminary identification of the 730 isolates was based on colony and conidial morphology on PDA and CLA, respectively. While F. oxysporum and F. sambucinum were isolated as expected from prior reports (3), three isolates of F. proliferatum were also identified. On CLA, macroconidia of F. proliferatum were sparse, slender, and mostly straight, with three to five septae (4). Microconidia were abundant, usually single celled, oval or club-shaped in short chains or false heads on monophialides and polyphialides (4), and chlamydospores were absent. On PDA, abundant white mycelium was produced and turned violet with age. Koch's postulates were confirmed through pathogenicity testing on disease-free potato tubers cvs. Atlantic and Russet Norkotah. Tubers were surface disinfested for 10 min in 0.6% sodium hypochlorite and rinsed twice in distilled water. Three tubers of each cultivar per isolate were wounded at the apical end of the tuber to a depth of 4 to 10 mm with a 4 mm diameter cork-borer. Tubers were inoculated by inserting a mycelial plug from a 7-day-old culture grown on PDA into the wound and incubating the tubers at 20°C for 21 days. All Fusarium isolates were tested. Control tubers were inoculated by inserting a water agar plug. Pathogenicity and virulence testing were replicated three times and repeated. Tubers inoculated with F. proliferatum developed typical potato dry rot symptoms but no dry rot symptoms were observed on control tubers. Fusarium proliferatum was re-isolated from symptomatic tubers, confirming Koch's postulates. To our knowledge, this is the first report of F. proliferatum causing potato dry rot in Michigan. References: (1) E. Gachango et al. Plant Dis. 96:1767. (2) D. Geiser et al. Eur. J. Plant Pathol. 110:473, 2004. (3) M. L. Lacy and R. Hammerschmidt. Fusarium dry rot. Extension Bulletin. Retrieved from http://web1.msue.msu.edu/msue/iac/onlinepubs/pubs/E/E2448POT, 23 May 2010. (4) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Wiley-Blackwell, Hoboken, NJ, 2006.


Salicylhydroxamic acid inhibits delta6 desaturation in the microalga Porphyridium cruentum.
Treatment of the microalga Porphyridium cruentum with salicylhydroxamic acid (SHAM) inhibited growth and affected fatty acid composition. At a relatively low concentration (40 microM) SHAM predominantly inhibits Delta6 desaturation. The effect of the inhibitor was most intense in phosphatidylcholine (PC) and phosphatidylethanolamine, in which the proportions of the downstream products of the Delta6 desaturase were reduced, whereas that of the substrate, 18:2, increased. As a result of the availability of 18:2, 18:3omega3, which under normal conditions is not observed, appeared predominantly in chloroplastic lipids. Pulse labeling with linoleic acid has shown that SHAM inhibits Delta6 desaturation almost immediately, suggesting an apparent inhibition of the activity of the desaturase, rather than its synthesis or that of its cofactors. Furthermore, the addition of gamma-linolenic acid to SHAM-inhibited cultures relieved the inhibition. Following exposure to the inhibitor, 18:3omega3 appeared first in chloroplastic glycolipids and only later in PC, indicating that the former are the substrates for the first dedicated step of the proposed omega3 pathway in this alga.


A new insight into superacute care for type A acute aortic dissection in the Tokyo Acute Aortic Super Network.
To determine the status of type A acute aortic dissection using the Tokyo Acute Aortic Super Network. Data of 6283 patients with acute aortic dissection between 2015 and 2019 were collected. Data of 3303 patients with type A acute aortic dissection were extracted for analysis. Overall, 51.0% of patients were nondirect admissions. On arrival, 23.1% of patients were in shock, 10.0% in cardiopulmonary arrest, and 11.8% in deep coma or coma. Overall, 9.8% of patients were assessed as untreatable. Of 2979 treatable patients, 18.3% underwent medical treatment, whereas 80.7% underwent surgery (open [78.8%], endovascular [1.9%], and peripheral [1.1%] repair). The early mortality rate was 20.5%, including untreatable cases. Among treatable patients, in-hospital mortality rates were 8.6% for open repair, 10.7% for endovascular repair, and 25.3% for medical treatment. Advanced age, preoperative comorbidities, classical dissection, and medical treatment were risk factors for in-hospital mortality. Nondirect admission did not cause increased deaths. The mortality rates were high during the superacute phase following symptom onset. This study demonstrated current practices in the emergency care of type A acute aortic dissection via the Tokyo Acute Aortic Super Network system, specifically a high rate of untreatable or inoperable cases and favorable outcomes in patients undergoing surgical treatment. High mortality rates were observed during the super acute phase after symptom onset or hospital arrival.


Test selection for antibody detection according to the seroprevalence level of Schmallenberg virus in sheep.
Schmallenberg virus (SBV), initially identified in Germany in 2011, spread rapidly throughout Europe causing significant economic losses in ruminant livestock. The ability to correctly detect emerging and re-emerging diseases such as SBV with reliable tests is of high importance. Firstly, we tested diagnostic performance, specificity, and sensitivity of three different assays used in SBV antibody detection using control sheep samples of determined status. After obtaining the results from the control samples, we assessed the potential of the assays to detect previously infected animals in field situations. The samples were investigated using IDEXX Schmallenberg virus Antibody Test Kit, ID Screen Schmallenberg virus Competition Multi-species ELISA and Serum Neutralisation Test (SNT). Analysis of control samples revealed that SNT was the most suitable test, which was therefore used to calculate concordance and test performance for the two other ELISA tests. To evaluate whether different assay performances had an impact under field conditions, sheep samples from two different contexts were tested: the emergence of SBV in Ireland and the re-emergence of SBV in Belgium. Comparing the results obtained from different assays to the non-reference standard assay SNT, we showed considerable differences in estimates of their sensitivity to detect SBV antibodies and to measure seroprevalence of the sheep flocks. Finally, a calculation of the number of randomly selected animals that needs to be screened from a finite flock, showed that SNT and ID.Vet are the most suitable to detect an introduction of the disease in low seroprevalence situations. The IDEXX ELISA test was only able to detect SBV antibodies in a higher seroprevalence context, which is not optimal for monitoring freedom of disease and surveillance studies.


Differential effects of tumor necrosis factor-alpha and -beta on rat ventromedial hypothalamic neurons in vitro.
The effects of tumor necrosis factor (TNF)-alpha and -beta on the spontaneous firing rate of ventromedial hypothalamic (VMH) neurons were examined in rat brain slice preparations. Of 89 neurons, 36 (40%) showed a decrease in the firing rate to -78.2 +/- 4.0% (n = 36, mean +/- SE) of the preapplication level after a bath application of 20 ng/ml (approximately 1.2 nM) of TNF-alpha. This response to TNF-alpha still persisted in a low-Ca2+, high-Mg2+ medium. Six (7%) of the 89 neurons were excited and 47 (53%) were unaffected by TNF-alpha. The inhibitory responses induced by TNF-alpha were abolished in a solution that contained sodium salicylate (1.9 x 10(-8)M). In contrast, TNF-beta at a dose of 20 ng/ml (approximately 1.1 nM) increased the firing rate to +39.2 +/- 6.5% (n = 11) of the preapplication level in 11 (24.5%) of 45 VMH neurons. Two of the 45 neurons (4.5%) were inhibited and 32 (71%) were unaffected by TNF-beta. The threshold concentration of TNF-alpha to alter the VMH neuron activity was lower than that of TNF-beta. Heat-inactivated TNFs were without effect. These findings suggest that TNF-alpha and -beta act as neuromodulators in the VMH, at least partly through prostaglandin synthesis, and differentially modulate the VMH neuron activity.


