The association of mood disorders with breast cancer survival: an investigation of linked cancer registration and hospital admission data for South East England.
Data linkage studies find that depression before or after a breast cancer diagnosis predicts reduced survival. This study aimed to determine whether depression or bipolar recorded in routine hospital admission data independently predicts survival in English breast cancer patients and whether onset in relation to cancer diagnosis is significant. Data on 77,173 women diagnosed with breast cancer (ICD-10 C50) in South East England, 2000-2009, were included. Of these, 131 women had a diagnosis of bipolar affective disorder (ICD-10 F31) and 955 of depression (either depressive episodes (ICD-10 F32) or depressive disorder (ICD-10 F33)) recorded in Hospital Episode Statistics between 3 years before and a year following cancer diagnosis. Kaplan-Meier plots were used to examine overall survival. Cox regression analyses were carried out overall and separately for mood disorder diagnoses before and after the cancer diagnosis and adjusted for confounding variables. A record of depression was a predictor of worse overall survival in breast cancer patients (adjusted HR = 1.33, 95% CI: 1.20-1.48, p < 0.001), while the effect of bipolar was not statistically significant (adjusted HR = 1.33, 95% CI: 0.97-1.82, p = 0.079). New recordings of depression and bipolar diagnoses following a cancer diagnosis appeared better predictors of overall survival than a prior history of either. There is evidence that English breast cancer patients with depression and bipolar recorded in routine hospital data have worse overall survival than those without these mood disorders. Further work exploring the concordance of records within administrative health data with clinical diagnosis and cause-specific death within these patient groups is needed.


Antioxidant and α -amylase inhibitory property of phyllanthus virgatus L.: an in vitro and molecular interaction study.
The present study on Phyllanthus virgatus, known traditionally for its remedial potential, for the first time provides descriptions of the antioxidant and inhibition of α -amylase enzyme activity first by in vitro analyses, followed by a confirmatory in silico study to create a stronger biochemical rationale. Our results illustrated that P. virgatus methanol extract exhibited strong antioxidant and oxidative DNA damage protective activity than other extracts, which was well correlated with its total phenolic content. In addition, P. virgatus methanol extract strongly inhibited the α -amylase activity (IC50 33.20 ± 0.556 μ g/mL), in a noncompetitive manner, than acarbose (IC50 76.88 ± 0.277 μ g/mL), which showed competitive inhibition. Moreover, this extract stimulated the glucose uptake activity in 3T3-L1 cells and also showed a good correlation between antioxidant and α -amylase activities. The molecular docking studies of the major bioactive compounds (9,12-octadecadienoic acid, asarone, 11-octadecenoic acid, and acrylic acid) revealed via GC-MS analysis from this extract mechanistically suggested that the inhibitory property may be due to the synergistic effect of these bioactive compounds. These results provide substantial basis for the future use of P. virgatus methanol extract and its bioactive compound in in vivo system for the treatment and management of diabetes as well as in the related condition of oxidative stress.


Stoichiometric plasticity of microbial communities is similar between litter and soil in a tropical rainforest.
Heterotrophic microorganisms are commonly thought to be stoichiometrically homeostatic but their stoichiometric plasticity has rarely been examined, particularly in terrestrial ecosystems. Using a fertilization experiment in a tropical rainforest, we evaluated how variable substrate stoichiometry may influence the stoichiometry of microbial communities in the leaf litter layer and in the underlying soil. C:N:P ratios of the microbial biomass were higher in the organic litter layer than in the underlying mineral soil. Regardless of higher ratios for litter microbial communities, C, N, and P fertilization effects on microbial stoichiometry were strong in both litter and soil, without any fundamental difference in plasticity between these two communities. Overall, N:P ratios were more constrained than C:nutrient ratios for both litter and soil microbial communities, suggesting that stoichiometric plasticity arises because of a decoupling between C and nutrients. Contrary to the simplifying premise of strict homeostasis in microbial decomposers, we conclude that both litter and soil communities can adapt their C:N:P stoichiometry in response to the stoichiometric imbalance of available resources.


Genetic diversity for agromorphological traits, phytochemical profile, and antioxidant activity in Moroccan sorghum ecotypes.
Sorghum, the fifth most important cereal crop, is a well-adapted cereal to arid/semi-arid regions. Sorghum is known for multiple end-uses as food, feed, fuel, forage, and as source of bioactive compounds that could be used for medical applications. Although the great improvement in the process of sorghum breeding, the average yield of this crop is still very low. Therefore, exploring the genetic diversity in sorghum accessions is a critical step for improving this crop. The main objective of the current work was to study the genetic variation existing in a Moroccan sorghum collection. Indeed, 10 sorghum ecotypes were characterized based on agromorphological descriptors. Both quantitative (25) and qualitative (7) traits revealed variability (p < 0.05) among the studied ecotypes. At the seedling stage, most of the ecotypes showed good to high vigor (70%). However, as the sorghum plants grow, the difference between genotypes become more apparent, especially at the generative phase. For instance, three different panicle shapes have been observed, erect (50%), semi-bent (30%), and bent (20%) with different degree of compactness (20% for loose, semi-compact, and compact panicles, and 30% for semi-loose panicles). In another part of this study, the phytochemical composition and antioxidant activities of the sorghum ecotypes have been determined. The results showed variable total phenolic contents, and total flavonoid contents ranging from 125.86 ± 1.36 to 314.91 ± 3.60 mg GAE/g dw and 114.0 ± 13.2 to 138.5 ± 10.8 (mg catechin equivalent/100 g, dw) respectively, with a differential antioxidant activities as well. These results indicate that for any crop breeding program, it is preferable to take into consideration both morphological and biochemical traits for a better selection of high yielding varieties with high added value compounds. Therefore, the implication of these results in the context of sorghum breeding activities could be a resourceful option for farmers.


Oxidant-inducible resistance to hydrogen peroxide killing in Agrobacterium tumefaciens requires the global peroxide sensor-regulator OxyR and KatA.
Induced adaptive and cross-protective responses to peroxide stress are important strategies used by bacteria to survive stressful environments. We have shown that exposure to low levels of peroxide (adaptive) and superoxide anions (cross-protection) induced high levels of resistance to peroxide killing in Agrobacterium tumefaciens. The mechanisms and genes involved in these processes have not been identified. Here, the roles played by peroxide (oxyR) and superoxide (soxR) global regulators and a catalase gene (katA) during these responses were investigated. H2O2-induced adaptive protection was completely abolished in both the oxyR and katA mutants. Superoxide generator (menadione)-induced cross-protection to H2O2 killing was observed in a soxR mutant, but not in either an oxyR or a katA mutant. In vivo analysis of the katA promoter, using a katA::lacZ transcriptional fusion, revealed that it could be induced by menadione in an oxyR-dependent manner. These results lead us to conclude that H2O2 and superoxide anions directly or indirectly oxidize OxyR and it is the resulting activation of katA expression that is responsible for the induced protection against lethal concentrations of H2O2.


The experience of resilience in newly graduated nurses: A qualitative metasynthesis.
The aim of the present study was to understand the experiences and perceptions of newly graduated nurses in relation to resilience by providing an interpretive synthesis of the existing qualitative literature on this topic. Resilience in newly graduated nurses has been associated with increased satisfaction and decreased turnover. As the experience of resilience is unique to each individual, qualitative studies are well suited to explore this concept, yet the existing data is heterogenous. A qualitative metasynthesis was conducted using a meta-ethnographic approach. The search was performed using PubMed, CINAHL, Embase, PsycINFO, ProQuest Dissertations and Theses Global for the English literature and NDSL, KCI, RISS, KISS and DBpia for the Korean literature. The JBI Critical Appraisal Checklist for Qualitative Research was used to assess the quality of studies. An a priori protocol was created and registered on the Open Science Framework (Randall & De Gagne, 2022). The final review included seven articles published between 2008 and 2021. Three main themes were identified: (1) internal experience of resilience; (2) external sources of resilience; and (3) building resilience over time. Subthemes were also identified. This study indicates that resilience can be developed over time during the period of transition from student nurse to professional nurse and is impacted by personal and organizational influences. The promotion of resilience presents considerations and opportunities for health care leaders and administrators.


Self-Weighing: Helpful or Harmful for Psychological Well-Being? A Review of the Literature.
Conflicting views as to the helpfulness or harmfulness of self-weighing for the control of body weight have been presented in the fields of obesity and eating disorders. Because self-weighing is increasingly being considered as an intervention to promote weight loss or prevent weight gain, it is timely to consider unintended psychological outcomes and behavioral correlates of this behavior. Twenty articles from the published literature examining self-weighing and psychological outcomes or weight control behaviors were reviewed. In evaluating self-weighing and affect (ten studies), self-esteem (four studies) and body evaluation (ten studies), and eating behaviors/cognitions (13 studies), in total, most studies found a negative relationship between self-weighing and outcomes (affect: 4/10, self-esteem: 3/4, body evaluation: 4/10, eating behaviors/cognitions: 6/13). Themes that emerged included relationships between self-weighing and negative outcomes for women and younger individuals, and lack of a relationship or positive outcomes for overweight, treatment seeking individuals. Though self-weighing has shown promise in aiding weight control, the degree to which weight loss, and not self-weighing, affects psychological outcomes is not clear. Further assessment of psychological outcomes in self-weighing research may be warranted, as this review suggests the potential for adverse effects of self-weighing in some individuals.


Vasculogenic Erectile Dysfunction: The Impact of Diet and Lifestyle.
Vasculogenic erectile dysfunction has been aptly called the "canary in the coal mine" for cardiovascular disease because it almost always precedes other manifestations of atherosclerotic cardiovascular disease, including myocardial infarction and stroke. It is common, associated with the presence of modifiable cardiovascular risk factors, and impacted by diet and lifestyle choices. This concise review provides an update on the use of dietary and other lifestyle interventions to improve vasculogenic erectile dysfunction and atherosclerotic cardiovascular disease.


