Long-term Outcomes of Kidney Transplantation in Patients With High Levels of Preformed DSA: The Necker High-Risk Transplant Program.
There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required. Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization. The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively. These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.


Draf IIB with superior septectomy: finding the "middle ground".
Previous studies have demonstrated a high failure rate of endoscopic sinus surgery (ESS) with Draf IIa in patients with diffuse polyposis, asthma, and aspirin-exacerbated respiratory disease. A high percentage of these patients progress to endoscopic modified Lothrop procedure (EMLP). We describe a modification of the Draf IIb with a superior septectomy (IIb+SS), which may provide similar therapeutic benefit as demonstrated by the distribution of sinus irrigations in the sinus cavity with ESS with IIb+SS vs ESS with EMLP. ESS with IIb+SS was performed on 6 cadaver heads. Fluorescein-dyed irrigations were performed on each head and penetration was recorded using video endoscopy. EMLP was subsequently performed on each head with repeat dye-irrigation and video endoscopy. The videos were reviewed by 4 blinded fellowship-trained rhinologists, and irrigant penetration of the maxillary, ethmoid, frontal, sphenoid sinuses, and olfactory cleft was graded 0 to 3 (3 implying complete staining). The mean scores when comparing IIb+SS to EMLP were as follows: overall 1.99 vs 1.97 (p = 0.816), maxillary sinus 2.67 vs 2.38 (p = 0.128), ethmoid sinus 1.88 vs 1.98 (p = 0.536), sphenoid sinus 2.58 vs 2.50 (p = 0.467), frontal sinus 1.13 vs 1.38 (p = 0.073), and olfactory cleft 1.71 vs 1.63 (p = 0.529). There was no significant difference between subsites. Interrater reliability was good (Cronbach's alpha = 0.781). Performing ESS with IIb+SS provides similar irrigation delivery benefits to ESS with EMLP, without the need for altering natural sinus outflow and creating circumferential scarring. Further studies evaluating its use in patients that are high risk for revision surgery are needed.


Ammonolysis of Glyoxal at the Air-Water Nanodroplet Interface.
The reactions of glyoxal (CHO)2) with amines in cloud processes contribute to the formation of brown carbon and oligomer particles in the atmosphere. However, their molecular mechanisms remain unknown. Herein, we investigate the ammonolysis mechanisms of glyoxal with amines at the air-water nanodroplet interface. We identified three and two distinct pathways for the ammonolysis of glyoxal with dimethylamine and methylamine by using metadynamics simulations at the air-water nanodroplet interface, respectively. Notably, the stepwise pathways mediated by the water dimer for the reactions of glyoxal with dimethylamine and methylamine display the lowest free energy barriers of 3.6 and 4.9 kcal·mol-1, respectively. These results showed that the air-water nanodroplet ammonolysis reactions of glyoxal with dimethylamine and methylamine were more feasible and occurred at faster rates than the corresponding gas phase ammonolysis, the OH + (CHO)2 reaction, and the aqueous phase reaction of glyoxal, leading to the dominant removal of glyoxal. Our results provide new and important insight into the reactions between carbonyl compounds and amines, which are crucial in forming nitrogen-containing aerosol particles.


[Relationship between isometric and isotonic contractile responses of the mammalian myocardium].
Effects of 6 and 12 mM of caffeine, 10(-5) M of verapamil, variation in stimulation frequency between 0.1 and 0.7 Hz, cooling to 15 degrees C after elevation of perfusate Ca2+ to 15 mM on isometric (IM) and isotonic (IT) contractions of guinea pig papillary muscles were studied. The first and the last interventions mentioned above were found to slow down relaxation phase and increase the IT/IM response amplitude ratio by 50-70%. Under the action of both interventions the maximum of IT response appears after the maximum of IM response with delay of 50-100 msec. A close correlation (r = 0.89) between changes of IT/IM and delay of IT peak was revealed. Different sensitivity of IM and IT responses to inotropic interventions could not be explained by the change of membrane electrical activity because the AP did not change after a transition from IM to IT mode. An analysis of experimental data suggests that the delay between IT and IM peaks and the ratio of their amplitudes depend on the rate of calcium uptake within the myocardial cell.


Plague Meningitis: A Systematic Review of Clinical Course, Antimicrobial Treatment, and Outcomes.
Plague meningitis is a serious and often fatal manifestation of Yersinia pestis infection. In the aftermath of a bioweapon attack with Y pestis, this typically rare manifestation may develop in a substantial number of patients, particularly if treatment delays occur. Risk factors, clinical evolution, and optimal treatment strategies for plague meningitis are not well understood. We searched PubMed Central and other databases for reports of plague meningitis in any language. Articles containing descriptions of patients with plague meningitis and their treatment and outcomes were included. Among 1,496 articles identified in our search, 56 articles describing 84 cases from 1898 to 2015 met inclusion criteria. The median age of patients was 16 years (range 6 weeks to 64 years); 68% were male. Most patients (n = 50, 60%) developed meningitis following primary bubonic plague. Common signs and symptoms included fever (n = 56, 66%), nuchal rigidity (n = 38, 45%), and headache (n = 33, 36%); 29% (n = 24) of patients had focal neurologic deficits such as cranial nerve abnormalities. Almost all (n = 23, 96%) of the 24 patients who did not receive antimicrobials died, and 42% (n = 25) of the 59 patients treated with antimicrobials died. The case fatality rate of patients grouped by antimicrobial received was 50% (1 out of 2) for fluoroquinolones, 19% (4 out of 21) for aminoglycosides, 14% (2 out of 14) for sulfonamides, 11% (2 out of 18) for chloramphenicol, and 0% (0 out of 13) for tetracyclines. Plague meningitis most often occurs as a complication of bubonic plague and can cause focal neurologic deficits. Survival is more likely in patients who receive antimicrobials; tetracyclines, aminoglycosides, and chloramphenicol had the lowest associated case fatality rates.


Hypereosinophilic syndrome: endomyocardial biopsy versus echocardiography to diagnose cardiac involvement.
To compare echocardiograms and endomyocardial biopsies to diagnose cardiac involvement in hypereosinophilic syndrome. We examined the agreement between echocardiography and endomyocardial biopsies to detect cardiac involvement in hypereosinophilic syndrome by reviewing cases identified as hypereosinophilia or hypereosinophilic syndrome in Mayo Clinic databases from January 1978 through June 2009. Single-organ cases of eosinophilia such as eosinophilic fasciitis and eosinophilic gastroenteritis were excluded. We recorded echocardiogram and endomyocardial biopsy results including biopsy staining for eosinophil granule major basic protein (if performed). Clinical and laboratory features documented included presenting symptom(s), maximum total eosinophil count, dose of prednisone (if any) and eosinophil count at the time of endomyocardial biopsy, cardiac enzymes, serum tryptase level, electrocardiogram result, the result of testing for the FIP1L1-PDGFRA fusion gene, complications associated with the biopsy procedures and available follow-up information. From a total of 387 patients' records screened 288 met the criteria for hypereosinophilic syndrome and of these 240 had echocardiograms. Among these patients there were 138 normal echocardiograms, 67 had echocardiograms without findings of hypereosinophilic syndrome but with one or more other abnormalities, and 35 had echocardiograms with findings consistent with hypereosinophilic syndrome. Twenty-five patients from this group of 35 patients had both echocardiogram and endomyocardial biopsy. In 15 patients there was agreement between both endomyocardial biopsy and echocardiography as to the presence (n = seven) or absence (n = eight) for findings of cardiac involvement. In 10 of 25 patients test results diverged: 3 patients with positive echocardiographic changes did not have confirmatory findings by endomyocardial biopsy and seven patients with positive biopsy findings had echocardiograms without findings of hypereosinophilic syndrome. Echocardiograms and endomyocardial biopsies agree for presence or absence of cardiac involvement 60% of the time. Endomyocardial biopsy detected cardiac involvement in 7 patients in whom the echocardiogram was negative for findings of hypereosinophilic syndrome.


From B cell to plasma cell: regulation of V(D)J recombination and antibody secretion.
B cell development culminates in the formation of plasma cells, potent secretors of the immunoglobulins (Ig), proteins crucial for the health of the organism. Two distinctive and crucial steps are required during B cell differentiation. First, variable gene segments encoding the antigen-binding region of Ig undergo directed rearrangement through a process known as V(D)J recombination. Second, alternative processing of the Ig heavy chain mRNA transcript enables plasma cells to secrete high levels of Ig protein. This review focuses on the molecular mechanisms that control V(D)J recombination in B cell progenitors and alternative RNA processing in plasma cells.


