Gender differences in coerced patients with schizophrenia.
Despite the recent increase of research interest in involuntary treatment and the use of coercive measures, gender differences among coerced schizophrenia patients still remain understudied. It is well recognized that there are gender differences both in biological correlates and clinical presentations in schizophrenia, which is one of the most common diagnoses among patients who are treated against their will. The extent to which these differences may result in a difference in the use of coercive measures for men and women during the acute phase of the disease has not been studied. 291 male and 231 female coerced patients with schizophrenia were included in this study, which utilized data gathered by the EUNOMIA project (European Evaluation of Coercion in Psychiatry and Harmonization of Best Clinical Practice) and was carried out as a multi-centre prospective cohort study at 13 centers in 12 European countries. Sociodemographic and clinical characteristics, social functioning and aggressive behavior in patients who received any form of coercive measure (seclusion and/or forced medication and/or physical restraint) during their hospital stay were assessed. When compared to the non-coerced inpatient population, there was no difference in sociodemographic or clinical characteristics across either gender. However coerced female patients did show a worse social functioning than their coerced male counterparts, a finding which contrasts with the non-coerced inpatient population. Moreover, patterns of aggressive behavior were different between men and women, such that women exhibited aggressive behavior more frequently, but men committed severe aggressive acts more frequently. Staff used forced medication in women more frequently and physical restraint and seclusion more frequently with men. Results of this study point towards a higher threshold of aggressive behavior the treatment of women with coercive measures. This may be because less serious aggressive actions trigger the application of coercive measures in men. Moreover coerced women showed diminished social functioning, and more importantly more severe symptoms from the "excitement/hostile" cluster in contrast to coerced men. National and international recommendation on coercive treatment practices should include appropriate consideration of the evidence of gender differences in clinical presentation and aggressive behaviors found in inpatient populations.


Gravity effects on mixing with magnetic micro-convection in microfluidics.
Mixing remains an important problem for the development of successful microfluidic and lab-on-a-chip devices, where simple and predictable systems are particularly interesting. One is magnetic micro-convection, an instability happening on the interface of miscible magnetic and non-magnetic fluids in a Hele-Shaw cell under applied field. Previous work proved that the Brinkman model quantitatively explains the experiments. However, a gravity-caused convective motion complicated the tests. Here we first improve the experimental system to exclude the parasitic convection. Afterwards, we experimentally observe the magnetic micro-convection, by finding and quantifying how gravity and laminar flow stabilizes the perturbations that create it. Accordingly, we improve our theoretical model for a zero-flow condition and perform a linear analysis. Two dimensionless quantities --magnetic and gravitational Rayleigh numbers-- are used to compare the experimental observations and theoretical predictions for the critical field of instability and the characteristic size of the emerging pattern. Finally, we discuss the conditions at which gravity plays an important role in microfluidic systems.


The immunoglobulin superfamily protein differentiation of embryonic stem cells 1 (dies1) has a regulatory role in preadipocyte to adipocyte conversion.
Differentiation of Embryonic Stem Cells 1 (Dies1) was recently identified as a novel type I immunoglobulin (IgG) domain-containing plasma membrane protein important for effective differentiation of a murine pluripotent embryonic stem cell line. In this setting, Dies1 enhances bone morphogenetic protein 4 (BMP4) signaling. Here we show Dies1 transcript expression is induced ∼225-fold during in vitro adipogenesis of 3T3-L1 murine preadipocytes. Immunocytochemical imaging using ectopic expression of Flag-tagged Dies1 in 3T3-L1 adipocytes revealed localization to the adipocyte plasma membrane. Modulation of adipocyte phenotype with with tumor necrosis factor-α (TNFα) treatment or by siRNA knockdown of the master pro-adipogenic transcription factor peroxisome proliferator activated receptor gamma (PPARγ) resulted in a 90% and 60% reduction of Dies1 transcript levels, respectively. Moreover, siRNA-mediated Dies1 knockdown in 3T3-L1 preadipocytes inhibited adipogenic conversion. Such cultures had a 35% decrease in lipid content and a 45%-65% reduction in expression of key adipocyte transcripts, including that for PPARγ. The standard protocol for full in vitro adipogenic conversion of committed preadipocytes, such as 3T3-L1, does not include BMP4 treatment. Thus we posit the positive role of Dies1 in adipogenesis, unlike that for Dies1 in differentiation of embryonic stem cells, does not include its pro-BMP4 effects. In support of this idea, 3T3-L1 adipocytes knocked down for Dies1 did not evidence decreased phospho-Smad1 levels upon BMP4 exposure. qPCR analysis of Dies1 transcript in multiple murine and human tissues reveals high enrichment in white adipose tissue (WAT). Interestingly, we observed a 10-fold induction of Dies1 transcript in WAT of fasted vs. fed mice, suggesting a role for Dies1 in nutritional response of mature fat cells in vivo. Together our data identify Dies1 as a new differentiation-dependent adipocyte plasma membrane protein whose expression is required for effective adipogenesis and that may also play a role in regard to nutritional status in WAT.


A novel pathway of nutrient absorption in crustaceans: branchial amino acid uptake in the green shore crab (Carcinus maenas).
Estuaries are environments enriched with dissolved nutrients such as amino acids. To date, marine arthropods are the only invertebrate group that have not been demonstrated to access this potentially important nutrient resource. Using in vitro gill perfusion techniques, we sought to investigate the ability of the green shore crab (Carcinus maenas) to take up the amino acid l-leucine directly from the water. Investigation of the concentration-dependent transport kinetics of radiolabelled l-leucine showed that there are two specific transport pathways across Carcinus gills, one with high affinity and low capacity, and the other with high capacity and low affinity. Using putative competitive substrates and reduced sodium preparations, we were able to identify the putative amino acid transport system associated with high-affinity uptake. This is the first study to demonstrate the absorption of dissolved organic nutrients across the gill epithelium of a marine arthropod.


Light-Chain Deposition Disease Presenting with Spontaneous Splenic Rupture.
Light-chain deposition disease is a rare paraproteinaemia characterized by deposition of monoclonal light-chain immunoglobulins with a non-amyloid structure, most frequently affecting the kidney. The authors present the case of a 58-year-old man admitted due to haemorrhagic shock caused by spontaneous splenic rupture. Investigation showed coagulopathy, homogeneous hepatomegaly with elevated cholestasis enzymes but normal bilirubinaemia, and a nephrotic syndrome with monoclonal kappa light chains. Liver and bone marrow biopsies revealed light-chain deposition disease. Splenic rupture as the presentation of a paraproteinaemia is rare. The diagnosis of light-chain deposition disease should be considered in case of a monoclonal plasma cell disorder with Congo-red negative deposits on histology. Spontaneous splenic rupture is a rare presentation of a paraproteinaemia.Light-chain deposition disease is a rare disease with non-fibrillar deposition of monoclonal light-chain immunoglobulins most frequently affecting the kidney.Light-chain deposition disease should be suspected in case of a monoclonal plasma cell disorder with Congo-red negative deposits on histology.


Changes in prolactin receptor homodimer availability may cause late feathering in chickens.
Chicken early (EF) and late feathering (LF) are sex-linked phenotypes conferred by wild-type k+ and dominant K alleles on chromosome Z, respectively. Besides prolactin (PRL) receptor (PRLR) and sperm flagellar 2 (SPEF2) genes, the K allele contains a fusion gene in which partially duplicated PRLR (dPRLR) and SPEF2 (dSPEF2) genes are linked in a tail-to-tail manner. The causative dPRLR gene encodes a C-terminal truncated receptor. LF chickens have short or no primaries at hatching; however, their feather growth rate is higher than that of EF chickens. This study aimed to elucidate the molecular basis of the K allele's biphasic effect on feather development. By 3'RACE and RT-PCR analyses, we demonstrated that dSPEF2 gene transcription occurred beyond all coding exons of the dPRLR gene on the opposite strand and that dPRLR mRNA was less abundant than PRLR mRNA. In addition, a 5'UTR splice variant (SPV) of PRL receptor mRNAs was increased in LF chickens. In vitro expression analysis of 5'UTR linked to the luciferase reporter gene revealed higher translation efficiency of SPV. RT-qPCR showed that the dPRLR mRNA level was higher in embryos; conversely, SPV was higher in hatched chickens, as was dSPEF2 mRNA. These findings suggest that the K allele inhibits feather development at the fetal stage by expressing dPRLR to attenuate PRLR function and promotes feather growth after hatching by increasing PRLR through dSPEF2 mRNA expression. Increased SPV may cause greater feather growth than that in EF chickens by increasing the availability of PRLR homodimers and enhancing PRL signaling.


Infectious disease consultation is effective in boosting vaccine coverage in patients awaiting kidney transplantation: A French prospective study.
Recommended preventive strategies before kidney transplantation include screening and treatment of latent tuberculosis infection (LTBI), and updating of the recommended vaccines. We prospectively evaluated in dedicated infectious diseases consultations, from 2014 to 2018, the clinical and vaccination data of new adult kidney allograft candidates. Patients were offered an updated vaccination schedule, if appropriate, and were screened for LTBI using chest imaging and interferon gamma release assay (IGRA). Overall, 467 patients with median age of 58 [46-66] years were evaluated, of whom 302 patients (65%) were men (sex ratio 1.83), and 333 (71%) were on dialysis. Main causes of renal insufficiency were diabetes (25%) and autoimmune nephropathies (18%). The vaccination coverage was low and varied according to the different types of vaccines and patients. Vaccination or immunization rates were 24%, 6%, 54%, and 51% for tetanus-diphtheria-polio-acellular pertussis, Pneumococcus, hepatitis B, and seasonal influenza, respectively. ID consultation successfully rose patients' vaccinations coverage, in fulfillment with recommendations, in 465 (99%) patients. LTBI treatment was administered in 78 (16.7%) patients and caused drug-related adverse events in 9 (11%). A dedicated infectious disease consultation should become a critical tool for coordinating infection prevention strategies.