Audiological manifestations of allergic rhinitis.
Allergic rhinitis is associated with excess specific immunoglobulin E. Inner ear involvement (via both cellular and humoral immunity) is poorly understood, but appears to arise from the endolymphatic sac and duct. To assess the otological and audiological status of patients with allergic rhinitis. Thirty allergic rhinitis patients (14 men, 16 women; age 17-45 years, mean 31 years) and 20 controls (12 men, eight women; age 21-42 years, mean 27 years) underwent audiological investigation. All study group patients had sensorineural (rather than conductive) hearing loss, worse at high frequencies. All had abnormal transient evoked otoacoustic emissions and 27 had abnormal distortion product otoacoustic emissions. All had a statistically significantly prolonged wave I latency, and shortened absolute wave I-III and I-V interpeak latencies, compared with controls. Allergic rhinitis patients had a higher prevalence of hearing loss and otoacoustic emission abnormalities than controls. The endolymphatic sac can process antigens and produce its own local antibody response; the resulting inflammatory mediators and toxic products may interfere with hair cell function. Additional research is needed to determine the clinical value of audiometry and otoacoustic emission testing in allergic rhinitis.


Mechanical efficiency during a cycling test is not lower in children with excess body weight and low aerobic fitness.
The aims of this study were to assess the association between (i) body weight status and mechanical efficiency (ME); and (ii) ME and aerobic fitness in children aged 8-10 years. The sample included 464 prepubertal children (258 boys). A total of 288 were normal-weight (NW); 84 overweight (OW); and 92 obese (OB). Subjects performed an incremental maximal cycling test with indirect calorimetry. MEcrude (%) was calculated for the first five stages of the protocol (25, 50, 75, 100, and 125 W) as follows: work produced, in watts total energy consumption, in watts(-1) · 100(-1). For MEnet, resting energy consumption was subtracted from total energy consumption. Energy consumption was calculated as follows: (4.94 · respiratory exchange ratio + 16.04) · VO2, in ml · min(-1) · 60(-1). MEcrude was significantly higher in NW compared to OW and OB children and in OW compared to OB children at 25, 50, 75, 100, and 125 W. In contrast, MEnet did not differ significantly among NW, OW, and OB children. No statistically significant association was found between crude or net ME and peak oxygen consumption (VO2 peak; in ml · kg(-1) · min(-1)); therefore, the ability to transfer chemical energy to mechanical work is maintained in children aged 8-10 years old regardless of body weight status and aerobic fitness. Moreover, higher values of MEcrude during exercise are explained by elevated oxygen consumption at rest and not by energy consumed during physical activity. These results highlight that prepubertal children are equally efficient since they are able to perform a physical task such as cycling using the same proportion of energy regardless of their body weight status.


Vergence adaptation and senescence.
The characteristics of prism adaptation have been evaluated by many previous studies but most have been performed on young subjects (typically 18 to 35 years of age). Because little information is available regarding the effect of age on vergence adaptation, we assessed prism adaptation on 25 visually normal subjects across a wide age range (19 to 85 years) for both convergent and divergent induced disparities. A "flashed" (125 ms) Maddox rod procedure was used for distance fixation (5 m) over a 3.5 min adaptation period and a 2.5 min recovery period. Stimulus presentation and occlusion time were controlled with an Apple lle microcomputer through a ClL Microsystems interface. Prism adaptation was shown to be present in all age groups, with convergence showing a greater amplitude than divergence. However, the magnitude of adaptation declined significantly as a function of increasing age at a rate of approximately 0.6% per year. An adaptation mechanism is present in all subjects but it operates with reduced gain in older subjects. The finding may explain the clinical observation that older patients readily accept prismatic correction to control oculomotor imbalance.


Novel delivery systems for anti-allergic agents: allergic disease and innovative treatments.
Anti-allergic agents are used to treat a great variety of diseases which usually involve an inflammation reaction. These compounds act by inhibiting the release and the effects of inflammatory mediators (e.g. histamine) in the target tissue. The purpose of anti-allergy therapy is to deliver the drug to its local of action in a therapeutic concentration, minimizing the undesired side effects. In order to solve some of the anti-allergic agents' physicochemical drawbacks and the limitations associated to conventional pharmaceutical formulations (e.g. poor solubility and absorption, skin permeation, stability), novel drug delivery systems, such as cyclodextrins, liposomes, micelles, microemulsions, nano and microparticles, have been developed. Depending on the allergic condition, several administration routes are used to deliver anti-allergic agents, each with its own disadvantages to overcome. In the literature, there are a vast number of papers concerning novel delivery systems for anti-allergic agents, making it difficult to evaluate the information and the promising outcomes. The aim of the present review article is to compile the recent (i.e. in the new millennium) improvements of novel drug delivery technology focusing on the achievement of anti-allergic therapeutic delivery. The potential intrinsic benefits of these systems will reflect an increased therapeutic adherence and better patients' life quality. A critical prospect of future clinical trial directions will also be discussed.


Iatrogenic hand injuries in outpatients.
Potentially serious iatrogenic hand injuries occurred in three patients in a general medicine practice. All resulted from technologic advances in patient care. Each resulted in substantial economic and emotional costs. One patient sustained a serious residual disability. Such injuries have rarely been reported in the past, but advances in medical technology and changes in reimbursement patterns may make outpatient iatrogenic hand injuries increasingly common. Physicians must be alert to such injuries.


Magnetoconductance modulations due to interlayer tunneling in radial superlattices.
Radial superlattices are nanostructured materials obtained by rolling up thin solid films into spiral-like tubular structures. The formation of these "high-order" superlattices from two-dimensional crystals or ultrathin films is expected to result in a transition of transport characteristics from two-dimensional to one-dimensional. Here, we show that a transport hallmark of radial superlattices is the appearance of magnetoconductance modulations in the presence of externally applied axial magnetic fields. This phenomenon critically relies on electronic interlayer tunneling processes that activate an unconventional Aharonov-Bohm-like effect. Using a combination of density functional theory calculations and low-energy continuum models, we determine the electronic states of a paradigmatic single-material radial superlattice - a two-winding carbon nanoscroll - and indeed show momentum-dependent oscillations of the magnetic states in the axial configuration, which we demonstrate to be entirely due to hopping between the two windings of the spiral-shaped scroll.