An entropic criterion for minimum uncertainty sensing in recognition and localization. I. Theoretical and conceptual aspects.
A criterion is presented for the automatic selection of a sensor measurement aimed at observing the state of a system which is described both by discrete variables and by continuous ones. The criterion is based on the expected value of the entropy variation associated to the sensor observation. This criterion is then applied to object recognition and localization tasks, in which the observed system is characterized by the object class, represented by a discrete variable, and by the object pose, i.e., position and orientation, represented by a vector of continuous parameters. The proposed criterion also accounts for the information obtained in the case the observed object is missed by the measurement.


Carbohydrate mouth rinse improves performance of mentally fatigued cyclists despite null effects on psychological responses.
Mental fatigue reduces exercise performance through an impaired psychological response such as increased perceived exertion. Carbohydrate (CHO) mouth rinses improve exercise performance and perceived exertion likely due to an improved activation in cerebral reward areas, then we investigated if the CHO mouth rinse-improved exercise performance in mentally fatigued individuals was associated with ameliorated reward-related psychological responses. We hypothesised that CHO mouth rinse would be beneficial for mentally fatigued cyclists mainly in high-metabolic disturbance intensities. After familiarization and baseline sessions, well trained cyclists (n = 20) performed a maximal incremental test (MIT) after mental fatigue induction. They completed the MIT either without mouth rinse (MF) or rinsing their mouth with CHO (MF+CHO) or placebo (FM+PLA) solutions at every 25 % of the MIT. Psychological responses such as ratings of perceived exertion (RPE), affective valence, emotional arousal, and motivation were assessed throughout the MIT, while performance was assessed as peak power output and time of exercise. Mental fatigue reduced MIT performance (P < 0.05), but CHO mouth rinse was effective to counteract this deleterious mental fatigue effect (P < 0.05). However, we found null effects of CHO mouth rinses in psychological responses above the VT2 (P > 0.05) such as RPE, affective valence, emotional arousal, and motivation. Correlational analysis showed a significant, but moderate negative correlation between motivation and time of exercise above the VT2 when participants used CHO mouth rinse. In conclusion, the ergogenic CHO mouth rinse effects on MIT performance of mentally fatigued cyclists were irrespective of ameliorated psychological responses to exercise.


Role of JNK in a Trp53-dependent mouse model of breast cancer.
The cJun NH2-terminal kinase (JNK) signal transduction pathway has been implicated in mammary carcinogenesis. To test the role of JNK, we examined the effect of ablation of the Jnk1 and Jnk2 genes in a Trp53-dependent model of breast cancer using BALB/c mice. We detected no defects in mammary gland development in virgin mice or during lactation and involution in control studies of Jnk1(-/-) and Jnk2(-/-) mice. In a Trp53(-/+) genetic background, mammary carcinomas were detected in 43% of control mice, 70% of Jnk1(-/-) mice, and 53% of Jnk2(-/-) mice. These data indicate that JNK1 and JNK2 are not essential for mammary carcinoma development in the Trp53(-/+) BALB/c model of breast cancer. In contrast, this analysis suggests that JNK may partially contribute to tumor suppression. This conclusion is consistent with the finding that tumor-free survival of JNK-deficient Trp53(-/+) mice was significantly reduced compared with control Trp53(-/+) mice. We conclude that JNK1 and JNK2 can act as suppressors of mammary tumor development.


Chromosome-level de novo genome assembly of Telopea speciosissima (New South Wales waratah) using long-reads, linked-reads and Hi-C.
Telopea speciosissima, the New South Wales waratah, is an Australian endemic woody shrub in the family Proteaceae. Waratahs have great potential as a model clade to better understand processes of speciation, introgression and adaptation, and are significant from a horticultural perspective. Here, we report the first chromosome-level genome for T. speciosissima. Combining Oxford Nanopore long-reads, 10x Genomics Chromium linked-reads and Hi-C data, the assembly spans 823 Mb (scaffold N50 of 69.0 Mb) with 97.8% of Embryophyta BUSCOs "Complete". We present a new method in Diploidocus (https://github.com/slimsuite/diploidocus) for classifying, curating and QC-filtering scaffolds, which combines read depths, k-mer frequencies and BUSCO predictions. We also present a new tool, DepthSizer (https://github.com/slimsuite/depthsizer), for genome size estimation from the read depth of single-copy orthologues and estimate the genome size to be approximately 900 Mb. The largest 11 scaffolds contained 94.1% of the assembly, conforming to the expected number of chromosomes (2n = 22). Genome annotation predicted 40,158 protein-coding genes, 351 rRNAs and 728 tRNAs. We investigated CYCLOIDEA (CYC) genes, which have a role in determination of floral symmetry, and confirm the presence of two copies in the genome. Read depth analysis of 180 "Duplicated" BUSCO genes using a new tool, DepthKopy (https://github.com/slimsuite/depthkopy), suggests almost all are real duplications, increasing confidence in the annotation and highlighting a possible need to revise the BUSCO set for this lineage. The chromosome-level T. speciosissima reference genome (Tspe_v1) provides an important new genomic resource of Proteaceae to support the conservation of flora in Australia and further afield.


Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy.
Phospholamban (PLN) p.Arg14del cardiomyopathy is associated with an increased risk of malignant ventricular arrhythmias and severe heart failure and a poor prognosis from late adolescence. It can be diagnosed in whole heart specimens, but rarely in right ventricular biopsy specimens, by PLN immunohistochemistry showing PLN-containing aggregates concentrated in cardiomyocytes in dense perinuclear aggresomes. The purpose of this study was to determine whether PLN immunohistochemistry can be used to diagnose PLN p.Arg14del cardiomyopathy using apical left ventricular myocardial specimens harvested during left ventricular assist device (LVAD) implantation. At that stage, a genetic diagnosis, which may guide treatment and referral of family members for further investigation, is frequently not established yet. Included were myocardial specimens from 30 diverse genetic cardiomyopathy cases with known variants (9 carriers of the pathogenic PLN p.Arg14del variant, 18 cases with other pathogenic or likely pathogenic variants in cardiomyopathy-related genes, and 3 with only variants of unknown significance). Immunohistochemical analysis revealed typical dense perinuclear globular PLN-positive aggregates, representing aggresomes, in all nine PLN p.Arg14del cases. In 20 non-PLN cases, PLN-staining was absent. In one non-PLN case, one of the two independent observers misinterpreted PLN staining of heavily wrinkled nuclear membranes of cardiomyocytes as perinuclear PLN aggregates. In this genetic cardiomyopathy cohort, PLN Immunohistochemical analysis in LVAD biopsies was found to be a highly sensitive (100%) and specific (95%) method for demonstration of PLN protein aggregates in PLN p.Arg14del cardiomyopathy. In clinical practice, PLN immunohistochemical analysis of LVAD specimens can be of incremental value in the diagnostic workup of this cardiomyopathy, even more so if genetic analysis is not readily available.


Coronavirus disease 2019 (COVID-19) manifestations during pregnancy in all three trimesters: A case series.
Coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the susceptibility amongst different groups of the population. Pregnant women are one such group. This study was conducted to investigate the effect of COVID-19 on pregnancy and maternal/neonatal outcomes. This case series was conducted on 16 pregnant women with COVID-19 from March 21 to May 11, 2020. Clinical characteristics, pregnancy complications, medication used, maternal/neonatal outcomes, and fatality rate were investigated through this study. The mean age of the patients was 30.06 yrs. Patients from all three trimesters were included (1 in first, 5 in second, and 10 in the third trimesters). The most common clinical symptoms were shortness of breath (n = 10), dry cough (n = 10), myalgia (n = 8), and chills (n = 7). Also, three cases had papulosquamous skin lesions with fissuring. The most common laboratory results were leukocytosis (n = 8), increased liver enzymes (n = 6), elevated CRP (n = 5), and thrombocytopenia (n = 4). There was one case of maternal mortality, five of premature labor pain (PLP), two of preeclampsia, and two of placenta accreta. Twelve pregnancies were terminated (nine cesarean sections, three vaginal deliveries). Among neonates, we had 6 cases of preterm labor. All neonates had negative PCR results. Clinical manifestations and paraclinical results were similar to non-pregnant patients. There was no evidence of vertical transmission. PLP and premature rupture of membranes (PROM) were the most common complications in the second and third trimesters of pregnant COVID-19 women, which can lead to rupture of the uterus. Termination and delivery should be planned individually.