Kikuchi's disease: a Singapore case series.
Kikuchi's disease is a benign form of cervical lymphadenopathy that commonly affects young adults. We report a case series from our hospital. The clinical features of 23 cases of Kikuchi's disease diagnosed at Changi General Hospital over a seven year period are presented. The cases were identified from pathology records using the search term histiocytic necrotising lymphadenitis. Most of our patients (78 percent) were young women who presented with cervical lymphadenopathy. The median age was 31 years. In the 18 cases who completed follow-up at the hospital, there was spontaneous resolution of symptoms within a six-month period. One patient demonstrated seropositivity for systemic lupus erythematosus (SLE) and was initially started on steroids. However, the treatment was discontinued shortly afterwards since she did not meet the diagnostic criteria for SLE. Excision biopsy of the affected lymph node was the diagnostic method of choice. Kikuchi's disease is not uncommon in the Singaporean population. Establishing an early diagnosis is crucial since the clinical presentation can mimic tuberculous lymphadenitis or malignant lymphoma. The diagnostic method of choice is excision biopsy.


c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks.
Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.


What do athletes drink during competitive sporting activities?
Although expert groups have developed guidelines for fluid intake during sports, there is debate about their real-world application. We reviewed the literature on self-selected hydration strategies during sporting competitions to determine what is apparently practical and valued by athletes. We found few studies of drinking practices involving elite or highly competitive athletes, even in popular sports. The available literature revealed wide variability in fluid intake and sweat losses across and within different events with varied strategies to allow fluid intake. Typical drinking practices appear to limit body mass (BM) losses to ~2 % in non-elite competitors. There are events, however, in which mean losses are greater, particularly among elite competitors and in hot weather, and evidence that individual participants fail to meet current guidelines by gaining BM or losing >2 % BM over the competition activity. Substantial (>5 %) BM loss is noted in the few studies of elite competitors in endurance and ultra-endurance events; while this may be consistent with winning outcomes, such observations cannot judge whether performance was optimal for that individual. A complex array of factors influence opportunities to drink during continuous competitive activities, many of which are outside the athlete's control: these include event rules and tactics, regulated availability of fluid, need to maintain optimal technique or speed, and gastrointestinal comfort. Therefore, it is questionable, particularly for top competitors, whether drinking can be truly ad libitum (defined as "whenever and in whatever volumes chosen by the athlete"). While there are variable relationships between fluid intake, fluid balance across races, and finishing times, in many situations it appears that top athletes take calculated risks in emphasizing the costs of drinking against the benefits. However, some non-elite competitors may need to be mindful of the disadvantages of drinking beyond requirements during long events. Across the sparse literature on competition hydration practices in other sports, there are examples of planned and/or ad hoc opportunities to consume fluid, where enhanced access to drinks may allow situations at least close to ad libitum drinking. However, this situation is not universal and, again, the complex array of factors that influence the opportunity to drink during an event is also often beyond the athletes' control. Additionally, some competition formats result in athletes commencing the event with a body fluid deficit because of their failure to rehydrate from a previous bout of training/competition or weight-making strategies. Finally, since fluids consumed during exercise may also be a source of other ingredients (e.g., carbohydrate, electrolytes, or caffeine) or characteristics (e.g., temperature) that can increase palatability or performance, there may be both desirable volumes and patterns of intake that are independent of hydration concerns or thirst, as well as benefits from undertaking a "paced" fluid plan. Further studies of real-life hydration practices in sports including information on motives for drinking or not, along with intervention studies that simulate the actual nature of real-life sport, are needed before conclusions can be made about ideal drinking strategies for sports. Different interpretations may be needed for elite competitors and recreational participants.


Inhibition of aldose reductase prevents lipopolysaccharide-induced inflammatory response in human lens epithelial cells.
Bacterial infections are one of the major causes of human eye disease. Because the bacterial endotoxin lipopolysaccharide (LPS) is known to cause cytotoxicity through oxidative stress and an earlier study has shown that aldose reductase (AR) mediates oxidative stress signals, the purpose of this study was to investigate the anti-inflammatory effects of AR inhibition on LPS-induced activation of NF-kappaB-dependent signals in human lens epithelial cells (HLECs). Growth-arrested HLECs were cultured without or with AR inhibitors or transfected with an AR small interfering (si)RNA. Subsequently, the cells were stimulated with LPS (1-10 mug/mL) for 24 hours. The cell viability was assessed by cell counts and MTT assay, and apoptosis was measured by nucleosomal degradation. Electrophoretic mobility gel shift assays were performed to determine the activation of NF-kappaB and AP1. The levels of nitric oxide, MMP-2, MMP-9, Cox-2, and TNF-alpha were measured by using specific ELISA kits. Western blot analysis was performed to determine the cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of PKC and mitogen-activated protein kinase (MAPK). Bacterial LPS caused apoptosis of HLECs. Inhibition of AR by two structurally unrelated inhibitors, sorbinil and tolrestat, or ablation by AR siRNA prevented the LPS-induced apoptosis, activation of caspase-3 and cleavage of PARP protein. Inhibition of AR in HLECs also prevented the LPS-induced activation of redox-sensitive transcription factors such as NF-kappaB and AP1 and their downstream signals that lead to expression of Cox-2, MMP-2, MMP-9, and TNF-alpha proteins. In addition, inhibition of AR prevented LPS-induced activation of protein kinases upstream to NF-kappaB activation such as PKC and MAPK in HLECs. The results indicate that AR mediates the bacterial endotoxin signaling that could damage HLECs by regulating the signals that activate the redox-sensitive transcription factor NF-kappaB and cause inflammation. Thus, inhibition of AR could be a therapeutic target for Gram-negative bacterial infection-induced visual complications.


The heritable activation of cryptic Suppressor-mutator elements by an active element.
A weakly active maize Suppressor-mutator (Spm-omega) element is able to heritably activate cryptic Spm elements in the maize genome. The spontaneous activation frequency, which is 1-5 x 10(-5) in the present genetic background, increases by about 100-fold in the presence of an Spm-omega and remains an order of magnitude above the background level a generation after removal of the activating Spm-omega. Sectorial somatic reactivation of cryptic elements can be detected phenotypically in kernels. Selection of such kernels constitutes an efficient selection for plants with reactivated Spm elements. Analysis of the reactivation process reveals that it is gradual and proceeds through genetically metastable intermediates that exhibit different patterns of element expression during plant development. Newly reactivated elements tend to return to an inactive form. However, the probability that an element will remain in a heritably active state increases when the element is maintained in the presence of an active Spm element for several generations.


Psychosomatic effects of blanketing in nursing care.
Blanketing, which involves covering patients with a blanket in order to maintain their body temperature and privacy and help alleviate the stress that is associated with medical procedures, is a fundamental skill in nursing care. However, the actual therapeutic effects of blanketing have not been adequately investigated. Therefore, the aim of the present study was to clarify the psychosomatic effects of blanketing in nursing care by observing autonomic nervous activity. This single-cohort, intra-participant, comparative cross-over study included 30 healthy female adolescents. Two of the 30 participants were excluded from the analysis. After splitting the participants into blanketing and non-blanketing groups, the stress and anxiety that patients undergo during nursing care was simulated and the responses were analyzed by using psychological and physiological indicators. The parametric data were analyzed by using a paired t-test or one-way ANOVA and the non-parametric data were analyzed by using the Wilcoxon signed-rank test. The significance level was <5%. No significant difference was seen between the two groups in vital signs, salivary alpha-amylase activity, respiratory movement or skin surface temperature. However, the postintervention scores for "Tension-Anxiety" in the Profile of Mood States - Brief Form were significantly lower for the blanketed than the non-blanketed arm, "sense of ease" and "feeling protected" were significantly higher for the blanketed arm, and in the middle intervention segment, the parasympathetic nervous activity and sympathetic nervous activity were significantly higher and lower, respectively, for the blanketed arm. These results suggest that blanketing is effective in relieving psychological stress and promoting a sense of ease among patients who are receiving nursing care.


Pediatric migraine and the International Headache Society (IHS) criteria.
The optimal criteria for the diagnosis of migraine without aura in children are controversial. One strategy for assessing the validity of diagnostic criteria is to compare them with expert clinical diagnoses. To study the agreement between clinical headache diagnoses assigned by pediatric neurologists and symptom-based diagnoses using the International Headache Society (IHS) criteria as well as alternative case definitions. We reviewed the records of 253 children and adolescents consecutively evaluated by pediatric neurologists at the Montefiore Headache Unit. Clinical diagnoses assigned by the physicians were used as the gold standard in evaluating the validity of the IHS criteria for the diagnosis of migraine without aura. Alternative symptom-based diagnoses were compared with the clinical gold standard. Detailed headache histories were abstracted from charts of 253 children; 167 children had complete data on all features required for IHS diagnosis. Eighty-eight (52.7%) children received a diagnosis of migraine without aura. Using the clinical diagnosis as the gold standard, the IHS criteria had a sensitivity of 27.3% and a specificity of 92.4%. The poor sensitivity of the IHS definition is a consequence of the rarity of certain features in children clinically diagnosed with migraine: duration of 2 hours or longer (55.7%), unilateral pain (34.1%), vomiting (47.7%), and phonophobia (27.3%). Based on these findings we suggested a definition for pediatric migraine headache without aura that is less complex, more sensitive (71.6%), and almost as specific as the IHS criteria. The IHS criteria for migraine without aura have poor sensitivity but high specificity using a clinical diagnosis as the gold standard. The IHS criteria should be modified to better reflect current pediatric clinical practice.