Urinary markers of nucleic acid oxidation and cancer in type 2 diabetes.
We investigated whether urinary markers of nucleic acid oxidation are associated with an increased risk of cancer in type 2 diabetes patients. Urine samples from 1381 newly diagnosed diabetes patients were assayed for the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Cox proportional hazards regression was used to examine the relationship between the urinary markers and cancer incidence. The crude analyses showed an association between overall cancer and urinary excretion of the RNA oxidation marker 8-oxoGuo (unadjusted hazard ratio for cancer per natural log increase in 8-oxoGuo 1.35 [95% CI, 1.01-1.81]), however, in the adjusted analyses, no significant associations between 8-oxodG or 8-oxoGuo and overall cancer were found. For site-specific cancers 8-oxodG was associated with breast cancer in the crude analyses (unadjusted hazard ratio for breast cancer per natural log increase in 8-oxodG was 2.37 [95% CI, 1.07-5.26]), although the association was attenuated in the adjusted analyses (sex- and age-adjusted hazard ratio 2.15 [95% CI, 0.92-5.02] and multivariate adjusted hazard ratio1.98 [95% CI, 0.95-4.10]). Urinary excretion of the nucleic acid oxidation markers 8-oxodG and 8-oxoGuo at the time of diagnosis was not associated with cancer overall in type 2 diabetes patients. For site-specific cancers, risk elevations were seen for breast cancer (8-oxodG). These findings should be examined in future and larger studies.


Muscarinic acetylcholine receptor modulation of mu (mu) opioid receptors in adult rat sphenopalatine ganglion neurons.
The sphenopalatine ganglion (SPG) neurons represent the parasympathetic branch of the autonomic nervous system involved in controlling cerebral blood flow. In the present study, we examined the coupling mechanism between mu (mu) opioid receptors (MOR) and muscarinic acetylcholine receptors (mAChR) with Ca(2+) channels in acutely dissociated adult rat SPG neurons. Successful MOR activation was recorded in approximately 40-45% of SPG neurons employing the whole cell variant of the patch-clamp technique. In addition, immunofluorescence assays indicated that MOR are not expressed in all SPG neurons while M(2) mAChR staining was evident in all neurons. The concentration-response relationships generated with morphine and [d-Ala2-N-Me-Phe4-Glycol5]-enkephalin (DAMGO) showed IC(50) values of 15.2 and 56.1 nM and maximal Ca(2+) current inhibition of 26.0 and 38.7%, respectively. Activation of MOR or M(2) mAChR with morphine or oxotremorine-methiodide (Oxo-M), respectively, resulted in voltage-dependent inhibition of Ca(2+) currents via coupling with Galpha(i/o) protein subunits. The acute prolonged exposure (10 min) of neurons to morphine or Oxo-M led to the homologous desensitization of MOR and M(2) mAChR, respectively. The prolonged stimulation of M(2) mAChR with Oxo-M resulted in heterologous desensitization of morphine-mediated Ca(2+) current inhibition, and was sensitive to the M(2) mAChR blocker methoctramine. On the other hand, when the neurons were exposed to morphine or DAMGO for 10 min, heterologous desensitization of M(2) mAChR was not observed. These results suggest that in rat SPG neurons activation of M(2) mAChR likely modulates opioid transmission in the brain vasculature to adequately maintain cerebral blood flow.


p53, proto-oncogene and rheumatoid arthritis.
To review the literature published in the past 6 years concerning the role of p53 tumor-suppressor protein in rheumatoid arthritis (RA). A MEDLINE search was performed to identify all publications that covered the role of p53 in RA. In addition, selected articles related to proto-oncogenes and matrix metalloproteinases were included in this review. p53 protein is expressed in RA fibroblast-like synoviocytes (FLSs), and its overexpression is a characteristic feature of RA. The overexpression of p53 is probably induced by DNA strand breaks caused by the genotoxic environment of RA joints, in some cases because of p53 mutations. Independent studies from 3 groups indicated that p53 mutations can and do occur in RA synovial tissue samples derived from a subset of RA patients. Inactivation of p53 may contribute to the invasiveness of FLSs and to the high-level expression of cartilage degradation enzymes as well. Gene transfer or gene knockout studies using a collagen-II-induced RA animal model to examine the role of p53 in RA have been reported. Initial results are positive and indicate that gene transfer of p53 may be clinically useful for the management of RA. p53 protein is expressed in RA FLSs, and its overexpression is a characteristic feature of RA. p53 mutations occur in the synovial tissues derived from a subset of RA patients. The clinical implications of p53 expression and the functional importance of somatic mutations in RA, however, are still unclear. Further research is needed to fully understand the implications of these findings and develop corresponding new therapeutic strategies.


A novel papillomavirus isolated from proliferative skin lesions of a wild American beaver (Castor canadensis).
Cutaneous papillomatosis was diagnosed in an adult American beaver (Castor canadensis). Gross lesions included numerous exophytic, roughly circular, lightly pigmented lesions on hairless areas of fore and hind feet and the nose. The most significant histopathologic findings were multifocal papilliform hyperplasia of the superficial stratified squamous epithelium, with multifocal koilocytes, and multiple cells with large, darkly basophilic intranuclear inclusion bodies. A virus with properties consistent with papillomavirus (PV) was recovered by virus isolation of skin lesions, utilizing rabbit and feline kidney cell lines. The presence of the virus was confirmed by PV-specific polymerase chain reaction. The partial sequences of E1 and L1 genes did not closely match those of any PVs in GenBank, suggesting that this might be a new type of PV. Partial E1 and L1 nucleotide sequences of the beaver papillomavirus (hereafter, ARbeaver-PV1) were used to create a phylogenetic tree employing the complete E1 and L1 open reading frame nucleotide sequences of 68 PVs. The phylogenetic tree placed the ARbeaver-PV1 in a clade that included the Mupapillomavirus (HPV1 and HPV63) and Kappapapillomavirus (OcPV1 and SfPV1) genera. The present article confirms the papillomaviral etiology of cutaneous exophytic lesions in the beaver.


Radiation dose produced by patients during radiopharmaceutical incorporation in nuclear medicine diagnostic procedures.
The aim of this study was to assess the dose received by members of the public due to close contact with patients undergoing nuclear medicine procedures during radiopharmaceutical incorporation, and comparing it with the emitted radiation dose when the test was complete, in order to establish recommendations. A prospective study was conducted on 194 patients. H*(10) dose rates were measured at 0.1, 0.5, and 1.0m after the radiopharmaceutical administration, before the image acquisition, and at the end of the nuclear medicine procedure. Effective dose for different close contact scenarios were calculated, according to 95th percentile value (bone scans) and the maximum value (remaining tests). During the radiopharmaceutical incorporation, a person who stays with another injected patient in the same waiting room may receive up to 0.59 mSv. If the patient had a medical appointment, or went to a restaurant or a coffee shop, members of the public could receive 23, 43, and 22 μSv, respectively. After finishing the procedure, these doses are reduced by a factor 3. In most of the studies, the use of private instead of public transport may reduce the dose by more than a factor 6. It is recommended to increase the distance between the patients during the radiopharmaceutical incorporation and to distribute them according to the diagnostic procedure. Patients should be encouraged to use private instead of public transport. Depending on the number of nuclear medicine outpatients per year attended by a physician, it could be necessary to apply restrictions.