Noninvasive localization of accessory pathways in patients with Wolff-Parkinson-White syndrome with the use of myocardial Doppler imaging.
This study sought to examine the diagnostic accuracy of noninvasive prediction of accessory pathway localization in patients with manifest Wolff-Parkinson-White syndrome with the use of myocardial Doppler imaging as a new noninvasive mapping procedure. Myocardial Doppler imaging measures myocardial velocities and therefore can determine the site of earliest ventricular activation in patients with accessory bypass tracts. Twenty-five patients with manifest preexcitation were studied with the use of pulsed wave and M-mode myocardial Doppler imaging for the evaluation of the shortest electromechanical time interval in 9 basal myocardial segments. The new diagnostic test was compared with 3 electrocardiographic algorithms. An invasive mapping procedure served as reference standard. Abnormally short electromechanical time intervals were found in preexcited segments (27 +/- 12 ms vs 64 +/- 27 ms). Myocardial Doppler imaging correctly localized 84% of the accessory pathways and electrocardiographic algorithms only 48% to 60% of cases. Noninvasive prediction of accessory pathway localization by myocardial Doppler imaging is accurate and proved to be superior to prediction based on electrocardiographic algorithms.


A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer.
Use of in vitro chemoresponse assays for informing effective treatment selection is a compelling clinical question and a topic of debate among oncologists. A prospective study was conducted evaluating the use of a chemoresponse assay in recurrent ovarian cancer patients. Women with persistent or recurrent ovarian cancer were enrolled under an IRB-approved protocol, and fresh tissue samples were collected for chemoresponse testing. Patients were treated with one of 15 protocol-designated treatments empirically selected by the oncologist, blinded to the assay results. Each treatment was classified by the assay as: sensitive (S), intermediate (I), or resistant (R). Patients were prospectively monitored for progression-free survival (PFS) and overall survival (OS). Associations of assay response for the physician-selected treatment with PFS and OS were analyzed. A total of 262 evaluable patients were enrolled. Patients treated with an assay-sensitive regimen demonstrated significantly improved PFS and OS while there was no difference in clinical outcomes between I and R groups. Median PFS was 8.8 months for S vs. 5.9 months for I+R (hazard ratio [HR]=0.67, p=0.009). The association with assay response was consistent in both platinum-sensitive and platinum-resistant tumors (HR: 0.71 vs. 0.66) and was independent of other covariates in multivariate analysis (HR=0.66, p=0.020). A statistically significant14-month improvement in mean OS (37.5 months for S vs. 23.9 months for I+R, HR=0.61, p=0.010) was demonstrated. This prospective study demonstrated improved PFS and OS for patients with either platinum-sensitive or platinum-resistant recurrent ovarian cancer treated with assay-sensitive agents.


Ultrasonographically defined parenchymal patterns of the breast: relationship to mammographic patterns and other risk factors for breast cancer.
We have used ultrasound of the breast to define four parenchymal patterns in which increasing proportions of the breast are replaced by densely echogenic tissue. A series of 452 symptomatic women examined by both ultrasound and conventional X-ray mammography was reviewed to determine whether these ultrasonographic images could predict the breast parenchymal pattern defined mammographically. A very strong correlation was demonstrated between the breast pattern on ultrasound and the volume of the breast replaced by either dysplasia (Kendall's tau-b = 0.731 +/- 0.026, p less than 0.0001) or ductal prominence (Kendall's tau-b = 0.641 +/- 0.049, p less than 0.0001). This was seen both on initial reporting and on a blind re-reading of a random sample of 100 cases. The strength of correlation was similar for subgroups defined by family history of breast cancer, age, menopausal status, and history of benign breast disease, and the breast parenchymal pattern assessed by mammography or ultrasound showed similar associations with these variables. Ultrasonographic parenchymal patterns of the breast can predict the tissue patterns defined mammographically and may therefore be useful as a marker of breast cancer risk.


Supracricoid partial laryngectomy with cricothyroidopexy: a treatment for anterior vocal commissure laryngeal squamous carcinoma.
The clinical efficiency and functional outcomes of supracricoid partial laryngectomy (SCPL) with cricothyroidopexy (CTP) were compared with those of the traditional SCPL with cricohyoidoepiglottopexy (CHEP) in treating laryngeal squamous carcinoma involving anterior vocal commissure (AVC). From January 2000 to June 2009, 50 patients diagnosed with early- or intermediate-stage (T1b-T3 classification) glottic cancer involving AVC were treated with SCPL-CHEP or SCPL-CTP. Postoperative complications, local recurrence, survival rate, and speech performance were compared between these 2 surgical procedures. Patients undergoing SCPL-CHEP or SCPL-CTP manifested similar levels of postoperative complications, tumor recurrence, and survival rates. However, the SCPL-CTP group showed significantly lower Voice Handicap Index (VHI) scores, higher maximum phonation time, and improved glottic reconstruction and closure than the SCPL-CHEP group. The SCPL-CTP procedure better preserves postoperative speech performance than the SCPL-CHEP procedure, underscoring the moderate effectiveness of SCPL-CTP as a treatment for laryngeal squamous carcinoma involving AVC.


Infective endocarditis in opiate addicts: analysis of 80 cases studied at necropsy.
Eighty opiate addicts were studied at necropsy. Fifty-nine patients had anatomic evidence of active infective endocarditis (IE); 11 had healed IE; and 10 had both. Of the 80 patients, the first episode of IE involved a single right-sided cardiac valve in 24 patients (30%); both a right- and a left-sided valve in 13 patients (16%); a single left-sided valve in 33 patients (41%); and both left-sided valves in 10 patients (13%). Of the 320 cardiac valves in the 80 patients, 103 were sites of vegetations, an average of 1.3 of the 4 valves. Of the 80 patients, the tricuspid valve was infected in 35 (44%), mitral in 34 (43%), aortic in 32 (40%) and pulmonic in 2 (3%). Of the 103 infected cardiac valves, the infection caused sufficient damage to cause dysfunction in 70 (68%): in 28 (88%) of 32 infected aortic valves; in 22 (63%) of 35 infected tricuspid valves; in 19 (56%) of the 34 infected mitral valves; and in 1 of the 2 infected pulmonic valves. Of the 80 patients, 57 (71%) had sufficient valvular damage to cause valvular dysfunction. Of the 80 patients, gross examination of the valves at necropsy indicated that the infected valve almost certainly had been anatomically normal in 65 patients (81%) and abnormal in 15 patients (19%) before the onset of IE. Of the 65 patients with previously anatomically normal valves, 86 (33%) of their 260 cardiac valves were sites of infection (average 1.3 valves/patient); of the 15 patients with infection superimposed on a previously abnormal valve, the infection in each involved previously abnormal valves (21 in the 15 patients) or 17 (28%) of their 60 cardiac valves were sites of infection (average 1.1 valve/patient). Of the 15 patients with abnormal cardiac valves before the infection, 7 had congenitally bicuspid aortic valves and 8 had diffuse fibrous thickening of the mitral valve typical of rheumatic heart disease with (6 patients) or without (2 patients) diffuse fibrous thickening of tricuspid aortic valves. Of the 80 patients, 42 (53%) died during their first episode of active IE, 17 (21%) underwent operative excision with or without valve replacement during the active IE, and in 21 patients (26%) the first episode of active IE healed. In 10 of the latter 21 patients, active IE recurred and was fatal. A total of 19 patients had cardiac valve excision with or without replacement, 17 during active IE and 2 after healing.(ABSTRACT TRUNCATED AT 250 WORDS)


Open reduction and internal fixation of high-energy tibial plateau fractures.
Proximal tibial articular fractures are caused by a variety of mechanisms and are characterized by numerous distinct fracture patterns. Surgical treatment for other than minimally displaced or nondisplaced fractures is recommended to restore joint congruity and limb alignment, and to allow early, stable, knee motion.


Deep Learning Estimation of 10-2 Visual Field Map Based on Circumpapillary Retinal Nerve Fiber Layer Thickness Measurements.
To estimate central 10-degree visual field (VF) map from spectral-domain optical coherence tomography (SD-OCT) retinal nerve fiber layer thickness (RNFL) measurements in glaucoma with artificial intelligence. Artificial intelligence (convolutional neural networks) study. This study included 5352 SD-OCT scans and 10-2 VF pairs from 1365 eyes of 724 healthy patients, patients with suspected glaucoma, and patients with glaucoma. Convolutional neural networks (CNNs) were developed to estimate the 68 individual sensitivity thresholds of 10-2 VF map using all-sectors (CNNA) and temporal-sectors (CNNT) RNFL thickness information of the SD-OCT circle scan (768 thickness points). 10-2 indices including pointwise total deviation (TD) values, mean deviation (MD), and pattern standard deviation (PSD) were generated using the CNN-estimated sensitivity thresholds at individual test locations. Linear regression (LR) models with the same input were used for comparison. The CNNA model achieved an average pointwise mean absolute error of 4.04 dB (95% confidence interval [CI] 3.76-4.35) and correlation coefficient (r) of 0.59 (95% CI 0.52-0.64) over 10-2 map and the mean absolute error and r of 2.88 dB (95% CI 2.63-3.15) and 0.74 (95% CI 0.67-0.80) for MD, and 2.31 dB (95% CI 2.03-2.61) and 0.59 (95% CI 0.51-0.65) for PSD estimations, respectively, significantly outperforming the LRA model. The proposed CNNA model improved the estimation of 10-2 VF map based on circumpapillary SD-OCT RNFL thickness measurements. These artificial intelligence methods using SD-OCT structural data show promise to individualize the frequency of central VF assessment in patients with glaucoma and would enable the reallocation of resources from patients at lowest risk to those at highest risk of central VF damage.