Clinical relevance of detecting anti-infliximab antibodies with a drug-tolerant assay: post hoc analysis of the TAXIT trial.
To evaluate the clinical relevance of antidrug antibodies (ADAs) measured using a drug-tolerant assay in a post hoc analysis of the Trough Concentration (TC) Adapted Infliximab Treatment (TAXIT) randomised controlled trial. ADA in serum samples (n=221) of 76 patients enrolled in TAXIT, who presented with an infliximab TC <3 µg/mL at screening, were reanalysed after optimisation and at the end of the study using a drug-tolerant ADA assay. Patients underwent dose escalation to achieve therapeutic TCs between 3 µg/mL and 7 µg/mL prior to randomisation. Patients were grouped into quartiles (Q1-4) according to ADA concentration at screening. Using a drug-tolerant assay, the immunogenicity detection rate increased from 21% (drug-sensitive assay) to 63% at screening, from 0% to 51% after optimisation and from 3% to 42% at the end of TAXIT. Patients in ADA Q4 required a higher cumulative infliximab dose (2390 (880-2998) mg) to achieve target TCs, resulting in a higher drug cost (€10 712 (4120-13 596)) compared with ADA-negative patients (€2060 (1648-3296)) and patients in ADA Q1/Q2 (€2060 (1648-4120)/€2060 (1751-3296), p<0.001). However, all but one patient belonging to ADA Q4 were also ADA-positive using a drug-sensitive assay. Upon dose intensification, low concentration ADAs, not detectable using a drug-sensitive assay, disappear in more than half of the patients over time and are clinically non-relevant. In contrast, high concentration ADAs which are typically also detected in a drug-sensitive assay, persist over time and necessitate a higher cumulative dose and drug cost. In the latter group, proactive drug switching may be more cost-efficient. 2011-002061-38; Post-results.


Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.
Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes. To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease. TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels. Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction. Change in plasma biomarker levels after donanemab treatment. In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively). Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation. ClinicalTrials.gov Identifier: NCT03367403.


Colistin MIC variability by method for contemporary clinical isolates of multidrug-resistant Gram-negative bacilli.
In vitro evaluation of colistin susceptibility is fraught with complications, due in part to the inherent cationic properties of colistin. In addition, no reference method has been defined against which to compare the results of colistin susceptibility testing. This study systematically evaluated the available methods for colistin MIC testing in two phases. In phase I, colistin MICs were determined in 107 fresh clinical isolates of multidrug-resistant (MDR) Gram-negative bacilli (GNB) by broth microdilution with polysorbate 80 (BMD-T), broth macrodilution (TDS), and the Etest. In phase II, 50 of these isolates, 10 of which were colistin resistant, were tested in parallel using BMD-T, TDS, agar dilution, broth microdilution without polysorbate 80 (BMD), and the TREK Gram-negative extra MIC format (GNXF) Sensititre. The Etest was also performed on these 50 isolates using Mueller-Hinton agar (MHA) from three different manufacturers. Colistin MIC results obtained from the five methods were compared to the MIC results obtained using BMD-T, the method that enables the highest nominal concentration of colistin in the test medium. Essential agreement ranged from 34% (BMD) to 83% (TDS), whereas categorical agreement was >90% for all methods except for BMD, which was 88%. Very major errors (VMEs) (i.e., false susceptibility) for the Etest were found in 47 to 53% of the resistant isolates, depending on the manufacturer of the MHA that was used. In contrast, VMEs were found for 10% (n = 1) of the resistant isolates by BMD and 0% of the isolates by the TDS, agar dilution, and Sensititre methods. Based on these data, we urge clinical laboratories to be aware of the variable results that can occur when using different methods for colistin MIC testing and, in particular, to use caution with the Etest.


Atomic-Resolution Electron Microscopy Unravelling the Role of Unusual Asymmetric Twin Boundaries in the Electron-Beam-Sensitive NASICON-Type Solid Electrolyte.
An atomic-scale understanding of the role of nonperiodic features is essential to the rational design of highly Li-ion-conductive solid electrolytes. Unfortunately, most solid electrolytes are easily damaged by the intense electron beam needed for atomic-resolution electron microscopy observation, so the reported in-depth atomic-scale studies are limited to Li0.33La0.56TiO3- and Li7La3Zr2O12-based materials. Here, we observe on an atomic scale a third type of solid electrolyte, Li1.3Al0.3Ti1.7(PO4)3 (LATP), through minimization of damage induced by specimen preparation. With this capability, LATP is found to contain large amounts of twin boundaries with an unusual asymmetric atomic configuration. On the basis of the experimentally determined structure, the theoretical calculations suggest that such asymmetric twin boundaries may considerably promote Li-ion transport. This discovery identifies a new entry point for optimizing ionic conductivity, and the method presented here will also greatly benefit the mechanistic study of solid electrolytes.


Gardner-Diamond syndrome: a systematic review of treatment options for a rare psychodermatological disorder.
Gardner-Diamond syndrome (GDS) is a rare psychodermatological condition characterized by the formation of spontaneous, painful skin lesions that develop into ecchymosis following episodes of severe physiological or psychological stress. The majority of GDS cases occur in young adult females, and although the etiology of this rare disorder is unknown, there appears to be a psychological component correlated with the coexistence of previous psychiatric diagnoses. Due to the rare nature of this disorder, there exist few guidelines for prompt clinical diagnosis and optimal treatment. Here, a systematic review was conducted to include 45 cases of patients with GDS to better understand clinical presentation as well as current treatment options. Ultimately, GDS is a diagnosis of exclusion after other coagulopathies and causes of purpura are ruled out. High clinical suspicion following laboratory and clinical exclusion of known physiological causes is necessary for diagnosis. Selective serotonin reuptake inhibitors (SSRIs) and corticosteroids are cost effective first line treatments for GDS with proven efficacy in symptomatic relief. GDS refractory to initial treatment may require regular psychotherapy and titrated SSRI dosages to achieve long-term success. This review of available case studies serves to comprehensively describe the clinical presentation and available treatment approaches to this rare psychodermatological disorder.


Wind drives temporal variation in pollinator visitation in a fragmented tropical forest.
Wind is a critical factor in the ecology of pollinating insects such as bees. However, the role of wind in determining patterns of bee abundance and floral visitation rates across space and time is not well understood. Orchid bees are an important and diverse group of neotropical pollinators that harvest pollen, nectar and resin from plants. In addition, male orchid bees collect volatile scents that they store in special chambers in their hind legs, and for which the wind-based dispersal of odours may play a particularly crucial role. Here, we take advantage of this specialized scent foraging behaviour to study the effects of wind on orchid bee visitation at scent sources in a fragmented tropical forest ecosystem. Consistent with previous work, forest cover increased orchid bee visitation. In addition, we find that temporal changes in wind speed and turbulence increase visitation to scent stations within sites. These results suggest that the increased dispersal of attractive scents provided by wind and turbulence outweighs any biomechanical or energetic costs that might deter bees from foraging in these conditions. Overall, our results highlight the significance of wind in the ecology of these important pollinators in neotropical forests.


Bayesian parentage analysis reliably controls the number of false assignments in natural populations.
Parentage analysis in natural populations is a powerful tool for addressing a wide range of ecological and evolutionary questions. However, identifying parent-offspring pairs in samples collected from natural populations is often more challenging than simply resolving the Mendelian pattern of shared alleles. For example, large numbers of pairwise comparisons and limited numbers of genetic markers can contribute to incorrect assignments, whereby unrelated individuals are falsely identified as parent-offspring pairs. Determining which parentage methods are the least susceptible to making false assignments is an important challenge facing molecular ecologists. In a recent paper, Harrison et al. (2013a) address this challenge by comparing three commonly used parentage methods, including a Bayesian approach, in order to explore the effects of varied proportions of sampled parents on the accuracy of parentage assignments. Unfortunately, Harrison et al. made a simple error in using the Bayesian approach, which led them to incorrectly conclude that this method could not control the rate of false assignment. Here, I briefly outline the basic principles behind the Bayesian approach, identify the error made by Harrison et al., and provide detailed guidelines as to how the method should be correctly applied. Furthermore, using the exact data from Harrison et al., I show that the Bayesian approach actually provides greater control over the number of false assignments than either of the other tested methods. Lastly, I conclude with a brief introduction to solomon, a recently updated version of the Bayesian approach that can account for genotyping error, missing data and false matching.