Evidences for a role of protein cross-links in transglutaminase-related disease.
Transglutaminases (TGs) are a large family of related and ubiquitous enzymes that catalyze the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. Considerable and intense progress has been made in the understanding of the chemistry, molecular biology and cell biology of TGs. The knowledge that very different physiological and pathological processes are dependent on the presence of adequate levels of these cross-linking enzymes and on the amount of both free and protein-conjugated polyamines by TG, has generated an incredible amount of original research and review articles. It is clear that TG-mediated reactions are essential for some biological processes, such as blood coagulation, skin barrier formation and extracellular matrix assembly, but may also be involved in pathogenetic mechanisms responsible for several human diseases, such as cancer, AIDS, neurodegenerative disorders, celiac disease, and eye lens opacification. We present here a comprehensive review of recent insights into the pathophysiology of TGs related to their protein cross-linking activity.


Chewing and food consistency: effects on bolus transport and swallow initiation.
Preswallow bolus formation usually occurs in the mouth for liquids and in the oropharynx for solid foods. We examined the effect of chewing on the relationship between bolus transport and swallow initiation. Fifteen healthy subjects were imaged with lateral projection videofluorography while eating liquids, solid foods, and a mixture of liquid and solid foods in upright and facedown postures. Videotapes were reviewed to measure the location of the leading edge of the barium at swallow initiation. Chewing and initial consistency each altered the relationship between food transport and swallow initiation. In particular, when chewing liquid (or consuming foods with both liquid and solid phases), a portion of the food commonly reached the hypopharynx well before swallow onset. This transport to the hypopharynx was highly dependent on gravity, but transport to the valleculae for chewed solid food was active, depending primarily on tongue-palate contact. Chewing appeared to reduce the effectiveness of the posterior tongue-palate seal, allowing oral contents to spill into the pharynx. Consuming two-phase foods with both solid and liquid phases may increase the risk of aspiration in dysphagic individuals with impaired airway protective reflexes.


Profiling the Oral Microbiome and Plasma Biochemistry of Obese Hyperglycemic Subjects in Qatar.
The present study is designed to compare demographic characteristics, plasma biochemistry, and the oral microbiome in obese (N = 37) and lean control (N = 36) subjects enrolled at Qatar Biobank, Qatar. Plasma hormones, enzymes, and lipid profiles were analyzed at Hamad Medical Cooperation Diagnostic Laboratory. Saliva microbiome characterization was carried out by 16S rRNA amplicon sequencing using Illumina MiSeq platform. Obese subjects had higher testosterone and sex hormone-binding globulin (SHBG) concentrations compared to the control group. A negative association between BMI and testosterone (P < 0.001, r = -0.64) and SHBG (P < 0.001, r = -0.34) was observed. Irrespective of the study groups, the oral microbiome was predominantly occupied by Streptococcus, Prevotella, and Veillonella species. A generalized linear model revealed that the Firmicutes/Bacteroidetes ratio (2.25 ± 1.83 vs. 1.76 ± 0.58; corrected P-value = 0.04) was higher, and phylum Fusobacteria concentration (4.5 ± 3.0 vs. 6.2 ± 4.3; corrected P-value = 0.05) was low in the obese group compared with the control group. However, no differences in microbiome diversity were observed between the two groups as evaluated by alpha (Kruskal-Wallis P ≥ 0.78) and beta (PERMANOVA P = 0.37) diversity indexes. Certain bacterial phyla (Acidobacteria, Bacteroidetes, Fusobacteria, Proteobacteria, Spirochaetes, and Firmicutes/Bacteroidetes) were positively associated (P = 0.05, r ≤ +0.5) with estradiol, fast food consumption, creatinine, breastfed during infancy, triglycerides, and thyroid-stimulating hormone concentrations. In conclusion, no differences in oral microbiome diversity were observed between the studied groups. However, the Firmicutes/Bacteroidetes ratio, a recognized obesogenic microbiome trait, was higher in the obese subjects. Further studies are warranted to confirm these findings in a larger cohort.


The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients.
Purpose: Cell-free DNA (cfDNA) sequencing provides a noninvasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (The Cancer Genome Atlas and COSMIC; r = 0.90-0.99), with the principal differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR = 5 × 10-7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations (>18.6% patients).Conclusions: Together, these retrospective analyses of a large cfDNA sequencing data set reveal subclonal structures and emerging resistance in advanced solid tumors. Clin Cancer Res; 24(15); 3528-38. ©2018 AACR.


Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target.
Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin αvβ5 (ITGαvβ5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target.


The contribution of mitochondria to energetic metabolism in photosynthetic cells.
Mitochondria fulfill important functions in photosynthetic cells not only in darkness but also in light. Mitochondrial oxidative phosphorylation is probably the main mechanism to supply ATP for extrachloroplastic functions in both conditions. Furthermore, during photosynthesis mitochondrial electron transport is important for regulation of the redox balance in the cell. This makes mitochondrial function an integral part of a flexible metabolic system in the photosynthetic cell. This flexibility is probably very important in order to allow the metabolism to override disturbances caused by the changing environment which plants are adapted to.


Technetium-99m production issues in the United Kingdom.
Nuclear Medicine developed when it was realised that a radioisotopic substitution of Iodine-131 for the stable Iodine-127 would follow the same metabolic pathway in the body enabling the thyroid to be imaged and the thyroid uptake measured. The Iodine could be complexed with pharmaceutical substrates to enable other organs to be imaged, but its use was limited and high gamma energy and beta emission restricted the activity of each radiopharmaceutical used, leading to long acquisition times and degraded images. As a pure gamma emitter of 140 keV and with a 6-h half-life, Technetium-99m is a better radionuclide and images a wider range of bodily organs. However, its short half-life also requires it to be eluted from its mother radionuclide, Mo-99, in a generator, delivered weekly from radiopharmaceutical companies who obtain the Mo-99 in liquid form from high-flux research reactors. All went well till around 2007, when the NRU Reactor in Canada was closed and all other reactors went down for various periods for unrelated problems, leading to widespread Mo-99 shortages. Although the reactors have since recovered, they are 48 to 57 years old, and it seems that few governments have made any future provision such as building replacement reactors.


Screening for personality disorders among adults seeking speech treatment for stuttering.
Stuttering is frequently associated with negative consequences which typically begin in early childhood. Despite this, no previous studies have investigated the presence of personality disorders among adults who stutter. Therefore, the aims of the present study were to screen for personality disorders among adults who stutter, and to compare these screening estimates with matched controls from a national population sample. Using a matched case-control design, participants were 94 adults seeking treatment for stuttering, 92 of whom completed the International Personality Disorders Examination Questionnaire (IPDEQ) as a first-stage screener, and 920 age- and gender-matched controls from the Australian National Survey of Mental Health and Well-Being (ANSMHWB). A conditional logistic regression model was used to estimate odds ratios for the primary outcome: first-stage presence of any personality disorder; as well as specific personality disorders. Based on first-stage screening, the presence of any personality disorder was significantly higher for adults in the stuttering group than matched controls, demonstrating almost threefold increased odds. This difference between groups remained significant for all specific personality disorders, with four- to sevenfold increased odds found for Dissocial, Anxious, Borderline, Dependent and Paranoid personality disorders, and two- to threefold increased odds found for Histrionic, Impulsive, Schizoid and Anankastic personality disorders. In conclusion, stuttering appears to be associated with a heightened risk for the development of personality disorders. These results highlight the need for research regarding the assessment and treatment of personality disorders among adults who stutter. The reader will be able to: (1) describe the nature of personality disorders, including factors thought to contribute to their development; (2) identify some of the negative consequences associated with stuttering which may contribute to the development of personality disorders among adults who stutter; (3) describe the process involved in screening for personality disorders, including various methods of scoring; and (4) summarize findings regarding the first-stage presence of personality disorders among adults seeking speech treatment for stuttering in the present sample in comparison with age- and gender-matched controls from a national population sample.


Stabilization and functionalization of iron oxide nanoparticles for biomedical applications.
Superparamagnetic iron oxide nanoparticles (NPs) are used in a rapidly expanding number of research and practical applications in the biomedical field, including magnetic cell labeling separation and tracking, for therapeutic purposes in hyperthermia and drug delivery, and for diagnostic purposes, e.g., as contrast agents for magnetic resonance imaging. These applications require good NP stability at physiological conditions, close control over NP size and controlled surface presentation of functionalities. This review is focused on different aspects of the stability of superparamagnetic iron oxide NPs, from its practical definition to its implementation by molecular design of the dispersant shell around the iron oxide core and further on to its influence on the magnetic properties of the superparamagnetic iron oxide NPs. Special attention is given to the selection of molecular anchors for the dispersant shell, because of their importance to ensure colloidal and functional stability of sterically stabilized superparamagnetic iron oxide NPs. We further detail how dispersants have been optimized to gain close control over iron oxide NP stability, size and functionalities by independently considering the influences of anchors and the attached sterically repulsive polymer brushes. A critical evaluation of different strategies to stabilize and functionalize core-shell superparamagnetic iron oxide NPs as well as a brief introduction to characterization methods to compare those strategies is given.