The yeast cell-type-specific repressor alpha 2 acts cooperatively with a non-cell-type-specific protein.
The yeast alpha 2 protein is a cell-type-specific transcriptional repressor. It acts by binding to an operator located upstream of each of its target genes. In this paper, we describe a protein (GRM) that is present in all cell types and binds cooperatively with alpha 2 resulting in an unusual arrangement of the two proteins at the operator. A dimer of alpha 2 occupies the two ends of the operator and straddles the GRM protein, which binds to the center of the operator. Using mutant operators, we show that the recognition sequences for both GRM and alpha 2 are required for repression of a test promoter in vivo. Finally, we deduce that the GRM/alpha 2 cooperativity is mediated through a protein-protein interaction between GRM and the N-terminal domain of alpha 2. This conclusion follows from the observation that the isolated C-terminal domain of alpha 2 can co-occupy the operator with GRM but does not bind cooperatively with GRM.


The effect of collateral sprouting on the density of innervation of normal target sites: implications for theories on the regulation of the size of developing synaptic domains.
The 'commissural' innervation of the dentate gyrus molecular layer has been analyzed in normal adult rats and in those in which the ipsilateral entorhinal cortex had been removed by aspiration at 14 days post-natal. This ablation severely deafferents the distal two-thirds of the molecular layer and induces 'sprouting' by the commissural afferents which are normally restricted to the more proximal dendritic zone. It was the objective of the present study to employ quantitative electron microscopy to determine (1) the extent of synaptic recovery in the deafferented field; (2) the magnitude of the contribution by the commissural fibers to the reinnervation of the deafferented field; and (3) if sprouting by the commissural projections causes a reduction in the density of the terminal field they generate in their normal target region. The synaptic density of the neonatally deafferented middle molecular layer was found to have returned to near control levels by adulthood. Degeneration studies performed in the adult revealed that commissural endings were located in equivalent numbers in the inner and middle molecular layers of rats in which the entorhinal cortex had been removed at 14 days post-natal; in normal rats (i.e. no neonatal surgery) the commissural terminals were found only in the inner molecular layer. Furthermore, and most importantly, the density of commissural terminals in the inner molecular layer was virtually identical in the 'sprouted' and control rats. Thus the tremendous areal expansion of the commissural terminal field which occurs after early deafferentation of the distal parts of the granule cell dendrites was not accompanied by any loss of input to the normal target of this afferent. Therefore, sprouting in this system represents an exaggeration of normal growth rather than a redistribution of a fixed population of endings. The relevance of these findings to theories concerned with the regulation of axonal growth and terminal proliferation during development is discussed.


Urologic causes of the acute abdomen.
This article reviews renal and perirenal infections, obstructing conditions of the renal pelvis and ureter, and acute intrascrotal events. Each subject is reviewed with regard to patterns of presentation, means of diagnosis, and treatment options. Emphasis is placed on new modalities in the evaluation and treatment of these conditions.


A Comparative Study of Liver Disease Care in the USA and Urban and Rural China.
Chronic liver disease is a major cause of morbidity and mortality in the USA and China, but the etiology of liver disease, medical practice, and patient expectations in these two countries are different. To compare patient knowledge about their liver disease, patient satisfaction with liver disease care, and patient medical decision-making preference in the USA and China. Three cohorts of established adult patients with liver disease seen in liver clinics in Ann Arbor, USA, and Beijing (urban) and Hebei (rural), China, completed a survey between May and September 2014. A total of 990 patients (395 USA, 398 Beijing, and 197 Hebei) were analyzed. Mean liver disease knowledge score (maximum 5) in the USA, Beijing, and Hebei patients was 4.1, 3.6, and 3.0, respectively (p < 0.001). US patients had a greater preference for collaborative decision-making: 71.8 % preferred to make treatment decisions together with the doctor, while most Chinese patients (74.6 % Beijing and 84.8 % Hebei) preferred passive decision-making. Mean satisfaction score (maximum 85) in the USA was higher than in Beijing, which in turn was higher than in Hebei (78.2 vs. 66.5 vs. 60.3, p < 0.001). There was a positive correlation between liver disease knowledge score and satisfaction score (r = 0.27, p < 0.001) and with collaborative medical decision-making (r = 0.22, p < 0.001) when responses from all sites were combined. Liver disease knowledge and patient satisfaction were greatest in the USA, followed by Beijing and then Hebei patients. Understanding these differences and associated factors may help to improve patient outcomes.


Parkinson's disease-associated DJ-1 mutations increase abnormal phosphorylation of tau protein through Akt/GSK-3β pathways.
Hyperphosphorylated tau protein is the main component of neurofibrillary tangles found in Alzheimer's disease and Parkinson's disease (PD). Mutations in DJ-1 have been identified as the causative gene for Parkinson's disease 7 (PARK7)-linked PD. DJ-1L166P and DJ-1D149A, two types of DJ-1 mutations, are most commonly studied as the loss-of-function mutations responsible for early-onset familial PD. Whether mutations in DJ-1 result in tauopathy is as yet unknown. In this study, we found that the L166P and D149A mutant isoforms of DJ-1 associated with familial PD cause tau phosphorylation at Ser202, Ser262, and PHF1 (396/404) sites in neuroblastoma 2a cells. Glycogen synthase kinase (GSK)-3β phosphorylation at serine 9 (Ser9) decreases around 50 % in DJ-1L166P- or DJ-1D149A-transfected cells, while there is no change in total levels of GSK-3β. Our results also indicate that overexpression of DJ-1L166P or DJ-1D149A leads to a significant decrease in the level of phosphorylation of Akt at Thr308, which plays a critical role in phosphorylating GSK-3β at Ser9 and inhibiting its kinase activity. Importantly, insulin, the activator for Akt, effectively attenuates the reduced phosphorylation level of GSK-3β at Ser9 induced by DJ-1L166P. Neither the expression of cyclin-dependent kinase 5 nor the level of PP2A activity was found to have changed, suggesting that the familial PD-associated DJ-1L166P and DJ-1D149A mutations increase tau phosphorylation by increasing the activity of GSK-3β. Finally, we found that administration of lithium chloride, a well-known GSK-3β inhibitor, resulted in decreased levels of phosphorylated tau in DJ-1L166P-transfected cells.


Nonyloxytryptamine mimics polysialic acid and modulates neuronal and glial functions in cell culture.
Polysialic acid (PSA) is a major regulator of cell-cell interactions in the developing nervous system and in neural plasticity in the adult. As a polyanionic molecule with high water-binding capacity, PSA increases the intercellular space generating permissive conditions for cell motility. PSA enhances stem cell migration and axon path finding and promotes repair in the lesioned peripheral and central nervous systems, thus contributing to regeneration. As a next step in developing an improved PSA-based approach to treat nervous system injuries, we searched for small organic compounds that mimic PSA and identified as a PSA mimetic 5-nonyloxytryptamine oxalate, described as a selective 5-hydroxytryptamine receptor 1B (5-HT1B ) agonist. Similar to PSA, 5-nonyloxytryptamine binds to the PSA-specific monoclonal antibody 735, enhances neurite outgrowth of cultured primary neurons and process formation of Schwann cells, protects neurons from oxidative stress, reduces migration of astrocytes and enhances myelination in vitro. Furthermore, nonyloxytryptamine treatment enhances expression of the neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM and reduces expression of the microtubule-associated protein MAP2 in cultured neuroblastoma cells. These results demonstrate that 5-nonyloxytryptamine mimics PSA and triggers PSA-mediated functions, thus contributing to the repertoire of molecules with the potential to improve recovery in acute and chronic injuries of the mammalian peripheral and central nervous systems. Polysialic acid (PSA) plays important roles in nervous system development, as well as synaptic plasticity and regeneration in the adult. 5-Nonyloxytryptamine oxalate (5-NOT) mimics PSA and triggers PSA-mediated functions in neurons and glial cells. 5-NOT stimulates neuritogenesis, myelination and Schwann cell migration. This study sets the basis to develop a PSA-mediated therapy of acute and chronic nervous system diseases.


[Repair of defect on finger skin with reverse fascial pedicle island flap of dorsal branch of digital artery].
To introduce the surgical procedure and indication of the reverse fascial pedicle island flap of the digital artery dorsal branches in repairing finger skin defect. By use of the dorsal branches of the digital artery as the pedicel, the reverse island flap was designed. The skin defects of the proximal interphalangeal joint and beyond in 35 cases (42 fingers) were repaired and the joint or extensor tendon was reconstructed simultaneously. Donor site was primarily closed or a skin graft was used. The flap size ranged from 1.0 cm x 2.5 cm to 1.5 cm x 3.5 cm. Thirty-five patients were followed up 3 months to 1 year, all the flaps survived. The two-point discrimination was between 6 mm and 10 mm. The function of interphalangeal joint was satisfactory. These flaps have the advantages of an extended skin paddle and a versatile pivot point on the phalanx, and they allow coverage of wide and distal defects.


Amenorrhoea in cystic fibrosis.
Menstrual history in relation to nutritional status and lung function was assessed in 45 adolescent and adult patients with cystic fibrosis (CF). Twenty patients had regular menstrual cycles (of whom six had been pregnant), 12 had primary or secondary amenorrhoea, 11 had irregular cycles and two were premenarcheal. Patients with regular menstruation had a significantly higher body mass index and percentage body fat (estimated from skinfold thickness measurements) than those with amenorrhoea (P less than 0.001), and also better lung function (P less than 0.01). A linear discriminant analysis indicated that of the four indices studied percentage body fat was the most important predictor of menstrual function. Ovarian and uterine morphology were studied by ultrasonography in 28 patients and 17 healthy controls. In 10 patients multicystic ovaries were noted. Even in patients with regular cycles uterine size was reduced (P less than 0.01) and in those with amenorrhoea appeared to be related to thinness. Amenorrhoea in CF is an appropriate adaptive response in preventing pregnancy, but the resultant oestrogen deficiency and psychological effects must be considered.