Non-invasive, simultaneous quantification of vascular oxygenation and glucose uptake in tissue.
We report the development of non-invasive, fiber-based diffuse optical spectroscopy for simultaneously quantifying vascular oxygenation (SO2) and glucose uptake in solid tumors in vivo. Glucose uptake was measured using a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Quantification of label-free SO2 and 2-NBDG-fluorescence-based glucose uptake 60 minutes after administration of the tracer (2-NBDG60) was performed using computational models of light-tissue interaction. This study was carried out on normal tissue and 4T1 and 4T07 murine mammary tumor xenografts in vivo. Injection of 2-NBDG did not cause a significant change in optical measurements of SO2, demonstrating its suitability as a functional reporter of tumor glucose uptake. Correction of measured 2-NBDG-fluorescence for the effects of absorption and scattering significantly improved contrast between tumor and normal tissue. The 4T1 and 4T07 tumors showed significantly decreased SO2, and 4T1 tumors demonstrated increased 2-NBDG60 compared with normal tissue (60 minutes after the administration of 2-NBDG when perfusion-mediated effects have cleared). 2-NBDG-fluorescence was found to be highly sensitive to food deprivation-induced reduction in blood glucose levels, demonstrating that this endpoint is indeed sensitive to glycolytic demand. 2-NBDG60 was also found to be linearly related to dose, underscoring the importance of calibrating for dose when comparing across animals or experiments. 4T1 tumors demonstrated an inverse relationship between 2-NBDG60 and SO2 that was consistent with the Pasteur effect, particularly when exposed to hypoxic gas breathing. Our results illustrate the potential of optical spectroscopy to provide valuable information about the metabolic status of tumors, with important implications for cancer prognosis.


Risk factors and incidence of repeat osteoporotic fractures among the elderly in Taiwan: a population-based cohort study.
The incidence of osteoporotic fracture (OF), a condition that leads to higher morbidity and mortality in the elderly, is increasing yearly worldwide. However, most studies of OF have focused on the epidemiology of initial fractures, mainly in female and white populations. This study aimed to explore the incidence and the risk factors for repeat osteoporotic fracture (ROF) in Taiwan.We performed a retrospective cohort study using the Taiwan National Health Insurance Database (NHIRD) from 1995 through 2011. Individuals aged 65 years or older who experienced an initial OF were included. The patients were followed until death, the end of registration in the NHIRD, ROF occurrence, or the end of the study period (December 31, 2011), whichever occurred first. The incidence of ROF over ≥ 5 years after the initial fracture was analyzed, and the risk factors for ROF were assessed using Cox proportional hazards models. The incidence rates of ROF were 950.5, 321.4, 158.7, 92.8, and 70.2 per 1000 person-years among subjects in their first, second, third, fourth, and fifth years after the initial OF, respectively. Nearly 45% of the subjects sustained a ROF in the first year after OF. ROF risk increased with age and Charlson Comorbidity Index (CCI) score. Greater risk for ROF was observed among female subjects and those who had suffered from hip and vertebral fracture at the first OF, had undergone OF-related surgery, and had received bone-related medications. The incidence of ROF in the Taiwanese elderly is higher during the first year after the initial OF, and ROF risk increases with age, female sex, high CCI score, and in those who have undergone OF-related surgery, sustained hip or vertebral fracture, and used bone-related medications.


Are biosensor arrays in one membrane possible? A combination of multifrequency impedance measurements and chemometrics.
A novel concept of a membrane-based micro-array biosensor is presented. The methodology is based on a single lipid membrane interrogated with electrochemical impedance techniques followed by multivariate data analysis. A single membrane is designed so that relaxation processes with a range of time constants can be probed at different potentials. A range of other approaches cited in the literature is reviewed.


Fit for purpose? Validation of a conceptual framework for personal recovery with current mental health consumers.
Mental health services in the UK, Australia and other Anglophone countries have moved towards supporting personal recovery as a primary orientation. To provide an empirically grounded foundation to identify and evaluate recovery-oriented interventions, we previously published a conceptual framework of personal recovery based on a systematic review and narrative synthesis of existing models. Our objective was to test the validity and relevance of this framework for people currently using mental health services. Seven focus groups were conducted with 48 current mental health consumers in three NHS trusts across England, as part of the REFOCUS Trial. Consumers were asked about the meaning and their experience of personal recovery. Deductive and inductive thematic analysis applying a constant comparison approach was used to analyse the data. The analysis aimed to explore the validity of the categories within the conceptual framework, and to highlight any areas of difference between the conceptual framework and the themes generated from new data collected from the focus groups. Both the inductive and deductive analysis broadly validated the conceptual framework, with the super-ordinate categories Connectedness, Hope and optimism, Identity, Meaning and purpose, and Empowerment (CHIME) evident in the analysis. Three areas of difference were, however, apparent in the inductive analysis. These included practical support; a greater emphasis on issues around diagnosis and medication; and scepticism surrounding recovery. This study suggests that the conceptual framework of personal recovery provides a defensible theoretical base for clinical and research purposes which is valid for use with current consumers. However, the three areas of difference further stress the individual nature of recovery and the need for an understanding of the population and context under investigation.


Alterations of the gut mycobiome in patients with MS.
The mycobiome is the fungal component of the gut microbiome and is implicated in several autoimmune diseases. However, its role in MS has not been studied. In this case-control observational study, we performed ITS sequencing and characterised the gut mycobiome in people with MS (pwMS) and healthy controls at baseline and after six months. The mycobiome had significantly higher alpha diversity and inter-subject variation in pwMS than controls. Saccharomyces and Aspergillus were over-represented in pwMS. Saccharomyces was positively correlated with circulating basophils and negatively correlated with regulatory B cells, while Aspergillus was positively correlated with activated CD16+ dendritic cells in pwMS. Different mycobiome profiles, defined as mycotypes, were associated with different bacterial microbiome and immune cell subsets in the blood. Initial treatment with dimethyl fumarate, a common immunomodulatory therapy which also has fungicidal activity, did not cause uniform gut mycobiome changes across all pwMS. There is an alteration of the gut mycobiome in pwMS, compared to healthy controls. Further study is required to assess any causal association of the mycobiome with MS and its direct or indirect interactions with bacteria and autoimmunity. This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS102633-04 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-1805-31003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG- 1907-34474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


Sequence Analysis of Staphylococcus hyicus ATCC 11249T, an Etiological Agent of Exudative Epidermitis in Swine, Reveals a Type VII Secretion System Locus and a Novel 116-Kilobase Genomic Island Harboring Toxin-Encoding Genes.
Staphylococcus hyicus is the primary etiological agent of exudative epidermitis in swine. Analysis of the complete genome sequence of the type strain revealed a locus encoding a type VII secretion system and a large chromosomal island harboring the genes encoding exfoliative toxin ExhA and an EDIN toxin homolog.


[Outcome research: rationales and objectives].
Outcome research measures the clinical, economic and humanistic outcomes of pharmacological therapies on patients suffering from different diseases. Outcome research can be applied either to phase II and III clinical trials to assess new drugs for registration or to already marketed drugs to assess their real value when used in clinical practice in a large population of patients. Oncology can be a major field of application because there is a large amount of new treatments put on the market, often without demonstration of significant improvement in survival or Quality of Life but with higher prices than the old molecules. Patients and disease specific outcomes have been identified for cancer by a Working Group set up by the American Society of Clinical Oncology, with the former being defined as more critical to establish the value of new treatments. Survival, drug toxicity and impact on Quality of Life are the most important patient's outcomes to consider before recommending anti-cancer therapies for use in clinical practice. The present paper will describe the outcomes in oncology and will deal with the transferability to clinical practice of the results of clinical trials.


[111In-pentetreotide in the study of tumors expressing somatostatin receptors].
The usefulness of 111In-pentetreotide scintigraphy in the diagnosis of neuroendocrine tumors was evaluated. 39 patients with clinical or biochemical suspicion of neuroendocrine tumors were studied. 29 patients underwent surgery and diagnosis was confirmed by anatomopathology findings (7 mixed tumors, 6 carcinoids, 3 insulinomas, 3 pheocromocytomas, 2 glucagonomas, 2 medullary thyroid carcinomas, 1 gastrinoma and 5 metastatic lesions). In 10 patients who did not undergo surgery, the diagnostic criteria were based on a 6 month follow-up. 111In-pentetreotide scintigraphy and computed tomography (CT) were performed in all of the patients. The scintigraphy correctly detected 58% of the primary tumors while the CT was positive in only 45% of the cases. Both techniques detected metastasis in 5 patients. 111In-pentetreotide scintigraphy is a useful technique to diagnose those tumors that have somatostatin receptors. In our series, the sensitivity of this method was higher than the CT.