Concepts of mental disorders in the United Kingdom: Similarities and differences between the lay public and psychiatrists.
The lay public often conceptualise mental disorders in a different way to mental health professionals, and this can negatively impact on outcomes when in treatment. This study explored which disorders the lay public are familiar with, which theoretical models they understand, which they endorse and how they compared to a sample of psychiatrists. The Maudsley Attitude Questionnaire (MAQ), typically used to assess mental health professional's concepts of mental disorders, was adapted for use by a lay community sample (N = 160). The results were compared with a sample of psychiatrists (N = 76). The MAQ appeared to be accessible to the lay public, providing some interesting preliminary findings: in order, the lay sample reported having the best understanding of depression followed by generalised anxiety, schizophrenia and finally antisocial personality disorder. They best understood spiritualist, nihilist and social realist theoretical models of these disorders, but were most likely to endorse biological, behavioural and cognitive models. The lay public were significantly more likely to endorse some models for certain disorders suggesting a nuanced understanding of the cause and likely cure, of various disorders. Ratings often differed significantly from the sample of psychiatrists who were relatively steadfast in their endorsement of the biological model. The adapted MAQ appeared accessible to the lay sample. Results suggest that the lay public are generally aligned with evidence-driven concepts of common disorders, but may not always understand or agree with how mental health professionals conceptualise them. The possible causes of these differences, future avenues for research and the implications for more collaborative, patient-clinician conceptualisations are discussed.


Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women.
To compare the effectiveness of cranberry extract with low-dose trimethoprim in the prevention of recurrent urinary tract infections (UTIs) in older women. One hundred and thirty-seven women with two or more antibiotic-treated UTIs in the previous 12 months were randomized to receive either 500 mg of cranberry extract or 100 mg of trimethoprim for 6 months. Thirty-nine of 137 participants (28%) had an antibiotic-treated UTI (25 in the cranberry group and 14 in the trimethoprim group); difference in proportions relative risk 1.616 (95% CI: 0.93, 2.79) P = 0.084. The time to first recurrence of UTI was not significantly different between the groups (P = 0.100). The median time to recurrence of UTI was 84.5 days for the cranberry group and 91 days for the trimethoprim group (U = 166, P = 0.479). There were 17/137 (12%) withdrawals from the study, 6/69 (9%) from the cranberry group and 11/68 (16%) from the trimethoprim group (P = 0.205), with a relative risk of withdrawal from the cranberry group of 0.54 (95% CI: 0.19, 1.37). Trimethoprim had a very limited advantage over cranberry extract in the prevention of recurrent UTIs in older women and had more adverse effects. Our findings will allow older women with recurrent UTIs to weigh up with their clinicians the inherent attractions of a cheap, natural product like cranberry extract whose use does not carry the risk of antimicrobial resistance or super-infection with Clostridium difficile or fungi.


Social and reproductive factors affecting cortisol levels in wild female golden lion tamarins (Leontopithecus rosalia).
The steroid hormone cortisol has been associated with different levels of "stress" as well as different reproductive conditions in many primates. In callitrichids, cortisol has more often been reflective of female reproductive status than of chronic stress. In this study, we addressed the hypothesis that wild golden lion tamarin (Leontopithecus rosalia) females, whose social structure is characterized by low aggression and high social support, would not show rank ("stress")-related differences in glucocorticoids but would show reproductive changes. We collected 710 fecal samples from 22 adult females in Poço das Antas Reserve, Brazil, and nearby reintroduction areas, and assayed them for cortisol. Differences in cortisol levels were found between different reproductive conditions. Females in the first trimester of pregnancy had lower cortisol levels than nonpregnant females, although we did not differentiate between basal and ovulating levels in nonpregnant females. Cortisol rose in the third trimester of pregnancy. Primiparous females had a higher rise in the third trimester than multiparous females. No differences in cortisol levels were found among dominant females, ovulatory subordinate females, or anovulatory subordinate females. These results are similar to those obtained in other studies of callitrichid females. The lack of differences in cortisol excretion between dominants and subordinates is likely due to the low levels of overt aggression and the high level of social support available to subordinate females.


Cloning of a novel surface antigen from the insect stages of Trypanosoma brucei by expression in COS cells.
Trypanosoma brucei cDNA libraries constructed in the vector pCDM8 were screened selectively for insect (procyclic) stage surface antigen cDNAs by transient expression in mammalian COS-7 fibroblasts and "panning" with a rabbit polyclonal antiserum. This strategy yielded two surface antigen cDNAs termed PSSA-1 and PSSA-2. The PSSA-1 cDNA encoded an isotype of procyclin, the major phosphatidylinositol-linked stage-specific glycoprotein antigen of the tsetse fly infective forms of T. brucei. The PSSA-2 cDNA encoded a new and previously unidentified stage-specific surface antigen with the features of a typical transmembrane glycoprotein but with an unusual cytoplasmic tail composed of a proline-rich tandem repeat. Fluorescent antibody staining of PSSA-1 transfected COS cells with a panel of procyclin-specific monoclonal antibodies confirmed that the protein was located on the outer surface of the plasma membrane. Furthermore, the antigen on COS cells was insensitive to treatment with phosphatidylinositol-specific phospholipase C suggesting that the inositol of the glycosylinositol phospholipid-lipid anchor contained the same fatty acyl modification reported recently for the procyclin molecule in cultured procyclic trypanosomes. In contrast the PSSA-2 antigen on COS cells was stained very weakly by whole parasite antisera. Northern blot hybridization revealed that the PSSA-2 antigen was encoded by a single 1.7-kilobase transcript which was present in parasites from the insect procyclic stage of the life cycle but not from the animal bloodstream stage. Southern blot hybridization analysis of DNA from procyclic stage trypanosomes indicated that the gene for PSSA-2 may be present in more than one copy in procyclic trypanosomes.


Elevated salivary C-reactive protein predicted by low cardio-respiratory fitness and being overweight in African children.
C-reactive protein (CRP) is a sensitive marker of systemic inflammation and is an independent risk factor for cardiovascular disease. The aim of the study was to examine the relationship between salivary CRP, cardio-respiratory fitness and body composition in a paediatric population. This was a cross-sectional study of 170 black South African children (age 9.41 ± 1.55 years, 100 females, 70 males) in grades 3 to 7. Unstimulated whole saliva samples were obtained for the analysis of CRP. Height, mass, skin-fold thickness, resting blood pressure, and waist and hip circumference measurements were obtained. Cardio-respiratory fitness was assessed using a 20-m multi-stage shuttle run. Children were classified as overweight/obese according to the Center for Disease Control and Prevention (CDC) body mass index (BMI) percentile ranking, and meeting percentage body fat recommendations, if percentage body fat was ≤ 25% in boys and ≤ 32% in girls. The cut-off point for low cardio-respiratory fitness was a predicted aerobic capacity value ≤ the 50th percentile for the group. Contributions of low cardio-respiratory fitness, overweight/obesity, and not meeting percentage body fat recommendations, to elevated salivary CRP (≥ 75th percentile) concentration and secretion rate were examined using binary logistic regression analysis with a backward stepwise selection technique based on likelihood ratios. Poor cardio-respiratory fitness was independently associated with elevated salivary CRP concentration (OR 3.9, 95% CI: 1.7-8.9, p = 0.001). Poor cardio-respiratory fitness (OR 2.7, 95% CI: 1.2-6.1, p = 0.02) and overweight/obesity (BMI ≥ 85th percentile) (OR 2.5, 95% CI: 1.1-5.9, p = 0.03) were independent predictors of elevated salivary CRP secretion rate. The results suggest a strong association between poor cardio-respiratory fitness and/or overweight/obesity and inflammatory status in children, based on elevated salivary CRP levels.


From transcriptional landscapes to the identification of biomarkers for robustness.
The ability of microorganisms to adapt to changing environments and gain cell robustness, challenges the prediction of their history-dependent behaviour. Using our model organism Bacillus cereus, a notorious Gram-positive food spoilage and pathogenic spore-forming bacterium, a strategy will be described that allows for identification of biomarkers for robustness. First an overview will be presented of its two-component systems that generally include a transmembrane sensor histidine kinase and its cognate response regulator, allowing rapid and robust responses to fluctuations in the environment. The role of the multisensor hybrid kinase RsbK and the PP2C-type phosphatase RsbY system in activation of the general stress sigma factor σB is highlighted. An extensive comparative analysis of transcriptional landscapes derived from B. cereus exposed to mild stress conditions such as heat, acid, salt and oxidative stress, revealed that, amongst others σB regulated genes were induced in most conditions tested. The information derived from the transcriptome data was subsequently implemented in a framework for identifying and selecting cellular biomarkers at their mRNA, protein and/or activity level, for mild stressinduced microbial robustness towards lethal stresses. Exposure of unstressed and mild stress-adapted cells to subsequent lethal stress conditions (heat, acid and oxidative stress) allowed for quantification of the robustness advantage provided by mild stress pretreatment using the plate-count method. The induction levels of the selected candidate-biomarkers, σB protein, catalase activity and transcripts of certain proteases upon mild stress treatment, were significantly correlated to mild stress-induced enhanced robustness towards lethal thermal, oxidative and acid stresses, and were therefore suitable to predict these adaptive traits. Cellular biomarkers that are quantitatively correlated to adaptive behavior will facilitate our ability to predict the impact of adaptive behavior on cell robustness and will allow to control and/or exploit these adaptive traits. Extrapolation to other species and genera is discussed such as avenues towards mechanism-based design of microbial fitness and robustness.