Physical Characterization and In Vitro Evaluation of Dissolution Rate from Cefpodoxime Proxetil Loaded Self Solidifying Solid SNEDDS.
Cefpodoxime Proxetil (CPD) is a broad-spectrum cephalosporin indicated in respiratory and urinary tract infections. CPD is a BCS class IV drug with pH-dependent solubility and has poor bioavailability. This study investigated the challenges of developing ternary components based on solid SNEDDS of CPD for in vitro dissolution rate enhancement and self-solidifying behaviour. Tween 80, Transcutol and PEG6000 were employed as surfactants, solvents and solidifiers for a base of ternary components to develop self-solidifying solid SNEDDS, respectively. Ternary phase diagrams were used to characterize solidifying behaviour of ternary components in different proportions. S-SNEDDS formulations were drawn on the solidification areas available in the phase diagram and characterized for IR, XRD, DSC and in vitro drug release in various pH media. Ternary components for the preparation of self-solidifying solid SNEDDS were selected based on drug solubility. FTIR and DSC characterization studies ruled out any drug interaction between CPD and components chosen to prepare S-SNEDDS. CPD was transformed from a crystalline into an amorphous state in ternary dispersions as revealed from XRD data. Optimized formulation (S-S 1) demonstrated more than 95% of drug release irrespective of the pH environments of the medium. Calculation of dissolution efficiency and similarity factors indicate that S SNEDDS resulted in a higher drug dissolution rate over binary dispersion (p<0.01). The stability studies showed that the S SNEDDS were stable in performances and CPD assay. The present investigation provides an alternative approach for enhancing the CPD dissolution rate using self-solidifying solid SNEDDS exhibited solidification behaviour at ambient temperature conditions and drug loading, which could be exploited over conventional dosage form.


Health-related quality of life scores of typically developing children and adolescents around the world: a meta-analysis with meta-regression.
In the context of identifying consequences and evaluating interventions for rare diseases, health-related quality of life (HRQL) measures are often used. Conclusions about HRQL are difficult to make as the participants are likely drawn from different countries. A global estimate of HRQL with estimates of variation would permit pooling of data from diverse sources. The aim was to estimate a global HRQL score of typically developing children and adolescents on the Pediatric Quality of Life Inventory (PedsQL™) and to identify sources of variation across studies. A systematic search was conducted in December 2018 on four databases: MEDLINE, EMBASE, CINAHL and PsycINFO. Inclusion criteria were all population health studies or validation studies using the self-report version of the PedsQL™ for typically developing children aged 5 to 18 years. Quality appraisal was conducted using the Appraisal Tool for Cross-Sectional Studies. Meta-analysis and meta-regression were conducted. A total of 66 studies with a sample size of 67,805 participants were included in this analysis. The average QOL score across all studies was 80.9 (CI 78.6-83.2). Univariate analyses showed that region, minimum age of sample and income of country, was associated with the total HRQL score. Subgroup analysis showed that there was an effect of age and region on HRQL scores. Results of this review provide ranges of pediatric HRQL across personal factors and regions that can be used for normative comparisons of HRQL. Interpretation of scores on generic measures should always take into consideration the contextual influences in the child's life. PROSPERO, CRD42019128313 https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019128313 .


Post-antifungal effect of the combination of anidulafungin with amphotericin B and fluconazole against fluconazole-susceptible and -resistant Candida albicans.
Invasive candidiasis is a life-threatening condition that kills a large number of immunocompromised patients each year worldwide. We used post-antifungal effect studies to analyze the activities of anidulafungin (AFG), as a clinically crucial antifungal drug, amphotericin B (AMB), and fluconazole (alone and in combinations) against FLC-susceptible and -resistant Candida albicans (C. albicans) isolates obtained from the cancer patients. We tested the phenomenon of post antifungal effects of FLC, AMB, AFG, and combinations of FLC+AFG, AFG+AMB, and FLC+AMB against 17 C. albicans isolates obtained from the oral cavity of cancer patients. Isolates that had not been exposed to antifungals, served as a control group. Colony counts were performed at 0, 2, 4, 6, and 24 h after a brief (1 h) exposure to antifungal. The FLC had no detectable post-antifungal effect independent of antifungal concentration and resembled drug-free FLC (control). Significant variations in the post-antifungal effect were observed when all AMB and AFG were compared to FLC. The combination of AFG and AMB with FLC resulted in effective activity compared to FLC alone. Combination regimens were rated as indifferent in general. Interestingly, low dosages of the AFG displayed increasing fungistatic action as it approached a fungistatic endpoint against C. albicans isolates (n=17). Our findings suggested that brief exposure to AFG, in combination with FLC and AMB, at low concentrations of the medicines utilized, could be effective in the evaluation and optimization of new dosage regimens to manage candidiasis. However, future studies will determine the clinical utility of our findings.


Emergency Room Utilization After Medically Complicated Pregnancies: A Medicaid Claims Analysis.
Women with pregnancy complications benefit from closer monitoring postpartum and beyond. Increased postpartum emergency room (ER) use may indicate unmet need for outpatient obstetrics and primary care. The purpose of this study was to evaluate whether women with pregnancy complications (gestational diabetes [GDM], gestational hypertension, and preeclampsia) have increased ER use in the first 6 months postpartum, compared with women without these complications. We conducted a retrospective population-based cohort study using a 2003-2010 Maryland Medicaid managed care claims data set, linked with U.S. Census data. Data included claims for outpatient and ER visits for women aged 12-45 years who were continuously enrolled in Medicaid for at least 100 days of pregnancy and 90 days postpartum. We used logistic regression to calculate the association between pregnancy complications and having ≥1 ER visit in the 6 months postpartum. We identified 26,074 pregnancies, of which 20% were complicated by GDM, gestational hypertension, or preeclampsia. Of these complicated pregnancies, 42.1% had GDM, 35.4% had gestational hypertension, and 42.5% had preeclampsia (diagnoses were not mutually exclusive). In the 6 months postpartum, 25% of women had ≥1 ER visits. Of the complicated pregnancy group, 27.7% had ≥1 ER visit, versus 23.6% of the comparison group (p<0.0001). In adjusted analyses, women with a pregnancy complication were more likely to have ≥1 ER visit compared with women without these complications (odds ratio [OR]1.14, 95% confidence interval [CI] 1.05-1.23). The strength of association was highest in women under age 25 (OR 1.20, 95% CI 1.09-1.33). Preconception medical comorbidities (type 2 diabetes, chronic hypertension, obesity, asthma, mental health, and substance abuse diagnoses) were also strongly associated with postpartum ER use (OR 1.61, 95% CI 1.51-1.73). Pregnancy complications increased ER utilization during the 6 months postpartum, especially among women under age 25 years. Interventions that improve discharge planning and early postpartum care may decrease ER use.


BIRC6 modifies risk of invasive bacterial infection in Kenyan children.
Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with Plasmodium falciparum parasitaemia. We construct a joint dataset including 1445 bacteraemia cases and 1143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data, we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so, we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.


PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the monocytic differentiation response to vitamin D3.
We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha fusion gene, the expression of which is under the control of the inducible metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ hence exhibit levels of PML-RAR alpha protein as high as fresh acute promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of morphology, membrane antigen pattern, and functional criteria. Conversely, in the presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal differentiation, as evaluated by the above parameters. Interestingly, retinoic acid (RA) treatment suppresses the differentiation blockade induced by high level PML-RAR alpha protein; indeed, Zn(2+)-treated MTPR9 cells incubated with RA plus D3 exhibited significant terminal monocytic maturation, comparable to that of cells treated with D3 alone or combined with RA in absence of Zn2+. Similar observations were made in NB4, a PML-RAR+ human acute leukemic line. As expected RA treatment of NB4 cells causes granulocytic differentiation. Interestingly, the cell line is only scarcely induced to mature monocytic cells by D3 or D3 plus TGF-beta 1 treatment, whereas it is effectively induced to monocytic maturation by combined treatment with D3 and RA. Accordingly, the rate of NB4 cell proliferation is only slightly affected by D3 or D3 plus TGF-beta 1 treatment, mildly inhibited by RA, and markedly decreased by D3 plus RA. These results indicate that in both U937 and NB4 cells high level PML/RAR alpha expression inhibits the monocytic terminal differentiation program triggered by D3 or D3 plus TGF-beta 1, whereas RA treatment effectively antagonizes this inhibitory PML-RAR alpha action and restores the D3 differentiative effect.