A randomized, controlled, comparative, proof-of-concept study to evaluate the efficacy and safety of Nisha-Amalaki capsules in prediabetic patients for preventing progression to diabetes.
Prediabetes is an intermediate state of hyperglycemia, which acts as a precursor to Diabetes mellitus if left untreated. Nisha (Curcuma longa) and Amalaki (Emblica officinalis) combination has been advocated as drugs of choice to treat the early manifestations of Diabetes mellitus. This prospective, randomized, single-blind, placebo-controlled, comparative study was planned to assess the efficacy and safety of Nisha-Amalaki capsules in preventing progression to Diabetes mellitus in prediabetic patients when administered for 6 months. The study was conducted on prediabetic participants randomized to receive either Nisha-Amalaki (500 mg) or placebo one capsule twice a day for six months. The effect of study medications on IDRS (Indian Diabetes Risk Score), BMI (Body Mass Index), blood sugar, serum insulin, HOMA-IR (Homeostasis Model Assessment-Estimated Insulin Resistance), HbA1c (glycated hemoglobin), oxidative markers, Ayurvedic symptoms and Quality of Life (QoL) scores was assessed at regular intervals. 58 of the 62 participants enrolled completed the study. Significant fall in IDRS score [p < 0.001], BMI [p < 0.001], fasting, and 2 h post-OGTT sugar, insulin, HbA1c, HOMA-IR, and oxidative stress markers [p < 0.001] was observed in patients receiving Nisha-Amalaki at 6 months. Ayurvedic symptoms and QoL scores also improved at 6 months in the treatment group. Treatment with Nisha-Amalaki capsules improved all study parameters including insulin sensitivity at 6 months as compared to placebo in prediabetic patients. Thus Nisha-Amalaki should be considered as prophylactic therapy in prediabetics to delay progression to diabetes.


The surgeon's expertise-outcome relationship in gastric cancer surgery.
The surgical caseload or duration of practice of a surgeon may influence the outcomes of gastric cancer surgery. This study aimed to clarify the surgical quality provided by specialized gastric cancer surgeons. The postoperative courses of 1,877 patients who underwent surgery for gastric cancer were retrospectively reviewed. For classification of the surgeon's expertise, the number of yearly resections performed by, and consecutive years of practice of, the surgeons were used. The outcome measures used were the 30-day mortality and long-term survival. Surgical mortalities of patients who underwent surgery by a specialized surgeon and those by a general surgeon revealed no statistically significant difference. A significant difference in the five-year survival rates was found with surgeons with at least two consecutive years of practice compared to those with less than two years, when 50 or more cases had been conducted per year (63.9% and 59.7%; p=0.0380). In cases of four-years of consecutive practice, the five-year survival rate was significantly improved, even if only 10 cases were performed annually (64.9% and 58.3%; p=0.0023), although the best survival rate was found with surgeons that had performed 50 or more surgeries per year. Improved survival rates, with acceptable surgical mortality, can be achieved for gastric cancer when the surgery is performed by a specialized surgeon. A specialized gastric cancer surgeon can be defined as one who has operated on more than 50 new cases per year, with 2 or more consecutive years of surgical practice.


[Effects of fenigidin treatment regimen on the state of peripheral hemodynamics of patients with stable effort angina pectoris and postinfarction cardiosclerosis].
To examine the impact of fenigidin treatment regimen on peripheral hemodynamics in patients with stable angina pectoris of effort and postinfarction cardiosclerosis without signs of heart failure. Thirty two patients with functional classes II and III stable angina of effort and 32 with postinfarction cardiosclerosis without signs of heart failure were examined. Monotherapy with fenigidin, 30-40 mg/day in patients with stable angina pectoris of effort and in those with postinfarction cardiosclerosis lowered systolic and mean blood pressures, total and specific peripheral vascular resistance, venous tone and increased additional venous volume and maximum vein emptying rate in the upper and lower extremities. Fenigidin therapy caused no side effects. Fenigidin monotherapy improves hemodynamic parameters in stable angina pectoris of effort and postinfarction cardiosclerosis without obvious signs of heart failure and causes no side effects when the drug is used in a dose of 30-40 mg/day for 3 weeks.


[Some pathophysiological mechanisms of muscular tone impairment].
Pathophysiological mechanisms of the muscular tone was studied clinicoelectrophysiologically (the method of stimulating electromyography with evoked H-reflex) in 130 healthy subjects and 63 patients with dystonia musculorum deformans (23 patients of the latter were examined before and after intake of a therapeutic dose of L-DOPA). It was found that patients with impaired muscular tone have low activity of spinal motoneurons on both sides of the body especially the activity of phasic motoneurons and on the right side of the body. L-DOPA activates motoneurons, higher activation seen for the phasic motoneurons and on the right side of the body.


LDL-C reductions and goal attainment among naive statin users in the Netherlands: real life results.
The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD). Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses. Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05). In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting.


[Immunobiological characteristics of surface proteins-adhesines of staphylococcus].
The paper is a generalization of the data concerning surface proteins of staphylococci available now in literature. Data about structure of fibronectinbinding proteins are systematized: FnbpA, FnbpB, Eap, Map, p70 and their characteristic features of adhesion and influence on pathogenesis of staphylococcal infection.


Role of side branches in determining suitable arterial segments for anastomosis in avulsion injuries: experimental studies.
The role of side branches, when the parent arterial trunk is stretched, with emphasis on preventing the effects of avulsion injury, was investigated in an experimental model. In ten New Zealand rabbits, the femoral arteries were isolated with and without side branches in the left and right legs, respectively, and controlled longitudinal traction was applied. The elongation of the arteries just before avulsion rupture at each side, with and without side branches, was compared, by measuring the initial and final length from the inguinal ligament to the mid-point of the distance between the inguinal ligament and the saphenous bifurcation. Side branches were observed to be tethered in a way that resisted elongation of the trunk artery. Arteries without side branches in the right legs elongated more, as they lacked the fixating and protective support provided by the side branches. Comparison of the two legs, with and without side branches, showed an average of 50 percent more arterial elongation, resulting in severe injury to the arteries without side branches. In the light of these results, the authors suggest performing microsurgical arterial anastomosis after resection past a minimum of two unruptured branch points of the avulsed part, in order to obtain a safer arterial segment for a better patency rate.


The quick are the dead: pheasants that are slow to reverse a learned association survive for longer in the wild.
Cognitive abilities probably evolve through natural selection if they provide individuals with fitness benefits. A growing number of studies demonstrate a positive relationship between performance in psychometric tasks and (proxy) measures of fitness. We assayed the performance of 154 common pheasant (Phasianus colchicus) chicks on tests of acquisition and reversal learning, using a different set of chicks and different set of cue types (spatial location and colour) in each of two years and then followed their fates after release into the wild. Across all birds, individuals that were slow to reverse previously learned associations were more likely to survive to four months old. For heavy birds, individuals that rapidly acquired an association had improved survival to four months, whereas for light birds, slow acquirers were more likely to be alive. Slow reversers also exhibited less exploratory behaviour in assays when five weeks old. Fast acquirers visited more artificial feeders after release. In contrast to most other studies, we showed that apparently 'poor' cognitive performance (slow reversal speed suggesting low behavioural flexibility) correlates with fitness benefits in at least some circumstances. This correlation suggests a novel mechanism by which continued exaggeration of cognitive abilities may be constrained.This article is part of the theme issue 'Causes and consequences of individual differences in cognitive abilities'.


How people with HIV/AIDS manage and assess their use of complementary therapies: a qualitative analysis.
The objective of this article is to provide a qualitative analysis of the practical concerns that people with HIV/AIDS have with regard to their use of complementary therapies. In-depth semistructured interviews were conducted with a diverse range of people with HIV/AIDS (N = 46). An inductive grounded approach was used to collect and analyze the data. There were five central concerns: (a) selecting which therapies to use, (b) judging which therapies work, (c) combining Western medicine with complementary therapies, (d) assessing the safety of complementary therapies, and (e) dealing with the barriers to the use of complementary therapies. A better understanding of the practical dimensions of complementary therapy use highlights the treatment and care issues that people with HIV/AIDS face and offers insights into the role that nurses might play in addressing some of these issues.