The role of CD8+ regulatory T cells and B cell subsets in patients with COVID-19.
Coronavirus disease 2019 (COVID-19) has a wide clinical spectrum from asymptomatic to mild, moderate, and severe cases. There are still many unknowns about the role of immunoregulatory mechanisms in COVID-19. We aimed to study regulatory T cells (Tregs) and B cell subsets and evaluate their correlations with severity of COVID-19. In total, 50 patients with COVID-19 confirmed by PCR (mean age = 49.9 ± 12.8 years) and 40 healthy control (mean age = 47.9 ± 14.7 years) were included in this study. The patients were classified as 14 mild (median age = 35.5 [24-73] years), 22 moderate (median age = 51.5 [28-67] years) and 14 severe (median age = 55.5 [42-67] years). Within 24 h of admission, flow cytometry was used to assess the lymphocyte subsets, Tregs and Bregs without receiving any relevant medication. In all patients with COVID-19, the proportion of CD3+CD8+ T cells was reduced (p = 0.004) and the CD8+ Tregs were increased compared with control (p = 0.001). While the levels of regulatory B cells, plasmablasts, and mature naive B cells were found to be significantly high, primarily memory B-cell levels were low in all patients compared with controls (p < 0.05). Total CD3+ T cells were negatively correlated with the length of stay in the hospital (r = -0.286, p = 0.044). The changes in T and B cell subsets may show the dysregulation in the immunity of patients with COVID-19. In this context, the association between CD8+ Tregs and COVID-19 severity may help clinicians to predict severe and fatal COVID-19 in hospitalized patients.


Local effects of natural alkylamides from Acmella oleracea and synthetic isobutylalkyl amide on neuropathic and postoperative pain models in mice.
Neuropathic and postoperative pain are clinical conditions that impair the patient's quality of life. The current pharmacotherapy of both painful states is ineffective and accompanied by several side effects. In order to develop new therapeutics targets, the secondary metabolites of plants have been extensively studied. Acmella oleracea ("jambu") is a native plant from the Amazon region and rich in alkylamides, bioactive compounds responsible for inducing anesthetic and chemesthetic sensations. We previously demonstrated that the intraplantar administration of an hexanic fraction (HF) rich in alkylamides from jambu and the synthetic isobutylalkyl amide (IBA) at 0.1 μg/20 μL can promote antinociceptive and anti-inflammatory effects. Thus, this study aimed to evaluate the local effect of HF and IBA (0.1 μg/20 μL) on neuropathic (partial sciatic nerve ligation, PSNL) and postoperative pain (plantar incision surgery, PIS) models in mice. Seven days after the PSNL, the mechanical (von Frey test) and cold (acetone-evoked evaporative cooling) allodynia, and digital gait parameters were analyzed. The intraplantar HF and IBA treatments attenuated the mechanical and cold allodynia as well as the static (max. Contact and print area) and dynamic (stand duration) parameters of digital gait analyses. On the day after PIS, the mechanical allodynia, heat hyperalgesia (hot plate, 52 ± 0.1°C), and spontaneous nociception scores were evaluated. Topical treatment with HF reduced the mechanical allodynia, heat hyperalgesia, and spontaneous nociception scores. In contrast, IBA treatment only partially reduced the mechanical allodynia. In summary, the local treatment with HF was effective on both neuropathic and postoperative pain, as opposed to IBA, which only had an effect on neuropathic pain.


[Kidney cancer in horseshoe kidney. A case report of an unexpected diagnosis].
The authors report a case of renal cell carcinoma in a horseshoe kidney and discuss diagnostic and therapeutical aspects arising from this combination. Renal carcinoid tumors and nephroblastoma seems to be more frequent in this malformation. Diagnosis of horseshoe kidney may be difficult and angiography examination is very useful to confirm renal anomaly, tumor situation, and to plan the surgical approach because vascularization vary case to case. Heminephrectomy adapted to neoplasic localisation remains the essential treatment.


Excitatory synaptic potentials due to activation of neurons with short projections in the myenteric plexus.
Intracellular microelectrodes have been used to examine the effects, on excitatory inputs to myenteric nerve cells, of lesions of intrinsic pathways in the myenteric plexus of the guinea-pig small intestine. The lesions consisted of circumferential cuts (myotomies) which severed the external musculature to the depth of the submucosa and thus interrupted pathways in the myenteric plexus. Sufficient time was allowed between creating the lesions and recording from the neurons for the endings of severed neurites to degenerate and this was confirmed histochemically by examining the distribution of varicose fibres with 5-hydroxytryptamine immunoreactivity in myenteric ganglia from which recordings were made. Two types of excitatory input, eliciting fast and slow excitatory post-synaptic potentials, respectively, were demonstrable in response to focal stimulation of nerves in the ganglia from which recordings were made. There were no differences in the proportions of neurons in which fast or slow excitatory synaptic potentials were evoked in unoperated preparations (controls), in islands 1.5-4 mm wide between myotomies, or within 1 mm on the oral or anal sides of myotomies. Possible differences in the amplitudes, durations at half amplitude, and threshold numbers of stimuli for initiation of slow excitatory synaptic potentials were analyzed. The only significant differences were found when data from control and oral areas were pooled and compared with combined data from island and anal areas (this assessed differences that could arise from severing nerve fibres running from oral to anal).(ABSTRACT TRUNCATED AT 250 WORDS)


Collagen-cellulose nanocrystal scaffolds containing curcumin-loaded microspheres on infected full-thickness burns repair.
Burn infection is a serious problem that delays wound healing and leads to death. Curcumin (Cur) has been shown to exhibit antioxidant, anti-inflammatory, antimicrobial and anticarcinogenic activity. However, its instability, extremely low aqueous solubility and bioavailability in physiological fluids may make it difficult to maintain local Cur concentrations above the minimum inhibitory concentration for burn infection treatment. The objective of this study was to construct complexes of Cur/gelatin microspheres (GMs) and porous collagen (Coll)-cellulose nanocrystals (CNCs) composite scaffolds for full-thickness burn infection treatment. The Cur/GMs/Coll-CNCs scaffolds had high porosity, available pore size, and a long and sustained Cur release profile. Furthermore, the composite scaffold exhibited remarkably strong antibacterial activity. Hence, we evaluated the wound-healing effects and antibacterial properties of Cur/GMs/Coll-CNCs scaffolds in a rat full-thickness burn infection model. The Cur/GMs/Coll-CNCs scaffold was able to prevent not only local inflammation but also accelerated dermis regeneration. Thus, we conclude that Cur/GMs/Coll-CNCs scaffolds can act as an effective dermal regeneration template for full-thickness burn wound infection healing in rats models. Copyright © 2017 John Wiley & Sons, Ltd.


The role of redox in the regulation of manganese-containing superoxide dismutase biosynthesis in Escherichia coli.
The manganese-containing superoxide dismutase in Escherichia coli is an inducible enzyme that protects cells against oxygen toxicity. The manganese-enzyme is induced by oxygen, nitrate, redox active compounds that react with oxygen to generate superoxide radicals, as well as iron chelators. In order to test the hypothesis that the redox state of the cell is involved in regulating manganese-superoxide dismutase biosynthesis, we studied the effects of several oxidants on growth and superoxide dismutase biosynthesis. The data showed, that under anaerobic conditions, the active manganese-enzyme is induced in the presence of potassium ferricyanide, copper-cyanide complex, ammonium persulfate, and hydrogen peroxide. Western blot analysis revealed that the induction of manganese-superoxide dismutase by the oxidants is associated with de novo protein biosynthesis. Potassium ferricyanide and hydrogen peroxide induced the enzyme under aerobic conditions as well. It is concluded that the redox state of the cell possibly influences the biosynthesis and/or activity of an iron-containing repressor protein that serves to negatively regulate manganese-superoxide dismutase biosynthesis.


Modulatory role of mineral nutrients on cadmium accumulation and stress tolerance in Oryza sativa L. seedlings.
Cadmium (Cd)-contaminated rice is a serious health concern. In the present study, Cd accumulation and stress responses in Oryza sativa L. cv MTU 7029 seedlings were characterized under varying concentrations of plant nutrients in Hoagland media. It has been found that nutrient supplement modulates Cd accumulation and related stress tolerance while efficacy of each nutrient varies. Supplementation of Fe, Mn, N, Ca, and S were found to reduce Cd accumulation in leaf whereas Mn and Fe supply effect was also observed in roots. Analysis of maximum quantum efficiency of photosynthesis indicated that Fe and S supplements confer highest Cd stress tolerance. The present study highlighted the potential of plant nutrients for minimizing Cd accumulation and its toxicity in rice seedlings.


Machine learning-driven QSAR models for predicting the mixture toxicity of nanoparticles.
Research on theoretical prediction methods for the mixture toxicity of engineered nanoparticles (ENPs) faces significant challenges. The application of in silico methods based on machine learning is emerging as an effective strategy to address the toxicity prediction of chemical mixtures. Herein, we combined toxicity data generated in our lab with experimental data reported in the literature to predict the combined toxicity of seven metallic ENPs for Escherichia coli at different mixing ratios (22 binary combinations). We thereafter applied two machine learning (ML) techniques, support vector machine (SVM) and neural network (NN), and compared the differences in the ability to predict the combined toxicity by means of the ML-based methods and two component-based mixture models: independent action and concentration addition. Among 72 developed quantitative structure-activity relationship (QSAR) models by the ML methods, two SVM-QSAR models and two NN-QSAR models showed good performance. Moreover, an NN-based QSAR model combined with two molecular descriptors, namely enthalpy of formation of a gaseous cation and metal oxide standard molar enthalpy of formation, showed the best predictive power for the internal dataset (R2test = 0.911, adjusted R2test = 0.733, RMSEtest = 0.091, and MAEtest = 0.067) and for the combination of internal and external datasets (R2test = 0.908, adjusted R2test = 0.871, RMSEtest = 0.255, and MAEtest = 0.181). In addition, the developed QSAR models performed better than the component-based models. The estimation of the applicability domain of the selected QSAR models showed that all the binary mixtures in training and test sets were in the applicability domain. This study approach could provide a methodological and theoretical basis for the ecological risk assessment of mixtures of ENPs.