Cerebrospinal Fluid Otorrhea After a Routine Tympanostomy Tube Placement: A Review of the Literature on Hyrtl Fissure.
To review the literature on Hyrtl fissure (HF) and contribute our experience with a 2-year old who developed cerebrospinal fluid (CSF) otorrhea during routine tympanostomy tube placement. Data Sources: Pubmed and Google Scholar searches were conducted of articles in the English language literature from all time periods using the words Hyrtl, Hyrtl's fissure, HF, and tympanomeningeal fissure. Study Selection: All relevant articles were reviewed to identify cases of HF. Data Extraction: Nineteen cases, including ours, are described. Patient characteristics, method(s) of diagnosis and repair, and outcomes are reported. Computed tomography and intraoperative endoscopic images from our case are included. Presentation is more common in children (66.7% of cases where age was stated, n = 10) than in adults (33.3%, n = 5), and is most commonly unilateral (89.5%, n = 17). Cerebrospinal fluid otorrhea was the most common presentation. Six were discovered after tympanostomy tube placements while 3 were identified during cochlear implant work-up or after device failure. Surgical approaches described include endaural, transcanal, retrosigmoid, postauricular, and posterior fossa endoscopic. Multiple materials including bone wax, bone pate, fascia, muscle, and tissue sealant have been used. Our case describes an endoscopic repair in a child, which was successful at a 2-year follow-up. Data Synthesis: The small number of cases limits the utility of statistical analysis (n = 19). Hyrtl fissure is a rare but important entity that may be discovered when routine procedures have unexpected results. Hyrtl fissure should be included in the differential diagnosis when there is persistent clear otorrhea after a tympanostomy tube, cochlear implant misinsertion, meningitis, or unexplained middle ear effusion in an adult.


ARNT deficiency represses pyruvate dehydrogenase kinase 1 to trigger ROS production and melanoma metastasis.
The metabolic changes in melanoma cells that are required for tumor metastasis have not been fully elucidated. In this study, we show that the increase in glucose uptake and mitochondrial oxidative phosphorylation confers metastatic ability as a result of aryl hydrocarbon receptor nuclear translocator (ARNT) deficiency. In clinical tissue specimens, increased ARNT, pyruvate dehydrogenase kinase 1 (PDK1), and NAD(P)H quinine oxidoreductase-1 (NQO1) was observed in benign nevi, whereas lower expression was observed in melanoma. The depletion of ARNT dramatically repressed PDK1 and NQO1 expression, which resulted in an increase of ROS levels. The elimination of ROS using N-acetylcysteine (NAC) and inhibition of oxidative phosphorylation using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and rotenone inhibited the ARNT and PDK1 deficiency-induced cell migration and invasion. In addition, ARNT deficiency in tumor cells manipulated the glycolytic pathway through enhancement of the glucose uptake rate, which reduced glucose dependence. Intriguingly, CCCP and NAC dramatically inhibited ARNT and PDK1 deficiency-induced tumor cell extravasation in mouse models. Our work demonstrates that downregulation of ARNT and PDK1 expression serves as a prognosticator, which confers metastatic potential as the metastasizing cells depend on metabolic changes.


A hospitalist's role in preventing patient falls.
Despite decades of fall prevention efforts, patient falls remain a common cause of harm in hospitalized older adults. While fall prevention strategies have been historically championed by nurses, hospitalist physicians, nurse practitioners, and physician assistants play a vital role in the multidisciplinary care team in ensuring the safety of our patients. Multiple fall risk assessment tools exist, but no one tool has demonstrated excellence in predicting patient falls in the hospital. Any fall risk assessment tool should be complemented by a clinician's individualized evaluation of patient-specific, situational, and environmental risk factors. A particular emphasis on medication review is critical, as numerous medication classes can increase the risk of falls, and medications are a potentially modifiable risk factor. Multiple studies of individual and multicomponent nursing-based interventions have failed to demonstrate success in reducing falls or fall injuries. Promising strategies for fall prevention include tailoring interventions to patient risk factors and individualized patient education. In addition to nursing-based interventions, the hospitalist's role in fall prevention is to (1) identify and address potentially modifiable risk factors, (2) reinforce individualized education to patients, and (3) advise behavior choices that promote safe mobility. If a patient does sustain a fall, the hospitalist should partner with the multidisciplinary care team in post fall care to assess for injury, evaluate underlying causes of the fall, and determine plans for secondary prevention.


Monkeypox scenario in India: a review study.
The monkeypox virus, which causes the viral zoonotic disease, is known as the most significant orthopoxvirus infection following the elimination of smallpox. The monkeypox virus, which was previously exclusive to West and Central African nations and caused endemic diseases in monkeys and people, has recently been linked to human infections in non-endemic areas including the United States of America (USA) and more than 30 additional countries. Guidelines for the diagnosis and treatment of monkeypox have also recently been made available by the Ministry of Health and Family Welfare of India and the Indian Government. The monkeypox outbreak continues to be a worldwide health emergency, the highest degree of alert recognised by the World Health Organization. The Centers for Disease Control and Prevention (CDC) advises vaccination for those who have been exposed to the disease as well as those who may be at higher risk of contracting it, such as those who have been identified by public health officials as a contact of someone who has the disease.


Hyperglycemia in Acutely Ill Non-diabetic Children in the Emergency Rooms of 2 Tertiary Hospitals in Lagos, Nigeria.
The study aimed to determine the prevalence of hyperglycemia in sick children admitted into the emergency rooms and to investigate its relationship with adverse outcomes. A prospective study involving 2 tertiary hospitals in Lagos. Study subjects included all children aged beyond 1 month. An Accu-Chek Active glucometer was used for the bedside blood glucose determination. Hyperglycemia was defined as blood glucose greater than 7.8 mmol/L. A total of 1045 patients were recruited with hyperglycemia being recorded in 135 patients (prevalence rate of 12.9%). Mean age of the hyperglycemic patients was 29.0 ± 31.23 months. Prevalence rates of hyperglycemia among the leading diagnoses were 17.4% in acute respiratory tract infections, 11% in malaria, 15.3% in septicemia, 14.9% in gastroenteritis, and 18.2% in burns. Other conditions include sickle cell anemia, meningitis, and malnutrition. Mortality rate was significantly higher overall in hyperglycemic compared with the normoglycemic patients (15.4% vs 8.0%, P = 0.011). With regard to specific diagnoses, significantly higher mortality rates were recorded in hyperglycemic patients with acute respiratory tract infections (28% vs 8%, P = 0.011) and malaria (21.4% vs 5.0%, P = 0.006) than in their normoglycemic counterparts. Hyperglycemia is common in ill children admitted to the emergency rooms and is associated with 2 to 4 times higher mortality in common childhood diseases encountered. Blood glucose determination is important in all acutely ill children at presentation. The practice of empirical administration of intravenous glucose in some resource-constrained facilities where blood glucose testing facilities are not readily available should be discouraged.