Systematic review and meta-analysis of intraoperative versus preoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones.
Most patients with gallbladder and common bile duct stones are treated by preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy. Recently, intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment. Data from randomized clinical trials related to safety and effectiveness of IOES versus POES were extracted by two independent reviewers. Risk ratios (RRs) or mean differences were calculated with 95 per cent confidence intervals based on intention-to-treat analysis whenever possible. Four trials with 532 patients comparing IOES with POES were included. There were no deaths. There was no significant difference in rates of ampullary cannulation (RR 1·01, 0·97 to 1·04; P = 0·70) or stone clearance by ES (RR 0·99, 0·96 to 1·02; P = 0·58) between the groups. The proportion of patients with at least one post-ES complication, including pancreatitis, bleeding, perforation, cholangitis, cholecystitis or gastric ulcer, was significantly lower in the IOES group (RR 0·37, 0·18 to 0·78; P = 0·009). There was no significant difference in morbidity after laparoscopic cholecystectomy or requirement for open operation between the groups. Mean hospital stay was 3 days shorter in the IOES group: mean difference - 2·83 (-3·66 to - 2·00) days (P < 0·001). In patients with gallbladder and common bile duct stones, IOES is as effective and safe as POES and results in a significantly shorter hospital stay.


Three-dimensional simulations in Glenn patients: clinically based boundary conditions, hemodynamic results and sensitivity to input data.
While many congenital heart defects can be treated without significant long term sequelae, some achieve successful palliation as their definitive endpoints. The single-ventricle defect is one such defect and leaves the child with only one operational ventricle, requiring the systemic and the pulmonary circulations to be placed in series through several operations performed during early childhood. Numerical simulations may be used to investigate these hemodynamic conditions and their relation to post-operative sequelae; however, they rely heavily on boundary condition prescription. In this study, we investigate the impact of hemodynamic input data uncertainties on simulation results. Imaged-based patient-specific models of the multi-branched pulmonary arteries and superior vena cava were built for five cavopulmonary connection (i.e. Glenn) patients. Magnetic resonance imaging and catheterization data were acquired for each patient prior to their Fontan surgery. Inflow and outflow boundary conditions were constructed to match available clinical data and resulted in the development of a framework to incorporate these types of clinical data into patient-specific simulations. Three-dimensional computational fluid dynamics simulations were run and hemodynamic indicators were computed. Power loss was low (and efficiency very high) and a linear correlation was found between power loss and cardiac index among the five patients. Other indicators such as low wall shear stress were considered to better characterize these patients. Flow was complex and oscillatory near the anastomosis, and laminar in the smaller branches. While common trends were seen among patients, results showed differences among patients, especially in the 3D maps, strengthening the importance of patient-specific simulations. A sensitivity analysis was performed to investigate the impact of input data (clinical and modeling) to construct boundary conditions on several indicators. Overall, the sensitivity of the output indicators to the input data was small but non-negligible. The sensitivity of commonly used hemodynamic indicators to compare patients is discussed in this context. Power efficiency was much more sensitive to pressure variation than power loss. To increase the precision of such indicators, mean flow split between right and left lungs needs to be measured with more accuracy with higher priority than refining the model of how the flow is distributed on average among the smaller branches. Although ± 10% flow split imprecision seemed reasonable in terms of patient comparison, this study suggests that the common practice of imposing a right pulmonary artery/left pulmonary artery flow split of 55%/45% when performing patient specific simulations should be avoided. This study constitutes a first step towards understanding the hemodynamic differences between pre- and post Fontan surgery, predicting these differences, and evaluating surgical outcomes based on preoperative data.


Paramedic Differentiation of Asthma and COPD in the Prehospital Setting Is Difficult.
Separate clinical practice guidelines (CPG) for asthma and chronic obstructive pulmonary disease (COPD) often guide prehospital care. However, having distinct CPGs implies that paramedics can accurately differentiate these conditions. We compared the accuracy of paramedic identification of these two conditions against the emergency department (ED) discharge diagnosis. A retrospective cohort of all patients transported to ED by ambulance in Perth, Western Australia between July 2012 and June 2013; and identified as "asthma" or "COPD" by paramedics. We linked ambulance data to emergency department discharge diagnosis. Of 1,067 patients identified by paramedics as having asthma, 41% had an ED discharge diagnosis of asthma, i.e., positive predictive value (PPV) = 41% (95% CI 38-44%). Of 1,048 patients recorded as COPD, 57% had an ED discharge diagnosis of COPD (PPV 57%; 95% CI 54-60%). Sensitivity for the paramedic identification of patients diagnosed with asthma or COPD in the ED was 66% for asthma (95% CI 63-70%) and 39% for COPD (95% CI 36-41%). Paramedics reported wheezing in 86% of asthma and 55% of COPD patients. Differentiating between asthma and COPD in the prehospital setting is difficult. A single CPG for respiratory distress would be more useful for the clinical management of these patients by paramedics.


Enrichment and purification of deoxyschizandrin and γ-schizandrin from the extract of Schisandra chinensis fruit by macroporous resins.
In present study, the performance and separation characteristics of 21 macroporous resins for the enrichment and purification of deoxyschizandrin and γ-schizandrin, the two major lignans from Schisandra chinensis extracts, were evaluated. According to our results, HPD5000, which adsorbs by the molecular tiers model, was the best macroporous resin, offering higher adsorption and desorption capacities and higher adsorption speed for deoxyschizandrin and γ-schizandrin than other resins. Columns packed with HPD5000 resin were used to perform dynamic adsorption and desorption tests to optimize the technical parameters of the separation process. The results showed that the best adsorption time is 4 h, the rate of adsorption is 0.85 mL/min (4 BV/h) and the rate of desorption is 0.43 mL/min (2 BV/h). After elution with 90% ethanol, the purity of deoxy-schizandrin increased 12.62-fold from 0.37% to 4.67%, the purity of γ-schizandrin increased 15.8-fold from 0.65% to 10.27%, and the recovery rate was more than 80%.


Diagnosis of coinfection by schistosomiasis and viral hepatitis B or C using 1H NMR-based metabonomics.
Diagnosis of liver involvement due to schistosomiasis in asymptomatic patients from endemic areas previously diagnosed with chronic hepatitis B (HBV) or C (HCV) and periportal fibrosis is challenging. H-1 Nuclear Magnetic Resonance (NMR)-based metabonomics strategy is a powerful tool for providing a profile of endogenous metabolites of low molecular weight in biofluids in a non-invasive way. The aim of this study was to diagnose periportal fibrosis due to schistosomiasis mansoni in patients with chronic HBV or HCV infection through NMR-based metabonomics models. The study included 40 patients divided into two groups: (i) 18 coinfected patients with schistosomiasis mansoni and HBV or HCV; and (ii) 22 HBV or HCV monoinfected patients. The serum samples were analyzed through H-1 NMR spectroscopy and the models were based on Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA). Ultrasonography examination was used to ascertain the diagnosis of periportal fibrosis. Exploratory analysis showed a clear separation between coinfected and monoinfected samples. The supervised model built from PLS-DA showed accuracy, R2 and Q2 values equal to 100%, 98.1% and 97.5%, respectively. According to the variable importance in the projection plot, lactate serum levels were higher in the coinfected group, while the signals attributed to HDL serum cholesterol were more intense in the monoinfected group. The metabonomics models constructed in this study are promising as an alternative tool for diagnosis of periportal fibrosis by schistosomiasis in patients with chronic HBV or HCV infection from endemic areas for Schistosoma mansoni.


[An evaluation of the quality of the fabrication of removable plate dentures by the histamine content in mixed saliva].
Clinical and laboratory study, aimed at development of an objective criterion that would permit assessment of the quality of plate dentures early after orthodontic treatment, was carried out in 66 subjects aged 45 to 74 years. The examinations carried out before and after orthodontic treatment revealed a relationship between histamine concentrations in the background salivary pool and the presence of inflammation signs in denture bed tissues in the first days after plate denture application. The detected relationship may be regarded as an additional objective criterion permitting assessment of the denture quality in early periods after orthodontic treatment.