Are blood pressure level and variability related to pregnancy outcome? Analysis of control of hypertension in pregnancy study data.
To examine the relationship between pregnancy outcomes and BP level and variability. Secondary analysis of CHIPS trial data (Control of Hypertension In Pregnancy Study, NCT01192412). International. Women with chronic or gestational hypertension. BP measurement was standardised in outpatient clinics. Adjusted (including for allocated group) mixed effects logistic regression was used to assess relationships between major CHIPS outcomes and both BP level (mean of clinic readings) and visit-to-visit within-participant BP variability (standard deviation and average real variability of absolute successive difference of BP values). BP values 7-28 days prior to outcomes (or birth for perinatal outcomes) were excluded in sensitivity analyses. Major CHIPS outcomes. Among 961 (97.4%) women, higher BP level was associated with more adverse maternal and perinatal outcomes (usually at p < 0.001) except for serious maternal complications. Among 913 (92.5%) women with at least two post-randomisation outpatient visits, higher BP variability was associated with increased odds of severe hypertension and pre-eclampsia (usually at p < 0.01). Sensitivity analyses suggested reverse causality for these maternal outcomes, but greater diastolic BP variability may have been associated with fewer adverse perinatal outcomes. Higher BP is an adverse prognostic marker, regardless of target BP. While the association between higher BP variability and severe hypertension and pre-eclampsia may be related to higher BP at diagnosis, our results suggest a possible advantage of BP variability for the fetus, through undefined mechanisms. Higher blood pressure (BP) is associated with more adverse pregnancy outcomes, but higher BP variability may be good for the baby.


Genomic characterization of the Atlantic cod sex-locus.
A variety of sex determination mechanisms can be observed in evolutionary divergent teleosts. Sex determination is genetic in Atlantic cod (Gadus morhua), however the genomic location or size of its sex-locus is unknown. Here, we characterize the sex-locus of Atlantic cod using whole genome sequence (WGS) data of 227 wild-caught specimens. Analyzing more than 55 million polymorphic loci, we identify 166 loci that are associated with sex. These loci are located in six distinct regions on five different linkage groups (LG) in the genome. The largest of these regions, an approximately 55 Kb region on LG11, contains the majority of genotypes that segregate closely according to a XX-XY system. Genotypes in this region can be used genetically determine sex, whereas those in the other regions are inconsistently sex-linked. The identified region on LG11 and its surrounding genes have no clear sequence homology with genes or regulatory elements associated with sex-determination or differentiation in other species. The functionality of this sex-locus therefore remains unknown. The WGS strategy used here proved adequate for detecting the small regions associated with sex in this species. Our results highlight the evolutionary flexibility in genomic architecture underlying teleost sex-determination and allow practical applications to genetically sex Atlantic cod.


The Privacy and Security Implications of Open Data in Healthcare.
The International Medical Informatics Association (IMIA) Open Source Working Group (OSWG) initiated a group discussion to discuss current privacy and security issues in the open data movement in the healthcare domain from the perspective of the OSWG membership. Working group members independently reviewed the recent academic and grey literature and sampled a number of current large-scale open data projects to inform the working group discussion. This paper presents an overview of open data repositories and a series of short case reports to highlight relevant issues present in the recent literature concerning the adoption of open approaches to sharing healthcare datasets. Important themes that emerged included data standardisation, the inter-connected nature of the open source and open data movements, and how publishing open data can impact on the ethics, security, and privacy of informatics projects. The open data and open source movements in healthcare share many common philosophies and approaches including developing international collaborations across multiple organisations and domains of expertise. Both movements aim to reduce the costs of advancing scientific research and improving healthcare provision for people around the world by adopting open intellectual property licence agreements and codes of practice. Implications of the increased adoption of open data in healthcare include the need to balance the security and privacy challenges of opening data sources with the potential benefits of open data for improving research and healthcare delivery.


Risk factors for multiple intracranial aneurysms.
Risk factors that predispose to the formation of multiple intracranial aneurysms, which are present in up to 34% of patients with intracranial aneurysms, are not well defined. In this study, we examined the association between known risk factors for cerebrovascular disease and presence of multiple intracranial aneurysms. We reviewed the medical records and results of conventional angiography in all patients with a diagnosis of intracranial aneurysms admitted to the Johns Hopkins University hospital between January 1990 and June 1997. We determined the independent association between various cerebrovascular risk factors and the presence of multiple aneurysms using logistic regression analysis. Of 419 patients admitted with intracranial aneurysms (298 ruptured and 121 unruptured), 127 (30%) had multiple intracranial aneurysms. In univariate analysis, female gender (odds ratio [OR] = 1.9; 95% confidence interval [CI], 1.1-3.3) and cigarette smoking at any time (OR = 1.8; 95% CI, 1.1-3.0) were significantly associated with presence of multiple aneurysms. In the multivariate analysis, cigarette smoking at any time (OR = 1.7; 95% CI, 1.1-2.8) and female gender (OR = 2.1; 95% CI 1.2-3.5) remained significantly associated with multiple aneurysms. Hypertension, diabetes mellitus, and alcohol and illicit drug use were not significantly associated with presence of multiple aneurysms. Cigarette smoking and female gender seem to increase the risk for multiple aneurysms in patients predisposed to intracranial aneurysm formation. Further studies are required to investigate the mechanism underlying the association between cigarette smoking and intracranial aneurysm formation.


Antiproliferative and molecular mechanism of eugenol-induced apoptosis in cancer cells.
Phenolic phytochemicals are a broad class of nutraceuticals found in plants which have been extensively researched by scientists for their health-promoting potential. One such a compound which has been comprehensively used is eugenol (4-allyl-2-methoxyphenol), which is the active component of Syzigium aromaticum (cloves). Aromatic plants like nutmeg, basil, cinnamon and bay leaves also contain eugenol. Eugenol has a wide range of applications like perfumeries, flavorings, essential oils and in medicine as a local antiseptic and anesthetic. Increasing volumes of literature showed eugenol possesses antioxidant, antimutagenic, antigenotoxic, anti-inflammatory and anticancer properties. Molecular mechanism of eugenol-induced apoptosis in melanoma, skin tumors, osteosarcoma, leukemia, gastric and mast cells has been well documented. This review article will highlight the antiproliferative activity and molecular mechanism of the eugenol induced apoptosis against the cancer cells and animal models.


Safety of hormone replacement therapy (HRT) in systemic lupus erythematosus (SLE).
Despite its obvious benefits, many physicians are reluctant to prescribe HRT to patients with SLE. We have performed a retrospective study in 60 postmenopausal women with SLE including 30 HRT users and 30 never users. The patients were studied for 12 months after the initiation of HRT. The two groups were well matched for disease characteristics. The HRT users experienced significant improvements in general well being, libido and depression. There was no significant difference in any other parameter measured. There was no increase in the number of thrombo-embolic events in the user group despite 7 patients having a positive thrombophilia screen. In conclusion, in stable postmenopausal SLE HRT appears well tolerated and safe.


Use of peroperative cefoxitin to prevent infection after colonic and rectal surgery.
A double-blind, controlled trial was performed to assess the effect of a short intraoperative course of Cefoxitin, a new broad spectrum cephamycin antibiotic, on the incidence of septic complications following elective colonic and rectal surgery. In addition to a two-day preoperative bowel preparation, patients entered in the study received a short course of either Cefoxitin (three 2g intravenous bolus doses at two-hour intervals, the first before skin incision) or a matching placebo. Thirty-two patients received Cefoxitin and 33 patients received the placebo. Postoperative abdominal wound infections developed in one (3%) of the Cefoxitin-treated patients and nine (27%) of the placebo-treated patients. This difference is statistically significant (p = 0.01). Septic complications remote from the abdominal wound, e.g. intra-abdominal abscesses, occurred in both Cefoxitin-treated and placebo-treated patients, but numbers were too small for meaningful analysis. The study shows that even a very short peroperative course of Cefoxitin is highly effective in reducing postoperative abdominal wound infections after elective colorectal surgery.


Transcriptional effects of estrogen on neuronal neurotensin gene expression involve cAMP/protein kinase A-dependent signaling mechanisms.
Steroid hormones exert dramatic effects on neuronal expression of genes that encode neuropeptides. Expression of the neurotensin/neuromedin (NT/N) gene in preoptic area neurons is dramatically enhanced by estrogen in vivo, even though its promoter lacks palindromic estrogen response elements. We report here that estrogen promotes transcription of this gene by interactions with the cAMP cascade in a neuronal cell line, SK-N-SH, and in a mouse model. In neuroblastoma cells, estrogen increases cAMP and the phosphorylation of the cAMP response element-binding protein in a time frame that precedes induction of NT/N gene transcription. Interference with the cAMP/protein kinase A signal transduction cascade blocks the ability of estrogen to elicit increases in transcription of this gene. Furthermore, in studies performed in vivo using mice deficient in protein kinase A, estrogen fails to induce increases in NT/N mRNA but retains its ability to promote estrogen response element-dependent progesterone receptor gene transcription. These data represent the first report of a nonclassical effect of estrogen on the expression of an endogenous estrogen-regulated neuropeptide gene through cAMP-mediated mechanisms both in a neuroblastoma cell line and in hypothalamic neurons. More importantly, this "cross-talk" may represent a more generalized mechanism by which steroid hormones act through other signal transduction cascades to regulate the expression of other genes in the brain.