Effect of Exogenous Enzymes Cocktail on Performance, Carcass Traits, Biochemical Metabolites, Intestinal Morphology, and Nutrient Digestibility of Broilers Fed Normal and Low-Energy Corn-Soybean Diets.
Ross 308 broilers in a randomized complete block design with a 2 × 2 factorial treatment arrangement (four treatments with 12 replications of six chicks each) were fed corn and SBMbased diets with two concentrations of metabolizable energy (ME) (normal (positive control, PC) and low (negative control, NC)) and two amounts of enzyme cocktail (EC) (0% and 0.005%) for 35 days. Performance, carcass traits, serum metabolites, ileal histology, and apparent nutrient digestibility were evaluated. Compared with the non-supplemented diet, the use of EC improved feed conversion ratio (FCR) over 26−35 and 0−35 days (p < 0.01), European performance efficiency factor (EPEF) over 26−35 days (p < 0.05), dressing yield (p < 0.01), villus height (p < 0.05), nitrogen-corrected apparent ME (AMEn) (p < 0.01), and serum glucose (p < 0.05). Compared with the NC diet, feeding the PC diet improved FCR over all experimental periods (p < 0.01, p < 0.05, p < 0.05, and p < 0.01, respectively), EPEF over 0−10 days (p < 0.05), and AMEn retention (p < 0.01). To conclude, the AMEn of broilers fed corn and SBM diets could be improved by adequately adjusting dietary ME and using a cocktail of non-starch polysaccharide-degrading enzymes, improving commercial benefits to producers.


Potential of microplastics participate in selective bioaccumulation of low-ring polycyclic aromatic hydrocarbons depending on the biological habits of fishes.
Currently, although the cumulative effects of microplastics (MPs) and organic pollutants (OPs) in the environment and within organisms are being investigated, whether and how MPs participate in bioaccumulation of OPs based on a carrier effect is still unclear. In the present study, water and aquatic organisms were collected from the Pearl River. Polycyclic aromatic hydrocarbons (PAHs) and MPs were separated by solid phase extraction and were measured by gas chromatography mass spectrometry and Fourier transform infrared spectroscopy, respectively. Higher PAH concentrations at the river outlet and higher MPs abundance in the inner river were observed, indicating a mismatched distribution between PAHs and MPs. No correlation between MP abundance and PAH concentration in fishes was detected, implying that MPs exerted limited influence on PAH concentrations. Interestingly, bioconcentration factors of one major low-ring PAH (phenanthrene) in fishes showed a significant correlation with MPs abundance, implying that although MPs did not affect the variation in PAH concentrations, they potentially participated in selective bioaccumulation of PAHs. Moreover, significant correlations between MPs abundance and PAHs in fishes with different feeding and living habits were found, indicating that MPs' participation in PAH bioaccumulation was dependent on fish biology and life history. Furthermore, the health risk posed by PAHs in fishes at the river outlet surpassed the line of potential high risk, while the ecological risk posed by MPs at the inner river was in the danger category, indicating the ecological risks posed by PAHs and MPs are uneven along the Pearl River. These findings deepen our understanding of the underlying mechanism of MPs participating in selective bioaccumulation of low-ring PAHs in fishes based on fish biology and point out the present risks posed by these two pollutants in the Pearl River and its estuary, which contribute to aquatic environmental protection and fishery production in this region.


Maternal and neonatal outcomes in pregnant women with heart disease with single evaluation vs. semi-structured evaluation by a cardio-obstetric team.
Cardiovascular diseases in pregnant women are challenging, with high maternal and perinatal morbidity and mortality, so a cardio-obstetric team is recommended for their care. Even so, little data evaluates the impact of these teams. Therefore, the present study aims to compare the obstetric, maternal, and neonatal outcomes of semi-structured follow-up (SSF) in a Cardio-obstetric clinic concerning regular or unstructured follow-up (USF) in pregnant women with heart disease. A prospective registry of pregnant women with heart disease was carried out. Patients with SSF by a cardio-obstetric team were compared with those with single evaluation or USF. The risk of events was calculated according to the modified World Health Organization (mWHO) classification and the CARPREG-II scale, and cardiac, obstetric, and neonatal outcomes were evaluated. One hundred sixty-eight patients were evaluated, 37 with SSF and 131 with single evaluation (USF). The primary diagnoses were congenital heart disease, arrhythmias, and valve disease. The average CARPREG-II in USF patients was 2.48 (SD 2.3); in SSF patients, it was 3.37 (SD 2.45; p = 0.041). The average of the mWHO in patients with USF was 2.1 (SD 1.6), and with SSF, it was 2.65 (SD 0.95; p = 0.0052). There were no significant differences in primary cardiac outcomes (13.8% in USF vs. 5.4% in SSF; p = 0.134), secondary cardiac (5.3% in USF vs. 2.7% in SSF; p = 0.410), obstetric (10% in USF vs. 16.2% in SSF; p = 0.253) and neonatal (35.9% in USF and 40.5% in SSF; p = 0.486) even though patients with SSF had a higher risk than patients with USF according to the mWHO and CARPREG-II scales. In pregnant women with heart disease, an SSF compared with a USF by a cardio-obstetric team did not show statistically significant differences in cardiovascular, obstetric, and neonatal outcomes. However, patients with SSF had a significantly higher risk of adverse outcomes due to the mWHO and CARPREG-II scales. This result suggests that the SSF achieves at least equal outcomes despite the higher risk of adverse events that patients in this group had.


Hypersensitivity reactions to chemotherapy agents in patients receiving chemoimmunotherapy with high-dose interleukin 2.
Treatment with the immune system modulator interleukin 2 (IL-2) can result in a number of immunologic abnormalities ranging from suppression of delayed-type hypersensitivity responses and neutrophil activity to autoimmune thyroiditis and hypersensitivity reactions against iodine-containing radiographic contrast media. There are a number of published reports of chemoimmunotherapy using IL-2 in combination with various chemotherapeutic agents to treat patients with certain cancers, but none have described hypersensitivity responses to the chemotherapeutic agents given. In the early stages of an ongoing clinical trial of the efficacy of combination chemoimmunotherapy for the treatment of patients with metastatic melanoma, we discovered that a number of the patients experienced unexpected hypersensitivity reactions after receiving chemotherapy. We therefore decided to examine these hypersensitivity reactions in detail. During the period of March 1993 through February 1994, 31 patients with metastatic melanoma were treated either by chemotherapy (dacarbazine, cisplatin, and tamoxifen) or by chemoimmunotherapy (the same drug regimen plus interferon alfa and high-dose IL-2). Twelve patients were treated in a non-randomized pilot study, with six receiving chemotherapy and six receiving chemoimmunotherapy. The six patients who received chemotherapy also received carmustine (BCNU). Nineteen subsequent patients were treated in a prospective, randomized study to compare the two therapeutic approaches. In total, 15 of the 31 patients were treated by chemotherapy alone, and 16 were treated by combination chemoimmunotherapy. Overall, the patients in the two groups were balanced in terms of age, sex, and stage of disease. Ten of 16 chemoimmunotherapy patients exhibited type I hypersensitivity reactions during chemotherapy administration, ranging from pruritus, erythema, and edema to hypotension with hemodynamic instability that required pressor therapy. None of the 15 patients on the chemotherapy regimen exhibited hypersensitivity reactions. All patients in the chemoimmunotherapy group gained weight and had elevated white blood cell and eosinophil counts during chemotherapy; these effects were more prominent in those with hypersensitivity reactions. Hypersensitivity reactions occurred within several hours after chemotherapy administration in patients who had previously received one to two cycles of high-dose IL-2, suggesting that prior IL-2 therapy sensitized patients to cisplatin or dacarbazine. This is the first report of IL-2-induced hypersensitivity to chemotherapy agents.


Toward Public Health Wellness: Psychosocial & Physical Health in the Community.
Public health plays a pivotal role in society [...].


Association of early inflammatory parameters after subarachnoid hemorrhage with functional outcome: A prospective cohort study.
Early brain injury after aneurysmal subarachnoid hemorrhage (aSAH) comprises a pronounced neuroinflammatory reaction. Nevertheless, its relevance for functional outcome and its role as outcome predictor remains uncertain. We evaluated the relationship of various early inflammatory parameters regarding functional outcome according to the modified Rankin Scale score (mRS) at discharge (primary objective) and six months after aSAH. A total of 81 patients (63% female) with a mean age of 53.8 ± 13.2 years were included. At admission clinical data and various inflammatory parameters in serum and - wherever applicable - cerebrospinal fluid (CSF) of patients after aSAH were assessed. Outcome was evaluated according to dichotomized mRS at discharge and six months after aSAH (unfavorable outcome: mRS 3-6). Univariate and thereafter multivariate logistic regression analyses were performed using SAS 9.2. Elevated levels of interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in serum and CSF were related to unfavorable outcome at discharge (p<0.05; univariate analyses). IL-6 remains the only parameter relevant for outcome applying a multivariate model including the relevant baseline characteristics. Six months after aSAH no significant correlation was found regarding the outcome, most likely due to the high drop-out rate (27%). A pronounced rise of LIF serum and CSF levels after aSAH was observed. Higher early IL-6 serum levels after aSAH are associated with poor outcome at discharge. In addition, involvement of LIF in the early inflammatory reaction after aSAH has been demonstrated.