Morphological, functional and biochemical characterization of canine gingival fibroblasts.
As dogs are good models for in vivo studies, it is interesting to evaluate the behavior of canine gingival fibroblasts (CGF) in vitro, so that these cells could be seeded on a matrix and later studied in vivo. The aim of this study was to perform a morphological, functional and biochemical analysis of CGF, comparing it with human gingival fibroblasts (HGF), as well as to evaluate the change of their characteristics over several passages. Using gingival fibroblasts from 3 dogs and 3 humans in the subculture (Sub), first (P1), third (P3), fifth (P5) and seventh (P7) passages, the following parameters were assessed: cell morphology, spreading, adhesion, viability and total protein content. The results showed no major differences between the passages in terms of morphology and spreading, and a tendency of greater adhesion and viability for HGF when compared with CGF. The total protein content was significantly higher for HGF. HGF exhibited greater functional and biochemical activity in vitro compared to CGF. Higher numbers at Sub were observed for both CGF and HGF in all evaluated parameters. The differences do not prevent the use of CGF for tissue engineering, but its use seems to be more appropriate in the subculture or first passage.


Identification, sequence analysis and phylogeny of the lef-2 gene of Helicoverpa armigera single-nucleocapsid baculovirus.
The baculovirus late expression factor 2 (LEF-2) is involved in DNA replication, and most likely function as a primase processivity factor. Lef-2 genes have been found in multinucleocapsid nucleopolyhedroviruses (MNPVs) and in granuloviruses (GVs), but not yet in single-nucleocapsid NPV (SNPV). Here, a lef-2 gene homolog was identified from SNPV of Helicoverpa armigera (HearNPV). The open reading frame of the HearNPV lef-2 gene is 696 nucleotides long, encoding a putative protein of 232 amino acids with an M(r) of about 26 kDa. The 5'-noncoding region contains two early (CAGT) consensus motifs for transcription initiation and three TATA boxes. Lef-2 transcripts started at a C, 29 nucleotides upstream of a putative translational start. A putative polyA signal, AATAAA, was found 76 nucleotides downstream of the translation stop codon. The HearNPV lef-2 gene has a low but significant degree of amino acid sequence identity (30%) to the lef-2 genes of 15 other baculoviruses of which nine were newly determined. The N-terminal half of the LEF-2 proteins contains one (I) and the C-terminal half two (II and III) conserved domains. Sixteen amino acids are absolutely conserved in those LEF-2 investigated and are probably critical for LEF-2 function. A phylogenetic tree of 16 baculovirus LEF-2 proteins was constructed by using maximum parsimony analysis and appeared to be comparable to a tree for ecdysteroid UDP-glucosyl transferases (Chen et al., 1997a). The genomic location of the lef-2 genes relative to polyhedrin/granulin and the clade structure of the gene trees suggest that genome organization and gene phylogeny are useful parameters to study the evolutionary history of baculoviruses. These two independent approaches also give a more complete picture of the ancestral relationship among baculovirus.


Theophylline distribution kinetics analyzed by reference to simultaneously injected urea and inulin.
Theophylline distribution kinetics were studied after i.v. injection in five anesthetized dogs. [14C]Urea and inulin were injected simultaneously as reference compounds to measure body fluid spaces and to calculate compartmental blood flows and permeability coefficient-surface area products for transcapillary exchange. The distribution of all three compounds was modeled with three-compartment systems in which the central compartment corresponds to intravascular space. The total volume of theophylline distribution averaged 0.72 +/- 0.09 liters/kg (+/- S.D.), indicating net tissue binding as reflected in a tissue/intracellular water partition coefficient of 1.17 +/- 0.10. Cardiac output measurements averaged 4.78 +/- 0.95 liters/min and were similar to the sum of compartmental blood flows estimated from the intercompartmental clearances of urea and inulin (4.62 +/- 1.10 liters/min) and to the sum of theophylline intercompartmental clearances (5.10 +/- 1.29 liters/min). Theophylline intercompartmental clearance to each peripheral compartment was faster than expected from its free-water diffusion coefficient and was similar to estimated compartmental blood flow. It is possible that theophylline transcapillary exchange is carrier mediated and that its rapidity contributes to the frequency of adverse reactions after i.v. administration of this drug.


Biological characterization of preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model: A multi-modality approach.
Osteosarcoma (OS) is a bone malignancy that affects children and adolescents. It is a highly aggressive tumor and typically metastasizes to lungs. Despite aggressive chemotherapy and surgical treatments, the current 5 year survival rate is 60-70%. Clinically relevant models are needed to understand OS pathobiology, metastatic progression from bones to lungs, and ultimately, to develop more efficacious treatment strategies and improve survival rates in OS patients with metastasis. The main goal of this study was to develop and characterize an in vivo OS model that will allow non-invasive tracking of tumor progression in real time, and aid in studying OS pathobiology, and screening of potential therapeutic agents against OS. In this study, we have used a multi-modality approach using bioluminescent imaging, electron microscopy, micro-computed tomography, and histopathology to develop and characterize a preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model, using 143B human OS cell line. The results of this study clearly demonstrate that the BOOM model represents the clinical disease as evidenced by a spectrum of changes associated with tumor establishment, progression and metastasis, and detection of known OS biomarkers in the primary and metastatic tumor tissue. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of renal metastasis in OS orthotopic model using 143B cells; (c) evidence of Runx2 expression in the metastatic lung tissue; and (d) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the BOOM model.


Turnover and lineage-specific broadening of the transcription start site in a testis-specific retrogene.
Proteasomes are large multisubunit complexes responsible for regulated protein degradation. Made of a core particle (20S) and regulatory caps (19S), proteasomal proteins are encoded by at least 33 genes, of which 12 have been shown to have testis-specific isoforms in Drosophila melanogaster. Pros28.1A (also known as Prosalpha4T1), a young retroduplicate copy of Pros28.1 (also known as Prosalpha4), is one of these isoforms. It is present in the D. melanogaster subgroup and was previously shown to be testis-specific in D. melanogaster. Here, we show its testis-specific transcription in all D. melanogaster subgroup species. Due to this conserved pattern of expression in the species harboring this insertion, we initially expected that a regulatory region common to these species evolved prior to the speciation event. We determined that the region driving testis expression in D. melanogaster is not far from the coding region (within 272 bp upstream of the ATG). However, different Transcription Start Sites (TSSs) are used in D. melanogaster and D. simulans, and a "broad" transcription start site is used in D. yakuba. These results suggest one of the following scenarios: (1) there is a conserved motif in the 5' region of the gene that can be used as an upstream or downstream element or at different distance depending on the species; (2) different species evolved diverse regulatory sequences for the same pattern of expression (i.e., "TSS turnover"); or (3) the transcription start site can be broad or narrow depending on the species. This work reveals the difficulties of studying gene regulation in one species and extrapolating those findings to close relatives.


Cadmium exposure and incident peripheral arterial disease.
Cadmium has been associated with peripheral arterial disease (PAD) in cross-sectional studies, but prospective evidence is lacking. Our goal was to evaluate the association of urine cadmium concentrations with incident PAD in a large population-based cohort. A prospective cohort study was performed with 2864 adult American Indians 45 to 74 years of age from Arizona, Oklahoma, and North and South Dakota who participated in the Strong Heart Study from 1989 to 1991 and were followed through 2 follow-up examination visits in 1993 to 1995 and 1997 to 1999. Participants were free of PAD, defined as an ankle brachial index <0.9 or >1.4 at baseline, and had complete baseline information on urine cadmium, potential confounders, and ankle brachial index determinations in the follow-up examinations. Urine cadmium was measured using inductively coupled plasma mass spectrometry and corrected for urinary dilution by normalization to urine creatinine. Multivariable-adjusted hazard ratios were computed using Cox-proportional hazards models for interval-censored data. A total of 470 cases of incident PAD, defined as an ankle brachial index <0.9 or >1.4, were identified. After adjustment for cardiovascular disease risk factors including smoking status and pack-years, the hazard ratio comparing the 80th to the 20th percentile of urine cadmium concentrations was 1.41 (1.05-1.81). The hazard ratio comparing the highest to the lowest tertile was 1.96 (1.32-2.81). The association persisted after excluding participants with ankle brachial index >1.4 only as well as in subgroups defined by sex and smoking status. Urine cadmium, a biomarker of long-term cadmium exposure, was independently associated with incident PAD, providing further support for cadmium as a cardiovascular disease risk factor.