Predictive Models of Maternal Harsh Parenting During COVID-19 in China, Italy, and Netherlands.
Background: The COVID-19 pandemic drastically impacted on family life and may have caused parental distress, which in turn may result in an overreliance on less effective parenting practices. Objective: The aim of the current study was to identify risk and protective factors associated with impaired parenting during the COVID-19 lockdown. Key factors predicting maternal harsh discipline were examined in China, Italy, and the Netherlands, using a cross-validation approach, with a particular focus on the role of allomaternal support from father and grandparents as a protective factor in predicting maternal harshness. Methods: The sample consisted of 900 Dutch, 641 Italian, and 922 Chinese mothers (age M = 36.74, SD = 5.58) who completed an online questionnaire during the lockdown. Results: Although marital conflict and psychopathology were shared risk factors predicting maternal harsh parenting in each of the three countries, cross-validation identified a unique risk factor model for each country. In the Netherlands and China, but not in Italy, work-related stressors were considered risk factors. In China, support from father and grandparents for mothers with a young child were protective factors. Conclusions: Our results indicate that the constellation of factors predicting maternal harshness during COVID-19 is not identical across countries, possibly due to cultural variations in support from fathers and grandparents. This information will be valuable for the identification of at-risk families during pandemics. Our findings show that shared childrearing can buffer against risks for harsh parenting during COVID-19. Hence, adopting approaches to build a pandemic-proof community of care may help at-risk parents during future pandemics.


Mixed lymphocyte reactivity in cattle.
Mixed lymphocyte reactivity (MLR) in cattle was assessed by measuring the extent of cellular proliferation between allogeneic lymphocytes in an in vitro test system. To test for involvement of the bovine major histocompatibility system (BoLA) the MLR tests were done using full-sibling cattle families which had been generated through the use of embryo transfer systems. The results showed that the responses in the MLR tests were associated with the BoLA antigen sharing status between the individuals being tested. Since the tests, were done using full-sibling combinations, this result suggests genetic linkage between the MLR controlling antigens and the BoLA complex.


RNA binding properties of novel gene silencing pyrrole-imidazole polyamides.
Pyrrole-imidazole (PI) polyamides are a novel group of gene-silencing compounds, which bind to a minor groove of double stranded (ds)DNA in a sequence-specific manner. To explore the RNA binding properties of PI polyamides targeting rat transforming growth factor-β1 (TGF-β1 Polyamide) and influenza A virus (PA polyamide), we designed dsRNAs with an identical sequence to the target DNA and analyzed RNA binding properties of the polyamide. Biacore assay showed fast binding of TGF-β1 Polyamide to the dsRNA, whereas mismatch polyamide did not bind to the dsRNA. Dissociation equilibrium constant (KD) value was 6.7×10(-7) of the target dsRNA. These results indicate that PI polyamide could bind to RNA with a 2 log lower binding affinity than its DNA-binding affinity. We designed a PI polyamide targeting the panhandle stem region of influenza A virus. KD value of the PI polyamide to dsRNA targeting influenza A virus was 4.6×10(-7). Gel-shift assay showed that TGF-β1 and PA polyamides bound to the appropriate dsDNA, whereas these PI polyamides did not show obvious gel-shift with the appropriate dsRNA. Structural modeling suggests that PI polyamide binds to the appropriate B-form dsDNA in the minor groove, whereas it does not fit in the minor groove to dsRNA. Thus PI polyamides have a lower binding affinity with target dsRNA than they do with dsDNA. The distinct binding properties of PI polyamides to dsRNA and dsDNA may be associated with differences of secondary structure and chemical binding properties between target RNA and DNA.


Kinetic analysis of iodide transport in dog thyroid slices: perchlorate-induced discharge.
Dog thyroid slices were incubated with methimazole (2 mM) and radioiodide. The medium radioactivity was continuously recorded for 8 h. Multiple data were collected for individual glands to calculate simultaneously by compartmental analysis the influx and efflux rates of iodide from the slices. A two-compartment thyroid model was necessary and sufficient to simulate the transport of inorganic iodide. The two compartments could be defined as the cellular and the luminal spaces, but interferences due to slice thickness, nonuniform follicle sizes, and open follicles were not excluded. Sodium perchlorate (1 mM) inhibited the influx of iodide into the follicles and discharged the trapped radioiode into the medium with increased efflux rates. Our data suggest that perchlorate decreases the inward influx rates by competition and enhances the outward efflux rates by countertransport and support the hypothesis of mobile iodide carriers at the basal and apical membranes of the thyroid cells.


Human nuclear receptor heterodimers: opportunities for detecting targets of transcriptional regulation using yeast.
Nuclear receptors are model transcription factors. This highly conserved superfamily of ligand binding transcription factors includes estrogen, progesterone, retinoic acid, thyroid hormone, vitamin D receptors, and several orphan receptors. Nuclear receptors function as homodimers, heterodimers, or monomers. Human thyroid hormone, retinoic acid, vitamin D, and several orphan receptors prefer to work as heterodimers with retinoic X receptor (RXR). RXR function is regulated by its cognate ligand 9-cisretinoic acid. In some cases heterodimers of RXR are subject to regulation by two different ligands. Mammalian cells are not entirely suited to study pure heterodimeric functions because they contain a repertoire of endogenous receptors and their ligands. Yeast does not contain nuclear receptors or its ligands. Ligand-dependent function of several human nuclear receptors has been reconstructed in yeast. Yeast can be used as a model system to dissect interaction between various heterodimeric partners. The molecular genetics and the speed of doing the experiments in yeast allows us to rapidly clone mammalian cofactors that prefer to work with different heterodimeric partners. Once the human genome sequence is complete, we predict that the total number of human nuclear receptors will increase from 150 to 500. Novel and efficient cell-based systems will be needed to understand the function of orphan receptors. Yeast is an ideal system to identify pure heterodimeric partners and discover novel ligands for orphan receptors. The advantages and disadvantages of yeast and mammalian system to study nuclear receptor function are discussed.


The Setting Questionnaire for the Ayahuasca Experience: Questionnaire Development and Internal Structure.
The growing interest in research on psychedelic consumption in naturalistic contexts and their possible medical and therapeutic benefits requires assessment of the relationships between the substance and the individual who consumes it (set) and its context of use (setting). This study provides a novel measurement scale for the setting of Ayahuasca consumption, the Setting Questionnaire for the Ayahuasca Experience (SQAE), and examines its psychometric properties. Construction of the scale began with a literature review, followed by interviews on 19 Ayahuasca users from different backgrounds and different consumption experience, and an online survey for quantitative data collection (n = 2,994). Exploratory Graph Analysis (EGA) was used to investigate the questionnaire's dimensional structure with (n = 1,497, half of the sample), and multidimensional item response theory (MIRT) was used to compare the fit of the theoretical dimensions with the EGA proposed dimensions (n = 1,497, independent other half). EGA identified six dimensions, which corresponded partially to the theorized model (Leadership, Decoration, Infrastructure, Comfort, Instruction, and Social). The MIRT comparison found that the proposed theoretical model fit significantly better than the EGA model, providing support for the former (χ2/df = 1,967; CFI = 0,972; TLI = 0,969; RMSEA = 0,059; WRMR = 1,087). Our findings present evidence of validity of this instrument, justifying its use for future research on the influence of the setting during the ayahuasca experience. Its findings may provide a basis for expanding the settings investigated in the use of psychedelics in general.