One year cumulative incidence of depression following myocardial infarction and impact on cardiac outcome.
Major depression has been identified as an independent risk factor for increased morbidity and mortality in mixed patients populations with first and recurrent myocardial infarction (MI). The aim of this study was to evaluate whether incidence of major and minor depression is as high in a population with merely first-MI patients as in recurrent MI populations. Furthermore, it was evaluated whether in first-MI patients major and minor depression, and depressive symptoms, had an impact on cardiac mortality and morbidity up to 3 years post MI. A consecutive cohort of 206 patients with a first MI were included in this study. One month following MI, all patients were interviewed using the Structured Clinical Interview for DSM-IV (SCID-I-R). Three, six, nine and twelve months following MI, patients filled out three psychiatric self-rating scales for depression, the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), and the 90-item Symptom Checklist (SCL-90). Patients, exceeding a previously defined cut-off value on at least one of these scales, were reinterviewed using the SCID. The BDI was applied to assess depressive symptoms in relation to cardiac outcome as the SCL-90 and HADS showed similar results. Cardiac outcome was defined as major cardiac event, i.e., death or recurrent MI, and health care consumption, i.e., cardiac rehospitalisation and/or frequent visits at the cardiac outpatient clinic. Depression outcome was assessed from 1 month post MI up to 1 year post MI whereas cardiac outcome was assessed between 1 month and 3 years post MI. A 1-year incidence of 31% of major and minor depression was found in first-MI patients. The highest incidence rate for both major and minor depression was found in the first month after MI. Compared with nondepressed patients, depressed patients were younger (P=.001), female (P=.04) and were known with a previous depressive episode (P=.002). Neither major/minor depression nor depressive symptoms significantly predicted major cardiac events, but did predict health care consumption (P=.04 and P<.001, respectively). Incidence of major and minor depression is similar in this first-MI patients population as in recurrent MI populations. Major/minor depressive disorder nor depressive symptoms predicted neither mortality nor reinfarction.


Incidence and risk factors for fluorescence abnormalities on near-infrared imaging using indocyanine green in stapled functional end-to-end anastomosis in laparoscopic colectomy.
Recently, several studies have suggested that near-infrared (NIR) imaging using indocyanine green (ICG) may contribute to the reduction of anastomotic leakage (AL) after colorectal cancer (CRC) surgery. However, few reports have focused on the usefulness of NIR imaging for AL after stapled functional end-to-end anastomosis (stapled FEEA). The purpose of this study was to clarify the frequency of fluorescence abnormalities on NIR imaging, in cases reconstructed with stapled FEEA. This retrospective study included patients with colon or appendiceal cancer who underwent laparoscopic colectomy with stapled FEEA reconstruction between March 2016 and August 2019. A total of 400 patients who were managed at our three institutions were included in the present study. The rate of Clavien-Dindo (CD) grade > III AL was 1.0% (4/400). The median length of postoperative hospital stay was 7 days (IQR 25-75th percentile 6-8 days). In 11 patients (2.8%), the transection line was changed by NIR imaging, due to fluorescence abnormalities. The rate of transverse colon involvement in anastomosis was significantly higher in cases with fluorescence abnormalities than in cases with normal fluorescence (p = 0.035). The frequency of fluorescence abnormalities on NIR was 2.8% in cases of colon resection with reconstruction by using stapled FEEA. There was a probability of abnormal fluorescence on NIR in cases where the transverse colon was involved in the anastomosis. This means that NIR may have potential benefit in such cases. UMIN000039977.


Bleeding "sarcomatosis" as a rare presentation of vascular graft-related angiosarcoma: case report and review of the literature.
Angiosarcoma is a rare malignant tumor, originating from vascular endothelial cells, accounting for approximatively 1-2% of soft tissue sarcomas. It is characterized by a rapid proliferation and high metastatic potential. Some cases of angiosarcoma are described in association with vascular prosthesis, orthopedic devices and foreign bodies. Hereby, we report a case of a patient treated with the endovascular placement of a PTFE aorto bis-iliac prosthesis for aortic aneurysm, who developed a graft-related angiosarcoma with bone and peritoneal localizations. The peritoneal "sarcomatosis" led to an acute presentation with hemoperitoneum and anemia. We perform a thorough review of the literature summarizing the description of similar cases, their epidemiology and the possibilities for treatment. An 84-year-old male with a history of abdominal aortic aneurysm endovascular repair presented to our emergency department complaining with low back pain radiating to the left limb. He underwent a type II endoleak embolization of the aneurysmal sac nine days before. During hospitalization he underwent a spine MRI which documented a vertebral alteration of non-univocal interpretation. Vertebral biopsy was performed revealing groups of cells of uncertain nature. He lately underwent percutaneous L2-L4 arthrodesis. Forty-two days after admission, he developed acute anemia. Emergency laparotomy revealed a massive hemoperitoneum and actively bleeding peritoneal nodules. Abdominal packing was performed, and several nodules were sent for definitive histological examination. After surgery, he developed progressive and severe hypovolemic shock and expired on postoperative day 5. Angiosarcoma associated with foreign bodies, especially vascular prosthesis, is a very rare entity. In patients who have a history of prosthetic vascular graft placement that present with lumbar pain, osteolytic changes at radiologic imaging or the development of ascites, angiosarcoma should be considered in the differential diagnosis. Despite the poor prognosis, a prompt diagnosis might give access to an adequate treatment planning, with the aim for disease control and increased survival.


Chronic Type A Aortic Dissection Repair in a Double Lung Transplant Recipient.
A 69-year-old man presented with a chronic Stanford Type A aortic dissection (CTAAD). The patient had undergone bilateral sequential lung transplantation 15 years prior for α-1-antitrypsin deficiency. We describe the management of CTAAD in the context of lung transplantation from the surgical and anesthetic perspectives.


Effects of demographic, audiologic, and hearing-aid-related variables on the outcomes of using hearing aids.
To examine the influence of demographic, audiologic, and hearing-aid (HA)-related variables on HA outcomes. In total, 235 adults with hearing loss (HL) who used HAs for at least 3 months were included in the study, and completed audiologic tests and the Chinese version of the International Outcome Inventory for Hearing Aids (IOI-HA). Spearman correlation analysis and Wilcoxon test were conducted to identify factors related to IOI-HA overall and subscales scores. Stepwise multiple linear regression analysis was subsequently performed to determine the influence of factors on HA outcomes. Age, daily use time, HA price, pure tone average (PTA) threshold, word recognition score (WRS), fitting (bilateral or unilateral), and HA style were associated with IOI-HA overall and subscales scores. However, only WRS, daily HA use time, HA price, and age entered the final regression model and were factors determining HA outcomes. HA outcome is a multi-dimensional construct. In this study, WRS had the greatest influence on HA outcomes and seemed to be a primary predictor. Thus, HA owners with a higher WRS before HA fitting may indicate better satisfaction. Daily use time, HA price, and patient age also made significant contributions to HA outcomes and should be considered in clinical practice to facilitate auditory rehabilitation.


Anti-agalactosyl immunoglobulin G antibodies in localized scleroderma.
Anti-agalactosyl immunoglobulin G (IgG) antibodies (anti-AG IgG) have been reported to be detected and correlated with disease activity in some collagen diseases. Forty-seven serum samples from patients with localized scleroderma were examined using an enzyme-linked immunosorbent assay. Anti-AG IgG were positive in 19% of patients with localized scleroderma. The frequency of anti-AG IgG in generalized morphea was much higher than that in linear scleroderma or that in morphea. There was a significant correlation between anti-AG IgG levels and the number of the sclerotic lesions and between anti-AG IgG levels and the number of involved areas. The levels of anti-AG IgG were significantly higher in patients with antinuclear antibody, antisingle-stranded DNA antibody or rheumatoid factor than in those without. Anti-AG IgG can be an indicator of the severity of localized scleroderma.


Observation of Ag Nanoparticles in/on Ag@MIL-100(Fe) Prepared Through Different Procedures.
Loading of active metals, metal clusters, and/or metal nanoparticles in Metal Organic Frameworks (MOFs) is an emergent field with applications in sensors, catalysis, medicine, and even in the polymeric industry. In the present work, MIL-100(Fe) has been synthesized and reacted with AgNO3 through liquid and incipient wetness, and also through solid-state reaction or solid grinding. The aim of this study is to evaluate whether the MIL-100 would uptake metal particles using a similar principle as that of the ion exchange in zeolites, or else, their inherent humidity would favor the "dissolution" of the metal salt, thus yielding very small metal particles. The immobilization of Ag nanoparticles inside the MOF pores was identified by Cs-corrected scanning transmission electron microscopy (Cs-corrected STEM) techniques.


[Barrett esophagus: epidemiologic data and risk of becoming malignant].
A series is presented of 152 patients diagnosed over a 9-year period by endoscopy and biopsy as Barrett's esophagus. We analyzed epidemiological data and the risk of malignancy, and calculated the prevalence and incidence in our series.


Genome-wide identification of the Dicer-like family in cotton and analysis of the DCL expression modulation in response to biotic stress in two contrasting commercial cultivars.
Dicer-like proteins (DCLs) are essential players in RNA-silencing mechanisms, acting in gene regulation via miRNAs and in antiviral protection in plants and have also been associated to other biotic and abiotic stresses. To the best of our knowledge, despite being identified in some crops, cotton DCLs haven't been characterized until now. In this work, we characterized the DCLs of three cotton species and analyzed their expression profiles during biotic stress. As main results, 11 DCLs in the allotetraploid cotton Gossypium hirsutum, 7 and 6 in the diploid G. arboreum and G. raimondii, were identified, respectively. Among some DCLs duplications observed in these genomes, the presence of an extra DCL3 in the three cotton species were detected, which haven't been found in others eudicots. All the DCL types identified by in silico analysis in the allotetraploid cotton genome were able to generate transcripts, as observed by gene expression analysis in distinct tissues. Based on the importance of DCLs for plant defense against virus, responses of cotton DCLs to virus infection and/or herbivore attack using two commercial cotton cultivars (cv.), one susceptible (FM966) and another resistant (DO) to polerovirus CLRDV infection, were analyzed. Both cvs. Responded differently to virus infection. At the inoculation site, the resistant cv. showed strong induction of DCL2a and b, while the susceptible cv. showed a down-regulation of these genes, wherever DCL4 expression was highly induced. A time course of DCL expression in aerial parts far from inoculation site along infection showed that DCL2b and DCL4 were repressed 24 h after infection in the susceptible cotton. As CLRDV is aphid-transmitted, herbivore attack was also checked. Opposite expression pattern of DCL2a and b and DCL4 was observed for R and S cottons, showing that aphid feeding alone may induce DCL modulation. Almost all the DCLs of the allotetraploide G. hirsutum cotton were found in their relative diploids. Duplications of DCL2 and DCL3 were found in the three species. All four classes of DCL responded to aphid attack and virus infection in G. hirsutum. DCLs initial responses against the virus itself and/or herbivore attack may be contributing towards virus resistance.