Differentiation of colonic metaplasia from adenocarcinoma of urinary bladder.
Colonic metaplasia and primary bladder adenocarcinoma are relatively uncommon entities that can have similar gross clinical appearances. Examples of colonic metaplasia histologically mimicking cancer have only rarely been reported. We retrospectively analyzed 38 cases of cystitis glandularis (18 cases of colonic metaplasia), 12 cases of adenocarcinoma of urinary bladder (two well-differentiated, WDA), and one in situ adenocarcinoma from the surgical pathology files of Johns Hopkins Hospital. Nine patients with colonic metaplasia had widespread lesions. Two showed superficial muscularis propria involvement, mimicking adenocarcinoma; one of these cases had been diagnosed as infiltrating WDA at both an academic center and a community hospital. Dissecting mucin pools were focally seen in four cases of widespread colonic metaplasia, also mimicking cancer. One of the nine cases showed minimal cytological atypia, but no cases showed mitoses or signet ring cells. Distinguishing WDA from colonic metaplasia was the finding in WDA of infiltrative architectural pattern (two of two), extensive muscle invasion (two of two), moderate anaplasia (one of two), mitotic figures (two of two), and extensive mucinous pools (one of two). The diagnosis of adenocarcinoma in situ was based on anaplasia. Clinically, colonic metaplasia may resemble cancer. Histologically, colonic metaplasia may mimic cancer based on extensive involvement of the lamina propria, focal mucinous pools, focal muscularis propria involvement, focal mild cytological atypia, and rare mitoses. Despite overlapping features with colonic metaplasia, the diagnosis of WDA is based on the greater degree and extent of these atypical findings in cancer.


Acetaldehyde inhibits the formation of retinoic acid from retinal in the rat esophagus.
It has already been demonstrated that the rat esophagus produces retinoic acid from retinol. In this study, this process is further characterized and the effect of acetaldehyde examined to elucidate the possible mechanisms behind the epidemiological evidence that the incidence of esophageal cancer is higher in alcoholics. Rat esophageal samples were incubated with all-trans retinal and newly formed all-trans retinoic acid (ATRA) was quantified using high-performance liquid chromatography (HPLC). Furthermore, beta-nicotinamide adenine dinucleotide (NAD)-dependent acetaldehyde oxidation by the rat esophagus was examined by tracing NAD reduction using a spectrophotometer. Rat esophageal samples produced ATRA from all-trans retinal in a NAD-dependent manner and the potential was significantly attenuated by phenetyl isothiocynate, an ALDH inhibitor, or acetaldehyde depending on the concentration used. Rat esophageal samples also oxidized acetaldehyde of various concentrations NAD dependently. The ATRA formation potential that was temporarily inhibited by acetaldehyde was recovered to the control level by dialysis when the specimen was incubated with up to 50 microM of acetaldehyde. The rat esophagus produces retinoic acid from retinal. An ALDH isoform(s) is responsible for this process and physiological concentration of acetaldehyde hampers the process, probably in a competitive manner. Since the disturbance of retinoic acid supply has been implicated in carcinogenicity, this finding may, at least in part, explain the high incidence of esophageal cancer in alcoholics, especially in those with inactive ALDH 2 whose blood acetaldehyde levels become higher than those with active ALDH 2.


Copper ion interaction with the RNase catalytic site fragment of the angiogenin protein: an experimental and theoretical investigation.
The angiogenin protein (Ang) is a member of the vertebrate-specific secreted ribonucleases and one of the most potent angiogenic factors known. Ang is a normal constituent of human plasma and its concentration increases under some physiological and pathological conditions to promote neovascularization. Ang was originally identified as an angiogenic tumour factor, but its biological activity has been found to extend from inducing angiogenesis to promoting cell survival in different neurodegenerative diseases. Ang exhibits weak ribonucleolytic activity, which is critical for its biological functions. The RNase catalytic sites are two histidine residues, His-13 and His-114, and the lysine Lys-40. Copper is also an essential cofactor in angiogenesis and influences angiogenin's biological properties. The main Cu(ii) anchoring site of Ang is His-114, where metal binding inhibits RNase activity of the protein. To reveal the Cu(ii) coordination environment in the C-terminal domain of the Ang protein, we report on the characterization, by means of potentiometric, voltammetric, and spectroscopic (CD, UV-Vis and EPR) methods and DFT calculations, of Cu(ii) complexes formed with a peptide fragment including the Ang sequence 112-117 (PVHLDQ). Potentiometric titrations indicated that [CuLH-2] is the predominant species at physiological pH. EPR, voltammetric data and DFT calculations are consistent with a CuN3O2 coordination mode in which a distorted square pyramidal arrangement of the peptide was observed with the equatorial positions occupied by the nitrogen atoms of the deprotonated amides of the Asp and Leu residues, the δ-N atom of histidine and the oxygen atom of the aspartic carboxylic group. Moreover, two analogous peptides encompassing the PVHLNQ and LVHLDQ sequences were also characterized by using thermodynamic, spectroscopic and DFT studies to reveal the role they play in Cu(ii) complex formation by the carboxylate side chain of the Asp and Pro residues, a known breaking-point in metal coordination.


Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia.
Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function; it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.


Effects of intratympanic gentamicin on vestibular afferents and hair cells in the chinchilla.
Gentamicin is toxic to vestibular hair cells, but its effects on vestibular afferents have not been defined. We treated anesthetized chinchillas with one injection of gentamicin (26.7 mg/ml) into the middle ear and made extracellular recordings from afferents after 5-25 (early) or 90-115 days (late). The relative proportions of regular, intermediate, and irregular afferents did not change after treatment. The spontaneous firing rate of regular afferents was lower (P < 0.001) on the treated side (early: 44.3 +/- 16.3; late: 33.9 +/- 13.2 spikes x s(-1)) than on the untreated side (54.9 +/- 16.8 spikes x s(-1)). Spontaneous rates of irregular and intermediate afferents did not change. The majority of treated afferents did not measurably respond to tilt or rotation (82% in the early group, 76% in the late group). Those that did respond had abnormally low sensitivities (P < 0.001). Treated canal units that responded to rotation had mean sensitivities only 5-7% of the values for untreated canal afferents. Treated otolith afferents had mean sensitivities 23-28% of the values for untreated otolith units. Sensitivity to externally applied galvanic currents was unaffected for all afferents. Intratympanic gentamicin treatment reduced the histological density of all hair cells by 57% (P = 0.04). The density of hair cells with calyx endings was reduced by 99% (P = 0.03), although some remaining hair cells had other features suggestive of type I morphology. Type II hair cell density was not significantly reduced. These findings suggest that a single intratympanic gentamicin injection causes partial damage and loss of vestibular hair cells, particularly type I hair cells or their calyceal afferent endings, does not damage the afferent spike initiation zones, and preserves enough hair cell synaptic activity to drive the spontaneous activity of vestibular afferents.


B Cell Metabolism and Autophagy in Autoimmunity.
B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.


Fatal, disseminated Acremonium strictum infection in a neutropenic host.
Disseminated Acremonium strictum infection in a neutropenic patient is reported. Positive fecal cultures preceded positive cutaneous and blood cultures by 18 and 21 days, respectively, which suggests gastrointestinal colonization and invasion as initiating events. Microscopic examination of cutaneous biopsy and pulmonary specimens revealed hyphae, phialides, and phialoconidia in vivo. These adventitious forms also can occur in infections due to other phialidic fungi such as Fusarium and Paecilomyces species and can be misdiagnosed as Candida species. Budding cells also can occur in vivo for species of Fusarium, Paecilomyces, and apparently Acremonium, further adding to the potential for misdiagnosis. The occurrence of adventitious forms in infections caused by species of Acremonium, Fusarium, Paecilomyces, Scedosporium, and Blastoschizomyces is suggested as a mechanism for dissemination of infection and as an explanation of the relatively higher frequency of positive blood cultures in these cases.


What's the fuss? Gender and academic leadership.
Women continue to be disproportionately represented in top leadership positions. Leadership development programs typically focus on skills attainment. The purpose of this paper is to explore the perceptions and experiences of academic leaders in order to inform how leadership development programs may more effectively address the gender gap in leadership. A sequential mixed methods study design was used. Participants completed the Leadership Practice Inventory ®(LPI) survey followed by individual interviews of a subset of participants. The survey results were analyzed and compared by gender using the t-test. Thematic analysis was used to compare themes across and between genders. Quantitative and qualitative findings were integrated in the final analysis. In total, 65 leaders (38 women; 27 men) (37.7 percent response rate) participated in the survey. There were no significant demographic or statistical differences between women and men on any of the LPI® components. Five women and five men were interviewed. Thematic analysis revealed common leadership aspirations and values. Gender differences were noted in leadership attainment, mentorship and the influence of gender on leadership. While the male narratives reflected cognitive awareness of gender inequities, the female narratives also included lived experiences. Male participants focused on the importance of meritocracy whereas the female participants emphasized the gendered social and structural influences on leadership attainment. Leadership development programs need go beyond generic "skills-building" in order to conceptualize leadership within a gendered social context. This framework will enable critical awareness and tools for developing both women and men's fullest leadership potential. This study was conducted in order to better understand how academic health leaders experience the intersection of gender and leadership. The findings contribute to the current literature by providing insight into perceptual gaps that exist at the level of practice between women and men leaders. In doing so, the authors discuss how leadership development programs may play a more effective role in addressing gender equity in leadership.