Milk Fat Globule-EGF Factor 8 Contributes to Progression of Hepatocellular Carcinoma.
Milk fat globule-EGF factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates a wide spectrum of pathophysiological processes. MFG-E8 has been studied as a key regulator of cancer cell invasion, migration, and proliferation in different tissues and organs. However, potential roles of MFG-E8 in the growth and progression of liver cancer have not been investigated to date. Here, we analyzed 33 human hepatocellular carcinoma (HCC) samples and found that levels of MFG-E8 expression were significantly higher in HCC cells than in normal liver tissues. In addition, our in vitro gain-of-function study in three different HCC cell lines revealed that overexpression of MFG-E8 promoted the proliferation and migration of HCC cells, as determined by RT-qPCR, MTT assays, and wound healing analyses. Conversely, an MFG-E8 loss-of function study showed that proliferation capacity was significantly reduced by MFG-E8 knockdown in HCC cells. Additionally, MFG-E8 activity-neutralizing antibodies profoundly inhibited both migration and proliferation of HCC cells, attenuating their tumorigenic properties. These reductions in migration and proliferation were rescued by treatment of HCC cells with recombinant MFG-E8 protein. Furthermore, an in vivo HCC xenograft study showed that the number of proliferating HCC cells and tumor volume/weight were all significantly increased by MFG-E8 overexpression, compared to control mice. These results clearly show that MFG-E8 plays an important role in HCC progression and may provide a basis for future mechanistic studies and new strategies for the treatment of liver cancer.


[Celiac disease and "gluten sensitivity"].
It is known that celiac disease is characterized by a huge variety of clinical forms ranging from classical ones to silent forms, potential ones and to an increased number of cases of gluten-sensitivity. The latter is an abnormal non-allergic sensibility to gluten. Clinical manifestations can be very different without a severe intestinal damage (Marsh/Oberhuber 0-I) and this condition seems to benefit from a gluten free diet. Cases of gluten-sensitivity appear very interesting in the search of histological markers with elevated specificity, which are able to identify slight and early gluten dependent enteropathy, especially in at risk patients for celiac disease even before classical autoantibodies appear: for instance, this is the case of intraepithelial lymphocytes T-cell receptor gamma delta and mucosal deposits of class IgA anti transglutaminase antibodies. Other studies are investigating transglutaminase isoenzimes (different from tissue one), that can be identified in patients with gluten dependent symptoms without classical autoantibodies. Forms of gluten allergy have a different pathogenesis from celiac disease and are represented by "backer's asthma" or by classical allergy to wheat proteins. Clinical manifestations can vary from anaphylactic reactions to dermatological, respiratory and intestinal symptoms. Also in these cases the therapeutic approach is based on gluten free diet.


Software Application Profile: dynamicLM-a tool for performing dynamic risk prediction using a landmark supermodel for survival data under competing risks.
Providing a dynamic assessment of prognosis is essential for improved personalized medicine. The landmark model for survival data provides a potentially powerful solution to the dynamic prediction of disease progression. However, a general framework and a flexible implementation of the model that incorporates various outcomes, such as competing events, have been lacking. We present an R package, dynamicLM, a user-friendly tool for the landmark model for the dynamic prediction of survival data under competing risks, which includes various functions for data preparation, model development, prediction and evaluation of predictive performance. dynamicLM as an R package. The package includes options for incorporating time-varying covariates, capturing time-dependent effects of predictors and fitting a cause-specific landmark model for time-to-event data with or without competing risks. Tools for evaluating the prediction performance include time-dependent area under the ROC curve, Brier Score and calibration. Available on GitHub [https://github.com/thehanlab/dynamicLM].


Very early management of acute heart failure syndromes.
Diagnosis and management of acute heart failure syndromes are described in the most recent ESC/ESICM guidelines. However, physicians dealing with these patients in their daily practice may need guidance in choosing therapeutic alternatives as soon as the dyspneic patient arrives to the emergency department. Herein, practical recommendations for the very early management of patients with acute heart failure syndromes are presented. Blood pressure- and symptom-driven strategy along with early initiation of goal-directed therapies are key take-home messages. Furthermore, early and frequent reassessment is also an imperative part of management so that adjustments in the initial therapeutic plan can be achieved in a timely fashion.


Patient characteristics and long-term outcomes beyond the first 6 months after a diagnosis of cancer-associated venous thromboembolism.
Little is known about the clinical course and treatment decisions in patients with cancer-associated venous thromboembolism (VTE) beyond the initial treatment period of 3 to 6 months. This information is important for clinicians and patients to inform their decisions regarding duration of anticoagulation. We reviewed health records from consecutive patients referred to our institution for cancer-associated VTE management between 2013 and 2015 to describe their clinical course and outcomes from 6 to 24 months following their index VTE. Details on patient and cancer characteristics, objectively documented recurrent venous thromboembolism (rVTE), clinically relevant bleeding (CRB) and overall mortality were captured. 524 patients met eligibility criteria and 322 were alive at 6 months after the index VTE. At 6 months, anticoagulation was continued in 222 patients (68.9%). During follow-up, there were 33 rVTE events in 30 patients (1-year cumulative incidence of 8.2%; 95% CI: 5.5%-11.6%), and 16 CRB events in 15 patients (1-year cumulative incidence of 4.1%; 95% CI: 2.3%-6.7%); 20 (60.6%) rVTE events and 13 (81.3%) CRB events occurred while on anticoagulation. One-year survival beyond 6 months was 73.7% (95% CI: 68.5%-78.2%). A higher proportion of patients with advanced cancer and receiving cancer treatment was found among those who continued anticoagulation beyond 6 months compared to those who stopped anticoagulation. Patients with cancer-associated VTE who are alive at 6 months after VTE diagnosis remain at high risk of rVTE, CRB and death.


Rearrangement of adherens junctions by transforming growth factor-beta1: role of contraction.
The signal transduction pathways that lead to disruption of pulmonary endothelial monolayer integrity by transforming growth factor-beta1 (TGF-beta1) have not been elucidated. The purpose of this investigation was to determine whether disassembly of the adherens junction is temporally associated with the TGF-beta1-induced decrease in pulmonary endothelial monolayer integrity. Measurement of albumin clearance and electrical resistance showed that monolayer integrity started to decrease between 1 and 2 h post-TGF-beta1 treatment and continued to slowly decrease over the next 6 h. Immunofluorescence microscopy of monolayers between 2 and 3 h post-TGF-beta1 showed that beta-catenin, plakoglobin, alpha-catenin, and cadherin-5 were colocalized both at the cell periphery and in newly formed bands that are perpendicular to the cell-cell border. At 4 h post-TGF-beta1, cells began separating; however, beta- and alpha-catenin, plakoglobin, and cadherin-5 could still be found at the cell periphery at areas of cell separation and in strands between separated cells. By 8 h, these junctional proteins were no longer present at the cell periphery at areas of cell separation. The myosin light chain kinase inhibitor KT-5926 prevented the TGF-beta1-induced change in integrity but did not inhibit the formation of actin stress fibers or the formation of bands containing adherens junction proteins that were perpendicular to the cell-cell junction. Overall, these results suggest that adherens junction disassembly occurs after cell separation during TGF-beta1-induced decreases in pulmonary endothelial monolayer integrity and that the loss of integrity may be due to the activation of a myosin light chain kinase-dependent signaling cascade.