Hedysarum polysaccharide alleviates oxidative stress to protect against diabetic peripheral neuropathy via modulation of the keap1/Nrf2 signaling pathway.
Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus. Oxidative stress is implicated in DPN progression, suggesting that antioxidant therapy could be a viable anti-DPN method. Hedysarum polysaccharide (HPS) is an active component of Radix Hedysari, a plant that has been widely used as food and a herb for treating multiple diseases. Here, we evaluated the mechanisms of action of anti-DPN effects of HPS in genetically obese (ob/ob) mice. Schwann cells (SCs) were exposed to glucose (100 mM) in vitro and then treated with HPS at concentrations of 30, 60, 120, and 240 mg/L. Notably, HPS significantly inhibited high glucose-mediated cytotoxicity and oxidative stress by reducing malondialdehyde (MDA) levels and upregulating the expression of antioxidant enzymes (γ-glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione reductase (GR)) in SCs. Moreover, HPS increased the expression of nerve growth factor, stimulated Nrf2 signaling, and decreased Keap1 expression levels. Analysis of DPN mice models gavaged with HPS at 50, 100, and 200 mg/kg/d or lipoic acid (LA) at 30 mg/kg/d (positive control) for 8 weeks revealed that HPS markedly increased motor nerve conduction velocity (MNCV), shortened thermal withdrawal latency (TWL), and inhibited oxidative stress in serum and sciatic nerves of DPN mice models. Mechanistically, HPS suppressed Keap1 signaling and enhanced Nrf2 signaling in sciatic nerves. These findings imply that HPS ameliorates DPN via antioxidant mechanisms and by activating Keap1/Nrf2 signaling, suggesting that HPS is a potential treatment option for DPN.


Riluzole attenuates the efficacy of glutamatergic transmission by interfering with the size of the readily releasable neurotransmitter pool.
Riluzole is a potent neuroprotective agent which primarily inhibits excitatory neurotransmission interfering with presynaptic release, uptake and postsynaptic actions of glutamate by mechanisms that are not well understood. Riluzole and related prodrugs with improved blood brain barrier penetrance, are shown to be effective for the treatment of amyotrophic lateral sclerosis, ataxias, epilepsy and mood disorders. Our study was undertaken to decipher molecular and subcellular mechanisms of riluzole's antiglutamatergic effect, particularly focusing on presynaptic active zone structure and function. Applying multifarious live cell imaging techniques and amperometric glutamate recordings, we measured the impact of riluzole on presynaptic activity, synaptic vesicle recycling and glutamate release. Our in vitro and in vivo data revealed a unique mechanism whereby riluzole reduces the efficacy of glutamatergic transmission by selectively lowering the size of the readily releasable pool. This effect was correlated with the inhibition of protein kinase C-dependent Munc18-1 phosphorylation which is known to interfere with neurotransmitter release.


Age-related changes in binding to excitatory amino acid uptake sites in human cerebellum.
In vitro autoradiography and test-tube assay of the sodium-dependent binding of D-[3H]aspartate were used to localize and quantify the uptake site for the excitatory amino acid neurotransmitters glutamate and aspartate in the cerebellar cortex of human cerebellar hemispheres. Autoradiograms revealed a pronounced heterogeneity in the distribution of D-[3H]aspartate binding in cortex from adult brains, with the highest binding density corresponding to the Purkinje cell layer, high binding in molecular layer and low binding in granule cell layer. In contrast, cerebellar cortex from infants at term (40 weeks gestation) had only low binding of the ligand in both the molecular and the Purkinje cell layers. Both methods employed for measuring D-[3H]aspartate binding showed that the number of binding sites in Purkinje and molecular layers increased rapidly from term to 20 weeks postnatal age and achieved levels higher than those found in adult cerebellum. It is concluded that a substantial increase in the numbers of glutamate/aspartate uptake sites takes place in the human cerebellum during the early postnatal period. It is deduced that the excess uptake sites are eliminated as the cerebellum matures.


The recovery of strontium ions from seawater reverse osmosis brine using novel composite materials of ferrocyanides modified roasted date pits.
In this study, three types of adsorbents were used to remove and recover strontium ions (Sr2+) from aqueous and brine solution of seawater reverse osmosis (SWRO), namely roasted date pits (RDP) and RDP modified using copper and nickel salts of potassium hexacyanoferrates to obtain RDP-FC-Cu, and RDP-FC-Ni, respectively. Additionally, the influence of various parameters, including pH, temperature, initial concentration, and co-existing ions was also evaluated. The results revealed that pH 10 was the optimum pH in which the maximum Sr2+ ions were adsorbed. Additionally, all adsorbents had a high adsorption capacity (99.9 mg/g) for removing Sr2+ ions at the highest concentration (100 mg/L) and a temperature of 45 °C was found to be the optimum temperature. A scanning electron microscopy for the adsorbents before and after the adsorption of strontium showed the remarkable pore filling onto the active sites of all adsorbents. The thermodynamics parameter demonstrated that the adsorption occurred in an endothermic environment, and that, the reaction was spontaneous, and favorable at all the temperatures investigated. According to isotherm studies, the Langmuir model was the best-fit isotherm model; indicating that strontium adsorption involved the formation of monolayers and multilayers at higher temperatures (45 °C). Furthermore, high desorption percentages (above 90%) were achieved for all the adsorbents when an HCl concentration of 0.5 M was used. This showed the high reusability of the adsorbents. Lastly, the adsorption of strontium from the SWRO brine containing a number of metal ions was extremely sufficient as all the adsorbents were efficient to adsorb a high amount of Sr2+ despite the presence of other competing ions.


Endoscopic Resection of Clival Malignancies.
Surgical management of clival lesions presents numerous therapeutic challenges because of the close proximity of surrounding critical structures. With a detailed understanding of the endoscopic endonasal approach and relevant considerations, appropriate lesions can be removed in a safe and minimally invasive manner. Use of this technique as a primary approach represents the standard of care for many lesions at leading skull base centers, although adjunct techniques may be necessary in extensive lesions and those with significant lateral extension.


Biochemical changes in fowl serum during infection with strains of Newcastle disease virus of differing virulence. Changes in serum proteins, uric acid, lipids and electrolytes.
Chickens aged five to six weeks were inoculated with three strains of Newcastle disease virus of differing pathogenicity. The serum level of the metabolites: total protein, albumin, globulin, uric acid, total lipids, cholesterol and electrolytes: calcium, magnesium, sodium and potassium were determined. The changes in serum levels of metabolites were as follows: velogenic infection was accompanied by decrease in total protein and albumin, reduction of lipids and cholesterol and increase in uric acid. No significant changes were found in the values of these metabolites in the serum of chickens infected with mesogenic strain. Lentogenic strain caused elevation of uric acid and cholesterol. All three strains caused decrease of the level of potassium in serum.


Transcriptome analysis reveals the genetic basis underlying the development of skin appendages and immunity in hedgehog (Atelerix albiventris).
The expression of hair features is an evolutionary adaptation resulting from interactions between many organisms and their environment. Elucidation of the mechanisms that underlie the expression of such traits is a topic in evolutionary biology research. Therefore, we assessed the de novo transcriptome of Atelerix albiventris at three developmental stages and compared gene expression profiles between abdomen hair and dorsal spine tissues. We identified 328,576 unigenes in our transcriptome, among which 4,435 were differentially expressed between hair- and spine-type tissues. Dorsal and abdomen skin tissues 5 days after birth were compared and the resulting DEGs were mainly enriched in keratin filament, epithelium cell differentiation, and epidermis development based on GO enrichment analysis, and tight junction, p53, and cell cycle signaling pathways based on KEGG enrichment analysis. MBP8, SFN, Wnt1 and KRT1 gene may involve in the development of hedgehog skin and its appendages. Strikingly, DEGs in hair-type tissues were also significantly enriched in immune-related terms and pathways with hair-type tissues exhibiting more upregulated immune genes than spine-type tissues. Our study provided a list of potential genes involved in skin appendage development and differentiation in A. albiventris, and the candidate genes provided valuable information for further studies of skin appendages.


Co-administration of raltegravir reduces daily darunavir exposure in HIV-1 infected patients.
The potential drug-to-drug interaction between darunavir and raltegravir in the setting of HIV infection is a highly debated issue still unresolved. In the present study we have evaluated the pharmacokinetics of darunavir and ritonavir in 53 HIV-1 infected patients with or without concomitant raltegravir administration. The assessment of trough plasma drug concentrations was carried out in all subjects and the potential influence of raltegravir on darunavir and ritonavir disposition, assessed by specific pharmacokinetic evaluations in a subgroup of 25 patients. No significant differences on darunavir and ritonavir plasma trough levels were observed between patients receiving or not raltegravir. Co-administration of raltegravir was, however, associated with a 40% reduction in darunavir C(max) and estimated AUC(0-24), as well a 60% increase in the estimated darunavir clearance compared with values measured in patients not given raltegravir. Notably, this interaction was independent of the dosage of darunavir and not due to effects of raltegravir on the pharmacokinetics of ritonavir. These results should be taken into account when darunavir-based regimens are implemented in the setting of HIV, especially considering that this drug is usually administered at fixed daily dose and no therapeutic drug monitoring is performed in most centres.


Integrative Multi-omics Analysis of Childhood Aggressive Behavior.
This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.


Relative abundance in an alien weed flora.
Both relative abundance and absolute abundance of alien weed species in a large geographic region increased from the year 1900 to 1980. The increase in relative abundance may have been due to competitive displacement among the weeds, patterns of landscape disturbance, or simply time. The increase in absolute abundance indicates the ineffectiveness of past weed control policies in stemming weed migration. Combined, the two scales of alien weed abundance suggest that in the future we can expect an increasing diversity of increasingly common weeds.