Chronotype, Light Exposure, Sleep, and Daytime Functioning in High School Students Attending Morning or Afternoon School Shifts: An Actigraphic Study.
Adolescent maturation is associated with delays of the endogenous circadian phase. Consequently, early school schedules may lead to a mismatch between internal and external time, which can be detrimental to adolescent sleep and health. In parallel, chronotype is known to play a role in adolescent health; evening chronotype adolescents are at higher risk for sleep problems and lower academic achievement. In the summer of 2008, Kénogami High School (Saguenay, Canada) was destroyed by fire. Kénogami students were subsequently relocated to Arvida High School (situated 5.3 km away) for the 2008-2009 academic year. A dual school schedule was implemented, with Arvida students attending a morning schedule (0740-1305 h) and Kénogami students an afternoon schedule (1325-1845 h). This study aimed to investigate the effects of such school schedules and chronotype on sleep, light exposure, and daytime functioning. Twenty-four morning and 33 afternoon schedule students wore an actigraph during 7 days to measure sleep and light exposure. Academic achievement was obtained from school. Subjects completed validated questionnaires on daytime sleepiness, psychological distress, social rhythms, school satisfaction, alcohol, and chronotype. Overall, afternoon schedule students had longer sleep duration, lower sleepiness, and lower light exposure than morning schedule students. Evening chronotypes (E-types) reported higher levels of sleepiness than morning chronotypes (M-types) in both morning and afternoon schedules. Furthermore, M-types attending the morning schedule reported higher sleepiness than M-types attending the afternoon schedule. No difference was found between morning and afternoon schedule students with regard to academic achievement, psychological distress, social rhythms, school satisfaction, and alcohol consumption. However, in both schedules, M-type had more regular social rhythms and lower alcohol consumption. In summary, this study emphasizes that an early school schedule is associated with detrimental effects in terms of sleep deprivation and daytime sleepiness, even for M-types. Furthermore, irrespective of school schedule, E-type adolescents face an increased risk for poor daytime functioning.


Use of heavier drinking contexts among heterosexuals, homosexuals and bisexuals: results from a National Household Probability Survey.
Extensive use of specific social contexts (bars and parties, for instance) by homosexuals and bisexuals is thought to be a factor in the higher rates of drinking among these groups. However, much of the empirical evidence behind these assumptions has been based on studies with methodological or sampling shortcomings. This article examines the epidemiological patterns of alcohol contexts in relation to sexual identity, using a large, national, probability population survey. We used the 2000 National Alcohol Survey for these analyses. The prevalence of spending leisure time in each of two social contexts (bars and parties) that are associated with heavier drinking is examined by sexual orientation (heterosexual, homosexual, bisexual and self-identified heterosexuals with same sex partners). In addition, we compare levels of drinking within these contexts by sexual orientation within these groups. Exclusively heterosexual women spent less time in these two contexts relative to all other groups of women. Gay men spent considerably more time in bars compared with the other groups of men. Heterosexual women who reported same sex partners drink more at bars, and bisexual women drink more alcohol at both bars and parties than exclusively heterosexual women. For men, there were no significant differences for average consumption in any of these contexts. Entry of background and demographic variables into logistic regression analyses did little to modify these associations. There is empirical evidence that some groups of homosexual and bisexual women and men spend more time than heterosexual individuals in heavier drinking contexts. The frequency of being in these two social contexts does not appear to be associated with heavier drinking within these contexts for men, but it may be related to heavier drinking in those places among some groups of women.


Heterogeneous delivery of silicate and metal to the Earth by large planetesimals.
After the Moon's formation, Earth experienced a protracted bombardment by leftover planetesimals. The mass delivered during this stage of late accretion has been estimated to be approximately 0.5% of Earth's present mass, based on highly siderophile element concentrations in the Earth's mantle and the assumption that all highly siderophile elements delivered by impacts were retained in the mantle. However, late accretion may have involved mostly large (≥ 1,500 km in diameter)-and therefore differentiated-projectiles in which highly siderophile elements were sequestered primarily in metallic cores. Here we present smoothed-particle hydrodynamics impact simulations that show that substantial portions of a large planetesimal's core may descend to the Earth's core or escape accretion entirely. Both outcomes reduce the delivery of highly siderophile elements to the Earth's mantle and imply a late accretion mass that may be two to five times greater than previously thought. Further, we demonstrate that projectile material can be concentrated within localized domains of Earth's mantle, producing both positive and negative 182W isotopic anomalies of the order of 10 to 100 ppm. In this scenario, some isotopic anomalies observed in terrestrial rocks can be explained as products of collisions after Moon formation.


SpyTag/SpyCatcher cyclization confers resilience to boiling on a mesophilic enzyme.
SpyTag is a peptide that spontaneously forms an amide bond with its protein partner SpyCatcher. SpyTag was fused at the N terminus of β-lactamase and SpyCatcher at the C terminus so that the partners could react to lock together the termini of the enzyme. The wild-type enzyme aggregates above 37 °C, with irreversible loss of activity. Cyclized β-lactamase was soluble even after heating at 100 °C; after cooling, the catalytic activity was restored. SpyTag/SpyCatcher cyclization led to a much larger increase in stability than that achieved through point mutation or alternative approaches to cyclization. Cyclized dihydrofolate reductase was similarly resilient. Analyzing unfolding through calorimetry indicated that cyclization did not increase the unfolding temperature but rather facilitated refolding after thermal stress. SpyTag/SpyCatcher sandwiching represents a simple and efficient route to enzyme cyclization, with potential to greatly enhance the robustness of biocatalysts.


Potential Drug Interactions Mediated by Renal Organic Anion Transporter OATP4C1.
Organic anion-transporting polypeptide 4C1 (OATP4C1) is an organic anion transporter expressed in the basolateral membrane of the renal proximal tubules. It plays a major role in the urinary excretion of both exogenous drugs and endogenous compounds. Our previous studies have indicated the importance of OATP4C1 in pathologic and physiologic conditions; however, the majority of its pharmacologic characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we clarified drug interactions mediated by OATP4C1. To elucidate potential drug interactions via OATP4C1, we screened 53 representative drugs commonly used in clinical settings. Next, we evaluated the IC50 values of drugs that inhibited OATP4C1 by more than 50%. To apply our results to clinical settings, we calculated the drug-drug interaction (DDI) indices. The screening analysis using an OATP4C1-expressing cell system demonstrated that 22 out of 53 therapeutic drugs inhibited OATP4C1-mediated triiodothyronine transport. In particular, OATP4C1-mediated transport was strongly inhibited by 10 drugs. The IC50 values of 10 drugs-nicardipine, spironolactone, fluvastatin, crizotinib, levofloxacin, clarithromycin, ritonavir, saquinavir, quinidine, and verapamil-obtained in this study were 51, 53, 41, 24, 420, 200, 8.5, 4.3, 100, and 110 µM, respectively. The IC50 values of these drugs were higher than the plasma concentrations obtained in clinical practice. However, ritonavir showed the highest DDI index (1.9) for OATP4C1, suggesting that it may strongly influence this transporter and thus cause drug interactions seen in clinical settings. Our finding gives new insight into the role of OATP4C1 in clinical DDIs.


Evolutionary divergence in life history traits among populations of the Lake Malawi cichlid fish Astatotilapia calliptera.
During the early stages of adaptive radiation, populations diverge in life history traits such as egg size and growth rates, in addition to eco-morphological and behavioral characteristics. However, there are few studies of life history divergence within ongoing adaptive radiations. Here, we studied Astatotilapia calliptera, a maternal mouthbrooding cichlid fish within the Lake Malawi haplochromine radiation. This species occupies a rich diversity of habitats, including the main body of Lake Malawi, as well as peripheral rivers and shallow lakes. We used common garden experiments to test for life history divergence among populations, focussing on clutch size, duration of incubation, egg mass, offspring size, and growth rates. In a first experiment, we found significant differences among populations in average clutch size and egg mass, and larger clutches were associated with smaller eggs. In a second experiment, we found significant differences among populations in brood size, duration of incubation, juvenile length when released, and growth rates. Larger broods were associated with smaller juveniles when released and shorter incubation times. Although juvenile growth rates differed between populations, these were not strongly related to initial size on release. Overall, differences in life history characters among populations were not predicted by major habitat classifications (Lake Malawi or peripheral habitats) or population genetic divergence (microsatellite-based FST). We suggest that the observed patterns are consistent with local selective forces driving the observed patterns of trait divergence. The results provide strong evidence of evolutionary divergence and covariance of life history traits among populations within a radiating cichlid species, highlighting opportunities for further work to identify the processes driving the observed divergence.