Incidence of anterior shoulder dislocation in Olmsted County, Minnesota.
The records of all Olmsted County, Minnesota residents treated for an initial traumatic anterior shoulder dislocation during a ten-year period were reviewed to study the incidence and natural history of this condition. One hundred twenty-four patients had been treated during the study period, and in 116 patients (93.5%) complete follow-up evaluation was available. The overall adjusted incidence of initial traumatic shoulder dislocations was 8.2/100,000 person-years; of all traumatic shoulder dislocations, the rate was at least 11.2/100,000 person-years. Incidence rates were significantly greater for men than for women. There was no urban versus rural difference in incidence or recurrence rates. The authors concluded that shoulder dislocation occurs most frequently in younger male patients and occurs with similar frequency in urban and rural settings. Except for age-related differences in recurrence rates no significant referral bias was found among patients treated at a tertiary care facility as compared with patients from the local community.


Sustainability pedagogy: Understanding, exploring and internalizing nature's complexity and coherence.
Online learning during the COVID-19 pandemic has affected student academic performance as well as mental, physical, and social wellbeing. During a lockdown at the University of Toronto in Canada (September 2020-April 2021), my students expressed an underlying sense of monotony yet uncertainty. I recalled a contrasting paradox from the teachings of Indigenous Cree on mental wellness in land-based experiences: a sense of stimulation and security that we can liken to variations of Appleton's prospect-refuge theory. I modified my Environmental Science and Pathways to Sustainability course to support stimulation and security through embodied, interactive pedagogy at student-selected individual field sites. My main goals were to (i) support student mental wellness and (ii) provide an alternative to experiential field trips for understanding and connecting with nature as an adaptive complex system. I prompted students with field activities contextualized by a course narrative that purposefully directed attention to nature through intrinsically motivated curiosity, exploration, and discovery; conditions more similar to evolutionary environments of adaptedness than "getting away" in passive retreats. Student weekly field observations and reflections culminated in a post-intervention Reflection Assignment (n = 15) which became the bases of thematic and narrative analysis. Other assignments were added to my evaluation of complexity comprehension. The intervention successfully instilled security and stimulation via purpose-directed attention to different aspects of nature in the same setting followed by periods of knowledge integration. This empowered students with sustainability mindsets indicated by greater self-reported: sense of coherence, change agency, cognitive and affective restoration, nature connectedness, nature relatedness, social connectedness, and pro-environmental values. Assignments demonstrated an understanding of the environment as an adaptive complex system that was not present at the beginning of the course. Some students' self-construct adopted nature and its complexity, empowering them with greater trait resilience. This work speaks to opportunities for merging psychological restoration and analytical curricula by integrating cognitive and sensory meaningfulness in sustainability narratives. It asks scholars to reflect on how we operationalize foundational theories of Environmental Psychology based on ancestral survival conditions and encourages empirical research to consider how sociocultural contexts can direct attention to nature through purposeful inquiry.


Aerobic degradation of polychlorinated biphenyls.
The microbial degradation of polychlorinated biphenyls (PCBs) has been extensively studied in recent years. The genetic organization of biphenyl catabolic genes has been elucidated in various groups of microorganisms, their structures have been analyzed with respect to their evolutionary relationships, and new information on mobile elements has become available. Key enzymes, specifically biphenyl 2,3-dioxygenases, have been intensively characterized, structure/sequence relationships have been determined and enzymes optimized for PCB transformation. However, due to the complex metabolic network responsible for PCB degradation, optimizing degradation by single bacterial species is necessarily limited. As PCBs are usually not mineralized by biphenyl-degrading organisms, and cometabolism can result in the formation of toxic metabolites, the degradation of chlorobenzoates has received special attention. A broad set of bacterial strategies to degrade chlorobenzoates has recently been elucidated, including new pathways for the degradation of chlorocatechols as central intermediates of various chloroaromatic catabolic pathways. To optimize PCB degradation in the environment beyond these metabolic limitations, enhancing degradation in the rhizosphere has been suggested, in addition to the application of surfactants to overcome bioavailability barriers. However, further research is necessary to understand the complex interactions between soil/sediment, pollutant, surfactant and microorganisms in different environments.


mRNA Expression of CDK2AP1 in Human Breast Cancer: Correlation with Clinical and Pathological Parameters.
Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) interacts with CDK2AP2, modulates the actions of transforming growth factor-B1, cyclin-dependent kinase 2 and retinoblastoma protein, and closely interacts with micro-RNA21 and micro-RNA25. Our objective was to determine if CDK2AP1 mRNA expression levels were consistent with tumour-suppressive functions in breast cancer. A total of 134 samples were analysed. CDK2AP1 mRNA levels were measured using quantitative polymerase chain reaction (RT-PCR) and normalised against glyceraldehyde 3-phosphate dehydrogenase mRNA. Levels in breast cancer and adjacent non-cancerous breast tissue were analysed against pathological and clinical parameters (TNM staging, survival over a 10-year follow-up period). Normalised CDK2AP1 expression was 38-fold higher in adjacent non-cancerous breast tissue than in breast cancer. CDK2AP1 expression in disease-free patients at 10 years was more than threefold that of patients who died of breast cancer. However, neither of these differences in expression levels reached statistical significance. CDK2AP1 mRNA levels were higher in TNM1 compared to TNM3 (p=0.016) and with TNM4 (p=0.016). There were no significant associations between CDK2AP1 expression and estrogen receptor status, tumour grade and tumour type. There was no significant difference in overall survival between patients with high and those with low CDK2AP1 mRNA levels after a median follow-up of 10 years (Kaplan-Meier analysis, p=0.872). To our knowledge, this is the first study in the literature to examine the mRNA expression of CDK2AP1 in human breast cancer over a long-term follow-up period. A compelling relationship exists between high CDK2AP1 mRNA expression and lower TNM classification of breast cancer, which is consistent with CDK2AP1 having a tumour-suppressive function.


Defining metabolic activity of nephrolithiasis - Appropriate evaluation and follow-up of stone formers.
Considering the variation in metabolic evaluation and medical management of kidney stone disease, this consensus review was created to discuss the metabolic activity of nephrolithiasis, define the difference between single and recurrent stone formers, and develop a schema for metabolic and radiologic follow-up. A systematic review of the literature was performed to identify studies of metabolic evaluation and follow-up of patients with nephrolithiasis. Both single and recurrent stone formers share many similarities in metabolic profiles. The study group determined that based on an assessment of risk for stone recurrence and metabolic activity, single and recurrent stone formers should be evaluated comprehensively, including two 24 h urine studies on a random diet. Targeted medication and dietary recommendations are effective for many patients in reducing the risk of stone recurrence. Follow-up of those with stone disease should be obtained depending on the level of metabolic activity of the patient, the risk of chronic kidney disease and the risk of osteoporosis/osteopenia. A standard scheme includes a baseline metabolic profile, a repeat study 3-6 months after initiation of treatment, and then yearly when stable, with abdominal imaging obtained every 1-2 years.