Comparing Outcomes of Robotically Assisted Latissimus Dorsi Harvest to the Traditional Open Approach in Breast Reconstruction.
Robotically assisted latissimus dorsi harvest permits harvest of the latissimus dorsi muscle without a back incision, as compared to the traditional open technique. The authors hypothesized that robotic harvest has lower donor-site complication rates, decreased opioid requirements, and a shorter length of stay than the traditional open technique. A retrospective review was performed of all consecutive pedicled latissimus dorsi flaps for breast reconstruction between 2011 and 2015. All procedures were conducted by two surgeons who performed both robotic and open cases. Fifty-two patients were identified; 25 underwent robotically assisted latissimus dorsi harvest and 27 underwent the open technique. Demographic data between the two groups were similar. Median length of stay for robotic harvest was shorter than that for the traditional technique (2 days versus 3 days; p = 0.031). Postoperative morphine requirement was less in the robotic compared to the traditional technique, but the difference was not significant (158 mg versus 184 mg; p = 0.826). Seroma rate was higher in the robotic group (16 percent versus 0 percent; p = 0.034). The mean duration of surgery was longer in the robotic cohort (388 minutes versus 311 minutes; p = 0.002). This study demonstrates robotically assisted latissimus dorsi harvest as an effective alternative to the traditional open technique in select patients. Advantages of robotic harvest include no back scar, a shorter length of stay, and lower opioid requirements, although the difference was not significant; disadvantages include longer operative time and a higher seroma rate. Therapeutic, III.


Interferon Inhibition for Lupus with Anifrolumab: Critical Appraisal of the Evidence Leading to FDA Approval.
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol 2017;69:376-86. Objective To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI [4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI [4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI [6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis. Results The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). Conclusion Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE. https://onlinelibrary.wiley.com/doi/10.1002/art.39962 Furie RA, Morand EF, Bruce IN, Manzi S, Kalunian KC, Vital EM, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019;1:E208-19. Background Type I interferons are involved in systemic lupus erythematosus (SLE) pathogenesis. In a phase 2 trial, anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, suppressed interferon gene signatures and substantially reduced SLE disease activity. Here, we sought to confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with SLE and moderate-to-severe disease activity despite standard-of-care treatment. Methods TULIP-1 was a double-blind, randomised, controlled, phase 3 trial done at 123 sites in 18 countries. Included patients were aged 18-70 years, with moderate-to-severe SLE, and ongoing stable treatment with either prednisone or equivalent, an antimalarial, azathioprine, mizoribine, mycophenolate mofetil or mycophenolic acid, or methotrexate. Patients were randomly assigned (2:1:2) to receive placebo, anifrolumab 150 mg, or anifrolumab 300 mg intravenously every 4 weeks for 48 weeks. Stable standard-of-care treatment continued except for mandatory attempts at oral corticosteroid tapering for patients receiving prednisone or equivalent of 10 mg/day or more at baseline. The primary outcome was the difference between the proportion of patients who achieved an SLE responder index-4 (SRI-4) response at week 52 with anifrolumab 300 mg versus with placebo. Key secondary outcomes were the difference between the anifrolumab 300 mg group and the placebo group in: proportion of patients in the interferon gene signature test-high subgroup who achieved SRI-4 at week 52; proportion of patients on 10 mg/day or more corticosteroids at baseline who achieved a sustained dose reduction to 7·5 mg/day or less from week 40 to 52; proportion of patients with a cutaneous lupus erythematosus disease area and severity index (CLASI) activity score of 10 or higher at baseline who achieved a 50% or more reduction in CLASI score by week 12; proportion of patients who achieved SRI-4 at week 24; and annualised flare rate through week 52. Other measures of disease activity were also assessed at week 52, including the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA). Safety was also assessed. Efficacy and safety analyses were done in the population of patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT02446912). Findings Between June 9, 2015, and June 16, 2017, 457 patients were randomly assigned to the anifrolumab 300 mg group (n = 180), the anifrolumab 150 mg group (n = 93), or the placebo group (n = 184). The proportion of patients at week 52 with an SRI-4 response was similar between anifrolumab 300 mg (65 [36%] of 180) and placebo (74 [40%] of 184; difference - 4·2 [95% CI -14·2 to 5·8], p = 0·41). Similarly, proportions of patients with an SRI-4 response at week 24, and at week 52 in patients in the interferon gene signature test-high subgroup, did not differ between the anifrolumab and placebo groups. In patients with baseline oral corticosteroids of at least 10 mg/day, sustained dose reduction to 7·5 mg/day or less was achieved by 42 (41%) of 103 patients in the anifrolumab 300 mg group and 33 (32%) of 102 patients in the placebo group (difference 8·9 [95% CI -4·1 to 21·9]). In patients with CLASI activity score of at least 10 at baseline, at least 50% reduction by week 12 was achieved by 24 (42%) of 58 patients in the anifrolumab 300 mg group and 14 (25%) of 54 in the placebo group (difference 17·0 [95% CI -0·3 to 34·3]). Annualised flare rates were 0·60 for anifrolumab and 0·72 for placebo (rate ratio 0·83 [95% CI 0·60 to 1·14]). BICLA response was achieved by 67 (37%) of 180 patients receiving anifrolumab 300 mg versus 49 (27%) of 184 receiving placebo (difference 10·1 [95% CI 0·6 to 19·7]). Anifrolumab's safety profile was similar to that observed in phase 2, with similar proportions of patients having a serious adverse event between groups (25 [14%] of 180 for anifrolumab 300 mg, ten [11%] of 93 for anifrolumab 150 mg, and 30 [16%] of 184 for placebo). Interpretation The primary endpoint was not reached. However, several secondary endpoints, including reduction in oral corticosteroid dose, CLASI responses, and BICLA responses, suggest clinical benefit of anifrolumab compared with placebo. Conclusive evidence for the efficacy of anifrolumab awaits further phase 3 trial data. Despite the inherent limitations of a 1-year phase 3 study, such as incomplete knowledge of applicability to the general population and scarce detection of rare safety signals, in addition to complications from prespecified restricted medication rules, our results suggest that anifrolumab might have the potential to provide a treatment option for patients who have active SLE while receiving standard therapy. Funding AstraZeneca. https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(19)30076-1/fulltext Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 2020;382:211-21. Background Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. Methods We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. Results A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. Conclusions Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.) https://www.nejm.org/doi/full/10.1056/nejmoa1912196.


Children and the global tuberculosis situation.
The current global strategy for control of tuberculosis, Directly Observed Treatment, Short-course (DOTS) focuses, as a priority, on the management of patients with sputum smear positive tuberculosis. As tuberculosis in children is rarely sputum smear positive, this has led many to believe that children are not important in tuberculosis control. This is a misconception. The ultimate goal of tuberculosis services should be the eradication of Mycobacterium tuberculosis. To date, only diseases for which effective vaccines are available have been eradicated. Vaccination aims to protect the population (and especially vulnerable groups, such as children) from the disease against which it is applied. Presently, there is no vaccine able to prevent infection with Mycobacterium tuberculosis. Protection against infection must be achieved in other ways. Thus, early identification and successful treatment of the most infectious cases of tuberculosis has become the focus of attempts and is presently the most effective means to protect children from infection with M. tuberculosis. This is the theory; does it really work? Evidence put forward to support this position has come primarily from industrialised countries where tuberculous infection was already on the decline before any substantial public health activities had been instituted. What of the situation in low income countries where the highest proportion of the tuberculosis patients live at the present time? There is very little evidence available to address this question. The most convincing information published to date comes from the Beijing Municipality of China where the DOTS strategy has been implemented since 1978. Progressive expansion of the strategy occurred over the first five years after which a very high proportion of all tuberculosis patients were managed by this means. The major impact was to progressively and rapidly reduce the prevalence of tuberculosis in the community. The incidence was only more slowly diminished over the same period, primarily because cases continued to arise from the large proportion of the population previously infected. Over the same period, tuberculous meningitis virtually disappeared and the prevalence of tuberculous infection declined to very low levels. This appears to confirm the impact of efficient management of adult tuberculosis patients as a means to protect children from infection. This, while effective, clearly is not sufficient. Every effort is required to develop an effective vaccine that is capable to preventing infection in children. Only then will the disease be eradicated.


Brominated flame retardants and other organobromines in Norwegian predatory bird eggs.
A set of 62 unhatched eggs was collected from six different predatory bird species throughout Norway after incubation period was completed. They were analysed for PBDE, PBB, TBBP A and naturally occurring halogenated compounds. BDE 47, 99 and 153 were the dominating congeners, with species dependent PBDE patterns. BDE 153 was observed as the most abundant congener in eggs of peregrine falcon, golden eagle and merlin. The highest PBDE level (sum of nine congeners) was found in eggs of white-tailed sea eagle with up to 800ng/gww (median sumPBDE: 184ng/gww), followed by eggs of peregrine falcon and osprey (median sumPBDE: 155 and 105ng/gww, respectively). Golden eagle eggs showed the lowest concentration of all species (median sumPBDE: 3ng/gww). The levels in the peregrine falcon are similar to those found earlier in the Baltic region [Lindberg, P., Sellstrom, U., Haggberg, L., de Wit, C.A., 2004. Higher brominated diphenyl ethers and hexabromocyclododecane found in eggs of peregrine falcons (Falco peregrinus) breeding in Sweden. Environmental Science & Technology. 38 (1), 93-96]. The differences between species are not fully explainable, due to lack of data from the major food species. BB 101 and 153 were found in eggs of all investigated bird species. Especially in samples of white-tailed sea eagle, peregrine falcon and goshawk additional unknown penta- and hexabrominated biphenyls were detected. TBBP A was detected in all of eight eggs analysed sampled from four different bird of prey species. The naturally occurring halogenated compounds Q1, the dibromotrichloro monoterpene MHC-1, and 2,4,6-tribromoanisole (TBA) were detected in all of seven analysed samples except for one peregrine falcon egg.