Can We Protect Those We Care for in A Pandemic? - Prevalence of Neutralizing Antibodies against SARS-CoV-2 in Nursing Homes.
In December 2019, the People's Republic of China and the World Health Organization first reported on a cluster of pneumonia with an unknown cause. Nine months later more than 1.4 million people have died from COVID 19. In this work, the effects of the COVID 19 pandemic on five nursing homes in Austria, which cared for 889 residents in the first half of 2020, were examined. The research question was whether the measures taken were appropriate to prevent an outbreak within the individual facilities. To detect previously unrecognized infections, the present study evaluated the prevalence of neutralizing antibodies against the SARS-CoV-2 virus in residents and employees of the nursing homes. Following the analysis of blood samples, the prospectively collected data was connected to data from screening examinations and data from contact tracing. The present study demonstrated an overall prevalence of neutralizing antibodies against the SARS-CoV-2 virus in nursing homes of 3.7%. Whereas the prevalence in those facilities that have never been hit by an outbreak is 0%, the prevalence in those facilities with an outbreak is up to 4.9%. Neutralizing antibodies against SARS-CoV-2 were detected in 35 persons. A retrospective analysis of all 5 included nursing homes demonstrated that upon regular clinical screening in combination with PCRs an infection with SARS-COV-2 was detected in 66 residents and 24 employees from different professional groups. In only 25 of the 35 persons with neutralizing antibodies against SARS-CoV-2 an infection was proven in advance. This study suggests that specific measures can prevent transmission within a health care facility. Nevertheless, the results also show that a risk reduction to 0% cannot be achieved. In preparation for further pandemic waves there is still the need to reduce the probability of a transmission in nursing homes with specific test strategies.


Emerging bacterial resistance patterns in febrile neutropenic patients: experience at a tertiary care hospital in Pakistan.
To look at the clinical presentations, spectrum and site of isolation of the organisms, sensitivity patterns of the organisms and the antibiotic prescribing practices for the treatment of febrile neutropenic patients at our hospital. The data were collected retrospectively from the records of all neutropenic patients with an absolute neutrophil count (ANC) of less than 500/ml admitted during the period of 3 years from August 1999 to July 2002 at AKUH. Out of the total of 404 patients, 65% had hematological malignancies and around half of them had leukaemia, 86% of the patients presented with fever. A total of 124 bacterial organisms were isolated from 96 patients among which 47% were gram positive and 53% were gram negative organisms; 16.1% of the patients had septicaemia. Coagulase Negative Staphylococci (CoNS) were the most common gram positive and E. coli was the most commonly isolated gram negative organism. Most of the gram positive organisms were isolated from blood (67%). There was emerging resistance to all commonly used antibiotics including imipenem, cloxacillin, vancomycin and amikacin. The average duration of neutropenia was 6.4 days. The mortality rate was 6%. There is increasing trend of gram negative organisms developing resistance to commonly used antibiotics. Gram positive bacteria including Enterococcus spp. and CoNS are also showing emerging resistance to vancomycin.


Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial.
To determine whether low intensity pulsed ultrasound (LIPUS), compared with sham treatment, accelerates functional recovery and radiographic healing in patients with operatively managed tibial fractures. A concealed, randomized, blinded, sham controlled clinical trial with a parallel group design of 501 patients, enrolled between October 2008 and September 2012, and followed for one year. 43 North American academic trauma centers. Skeletally mature men or women with an open or closed tibial fracture amenable to intramedullary nail fixation. Exclusions comprised pilon fractures, tibial shaft fractures that extended into the joint and required reduction, pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures >7.5 cm in length, concomitant injuries that were likely to impair function for at least as long as the patient's tibial fracture, and tibial fractures that showed <25% cortical contact and >1 cm gap after surgical fixation. 3105 consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599 were eligible and 501 provided informed consent and were enrolled. Patients were allocated centrally to self administer daily LIPUS (n=250) or use a sham device (n=251) until their tibial fracture showed radiographic healing or until one year after intramedullary fixation. Primary registry specified outcome was time to radiographic healing within one year of fixation; secondary outcome was rate of non-union. Additional protocol specified outcomes included short form-36 (SF-36) physical component summary (PCS) scores, return to work, return to household activities, return to ≥80% of function before injury, return to leisure activities, time to full weight bearing, scores on the health utilities index (mark 3), and adverse events related to the device. SF-36 PCS data were acquired from 481/501 (96%) patients, for whom we had 2303/2886 (80%) observations, and radiographic healing data were acquired from 482/501 (96%) patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control groups (mean difference 0.55, 95% confidence interval -0.75 to 1.84; P=0.41) or for the interaction between time and treatment (P=0.30); minimal important difference is 3-5 points) or in other functional measures. There was also no difference in time to radiographic healing (hazard ratio 1.07, 95% confidence interval 0.86 to 1.34; P=0.55). There were no differences in safety outcomes between treatment groups. Patient compliance was moderate; 73% of patients administered ≥50% of all recommended treatments. Postoperative use of LIPUS after tibial fracture fixation does not accelerate radiographic healing and fails to improve functional recovery.Study registration ClinicalTrialGov Identifier: NCT00667849.


Stroke rehabilitation research translation in Australia: a survey of clinical trialists.
Translation of findings from stroke trials into clinical practice remains low. Little is known about planned translation activities from the perspective of trialists who generate the evidence. This study aims to investigate perceptions of Australian stroke clinical trialists' about implementation of their findings into practice, and what translation activities they embedded into trial protocols. A descriptive cohort design and electronic survey was conducted. Three databases were searched to identify Australian stroke rehabilitation trials published between 2007 and 2017. Corresponding authors of the included trials were invited to complete an anonymous online survey about implementation of their trial intervention. Fifty-one trialists were invited to participate and 38 completed the survey (74% response rate). The majority (79%) considered their trial results to be clinically significant and 68% had pre-planned knowledge translation activities. The most common planned translation activities were publication (89%), conference presentation (87%), and feedback of results to target audiences (58%). Mixed opinions were evident regarding when and how to design knowledge translation activities for inclusion in trial protocols. Stroke rehabilitation trialists rely mostly on anecdotal reports about implementation of trial interventions, with few formally measuring uptake.Implications for rehabilitationThe most common knowledge translation activities planned for by researchers are publication of findings in academic journals, and conference presentations.Mixed opinions exist regarding when and how to design for knowledge translation activities in trial protocols.Limited formal measurement of intervention uptake is completed.Further implementation research is required to support and measure effective translation efforts when embedded into trial protocols.


Functionalization density dependence of single-walled carbon nanotubes cytotoxicity in vitro.
The cytotoxic response of cells in culture is dependant on the degree of functionalization of the single-walled carbon nanotube (SWNT). After characterizing a set of water-dispersible SWNTs, we performed in vitro cytotoxicity screens on cultured human dermal fibroblasts (HDF). The SWNT samples used in this exposure include SWNT-phenyl-SO(3)H and SWNT-phenyl-SO(3)Na (six samples with carbon/-phenyl-SO(3)X ratios of 18, 41, and 80), SWNT-phenyl-(COOH)(2) (one sample with carbon/-phenyl-(COOH)(2) ratio of 23), and underivatized SWNT stabilized in 1% Pluronic F108. We have found that as the degree of sidewall functionalization increases, the SWNT sample becomes less cytotoxic. Further, sidewall functionalized SWNT samples are substantially less cytotoxic than surfactant stabilized SWNTs. Even though cell death did not exceed 50% for cells dosed with sidewall functionalized SWNTs, optical and atomic force microscopies show direct contact between cellular membranes and water-dispersible SWNTs; i.e. the SWNTs in aqueous suspension precipitate out and selectively deposit on the membrane.


The effect of propofol on the electroencephalogram of patients with epilepsy.
The effect of propofol on the electroencephalogram (EEG) in patients with epilepsy is still unclear. Case reports with electroencephalographic documentation highlight pro- and anticonvulsant effects and beta activation of the EEG. This prospective study sought to determine the effect of propofol in 17 patients undergoing cortical resection for intractable epilepsy. Each patient received 2 mg/kg of propofol intravenously and the EEG was recorded from chronically implanted subdural electrodes placed during a previous craniotomy. Frequency of interictal spikes, time to burst suppression, and appearance of beta activation were recorded. The median frequency of interictal spikes decreased significantly from 2 spikes/min before to 0 spikes/min after propofol (P = 0.001). Seizure activity did not increase after propofol. Profound burst suppression and an increase in beta activity were noted consistently. The use of propofol in patients with epilepsy seems to be safe but may interfere with the recording of EEG spikes.


Encoding and the frontal lobes: a dissociation between retrograde and anterograde memories.
Recent functional neuroimaging studies have suggested that different neural substrates within the frontal lobes are associated with memory encoding, retrieval and monitoring. If this is the case, then it should be possible to find frontal patients with selective deficits to these processes. However, most laboratory based memory tests (e.g. Wechsler Memory Scale) require a combination of all these processes making it hard to find clear dissociations between patients. Using tests of everyday memory, this study documents a clear dissociation between a frontal patient's (JB) impaired ability to retrieve events from the anterograde period relative to spared ability to retrieve events from the retrograde period. This is consistent with specific disruption to frontal mechanisms associated with encoding which disrupts the formation of new episodic memories. The defective mechanism may be related to more general aspects of cognitive processing (e.g. selection demands), but it is unlikely to reflect damage to working memory (as assessed by the n-back task) as there is a clear dissociation between spared performance on this task and impaired performance on a comparable episodic recognition memory task.