Differential effects of tumor-platelet interaction in vitro and in vivo in glioblastoma.
An elevated platelet count is considered an independent predictor of short survival in glioblastoma and various other tumor entities. Prothrombotic activity of the tumor microcirculation resulting in platelet activation and release of cytokines from activated platelets has been suggested to play a role. This study was designed to analyze the effects of platelet-released cytokines on glioblastoma and endothelial cell proliferation and migration in vitro, and the influence of platelet count on glioblastoma growth and angiogenesis in vivo. In cultured human glioblastoma, umbilical cord and cerebral microvascular endothelial cells platelet-released cytokines significantly stimulated proliferation and migration as well as sprouting and formation of capillary-like structures. In vivo, glioblastoma cells were implanted in mice followed by platelet depletion starting 1 or 8 days later. Tumor volume, proliferative index, and vessel density analyzed 14 days after engraftment did not differ between animals with a normal and a low platelet count. Likewise, no effect of platelet depletion over 20 days upon the volume of intracerebrally growing tumors was observed in mice. Additionally, proliferative activity and vessel density determined in tumor samples from patients operated upon glioblastoma did not show any correlation with the patients' preoperative platelet count. Thus, we conclude that distinct proliferation- and chemotaxis-stimulating effects of platelet-derived cytokines can be achieved in vitro, while the platelet count does not exert a major influence on tumor growth and tumor angiogenesis in GBM in vivo.


Expression and mutagenesis of the catalytic domain of cGMP-inhibited phosphodiesterase (PDE3) cloned from human platelets.
We have used reverse transcriptase PCR, platelet mRNA and degenerate primers based on platelet peptide sequences, to amplify a fragment of platelet cGMP-inhibited phosphodiesterase (cGI-PDE; PDE3). Sequence analysis of this clone established that both the platelet and the cardiac forms of PDE3 were derived from the same gene (PDE3A). A RT-PCR product representing the C-terminal half of platelet PDE3 cDNA and corresponding to amino acid residues 560-1141 of the cardiac enzyme, was cloned and expressed in Escherichia coli cGI-PDEDelta1. Further deletion mutants were constructed by removing either an additional 100 amino acids from the N-terminus (cGI-PDEDelta2) or the 44-amino-acid insert characteristic of the PDE3 family, from the catalytic domain (cGI-PDEDelta1Deltai). In addition, site-directed mutagenesis was performed to explore the function of the 44-amino-acid insert. All mutants were evaluated for their ability to hydrolyse cAMP and cGMP, their ability to be photolabelled by [32P]cGMP and for the effects of PDE3 inhibitors. The Km values for hydrolysis of cAMP and cGMP by immunoprecipitates of cGI-PDEDelta1 (182+/-12 nM and 153+/-12 nM respectively) and cGI-PDEDelta2 (131+/-17 nM and 99+/-1 nM respectively) were significantly lower than those for immunoprecipitates of intact platelet PDE3 (398+/-50 nM and 252+/-16 nM respectively). Moreover, N-terminal truncations of platelet enzyme increased the ratio of Vmax for cGMP/Vmax for cAMP from 0.16+/-0.01 in intact platelet enzyme, to 0.37+/-0.05 in cGI-PDEDelta1 and to 0.49+/-0.04 in cGI-PDEDelta2. Thus deletion of the N-terminus enhanced hydrolysis of cGMP relative to cAMP, suggesting that N-terminal sequences may exert selective effects on enzyme activity. Removal of the 44-amino-acid insert generated a mutant with a catalytic domain closely resembling those of other PDE gene families but despite a limited ability to be photolabelled by [32P]cGMP, no cyclic nucleotide hydrolytic activities of the mutant were detectable. Mutation of amino acid residues in putative beta-turns at the beginning and end of the 44-amino-acid insert to alanine residues markedly reduced the ability of the enzyme to hydrolyse cyclic nucleotides. The PDE3 inhibitor, lixazinone, retained the ability to inhibit cAMP hydrolysis and [32P]cGMP binding by the N-terminal deletion mutants and the site-directed mutants, suggesting that PDE3 inhibitors may interact exclusively with the catalytic domain of the enzyme.


Long term immunity against Peste Des Petits Ruminants mediated by a recombinant Newcastle disease virus vaccine.
Peste des Petits Ruminants (PPR) is a highly contagious and often fatal disease of sheep and goats. Conventional live vaccines have been successfully used in endemic countries however, there are not completely safe and not allowing differentiation between vaccinated and infected animals (DIVA). In this study, a recombinant Newcastle disease virus (NDV) expressing the hemagglutinin of PPRV (NDV-PPRVH) was evaluated on small ruminants by serology response in sheep and goats, experimental infection in goats and immunity duration in sheep. The NDV-PPRVH vaccine injected twice at 28 days' interval, provided full protection against challenge with a virulent PPR strain in the most sensitive species and induced significant neutralizing antibodies. Immunological response in goats was slightly higher than sheep and the vaccine injected at 108.0 50 % egg infective dose/mL allowed anti-PPRV antibodies that lasted at least 12 months as shown by antibody response monitoring in sheep. The NDV vector presented a limited replication in the host and vaccinated animals remained negative when tested by cELISA based on PPRV nucleoprotein allowing DIVA. This recombinant vaccine appears to be a promising candidate in a free at risk countries and may be an important component of the global strategy for PPR eradication.


Risk Reduction of Cerebral Stroke After Stereotactic Radiosurgery for Small Unruptured Brain Arteriovenous Malformations.
A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) indicated the superiority of medical management in reducing the risks for strokes and other neurological deficits over observation alone. The aim of our study was to verify the rationale for stereotactic radiosurgery (SRS) for small unruptured arteriovenous malformation. A retrospective review was performed for 292 patients with unruptured arteriovenous malformations referred for SRS. The risks for cerebral hemorrhages were statistically compared before and after SRS. Of the 292 patients in whom arteriovenous malformation was found unruptured at initial diagnosis, 17 sustained hemorrhages in the period between the diagnosis and the initial therapeutic intervention (annual bleeding rate, 2.1%; 95% confidence interval [CI], 1.2%-3.4%). Of the remaining 275 patients, 240 were initially treated with SRS, and 16 sustained a hemorrhage after SRS (annual bleeding rate, 1.1%; 95% CI, 0.6%-1.8%), but only 2 sustained a hemorrhage after angiographic obliteration (annual bleeding rate, 0.3%; 95% CI, 0.04%-1.2%). Comparing the risk of hemorrhage between the periods before and after SRS, a 53% risk reduction was achieved after SRS (hazard ratio, 0.47; 95% CI, 0.24-0.94; P=0.03), and 85% reduction was achieved after angiographic obliteration (hazard ratio, 0.15; 95% CI, 0.02-0.53; P=0.002). SRS can significantly reduce the risk of stroke in the patients with small unruptured arteriovenous malformations. To definitively determine the clinical benefits of SRS, a longer follow-up will be necessary. However, based on our results, we can recommend SRS for patients who face a latent risk for stroke from this intractable vascular disease.


[Responses of isolated arterial segment to a slow changing of perfusion pressure in it].
In in vitro experiments, segments of the Wistar rat tail artery's segments were perfused with the Krebs-Henselite solution. Increase of the perfusion pressure with the velocity of 5 mm Hg/min from 0 to 110 mm Hg with its subsequent drop with the same velocity down to zero showed that, within the limits of the above interval of values of the intravascular pressure, existed a range where two values of the artery diameter corresponded to each established value of the pressure. The data obtained prompt a further deciphering of mechanisms of the mechanogenic regulation of the blood vessels.


Contrast-induced nephropathy and risk of acute kidney injury and mortality after cardiac operations.
Contrast-induced nephropathy (CIN) is a predictor of long-term morbidity and mortality. We assessed whether patients in whom CIN developed at diagnostic coronary angiography also had an increased risk of acute kidney injury (AKI) and higher mortality after cardiac operations. We evaluated 949 patients who underwent cardiac procedures at the Minneapolis Veterans Administration (VA) Medical Center from 2004 to 2010. CIN was defined as a rise in the serum creatinine (SCr) level to ≥0.5 mg/dL from baseline within 5 days after angiography. Outcomes were operative mortality and postoperative AKI using the Acute Injury Network and Risk, Injury, Failure, Loss, End-Stage (RIFLE) definitions. Multivariable logistic regression analysis adjusting for the VA mortality risk score was performed to assess the effect of CIN on postoperative mortality. Of the 949 patients, 62 (6.5%) experienced CIN after coronary angiography. Short (30-day) and long-term postoperative mortality was higher in patients who experienced CIN versus those who did not (6.5% versus 1.2% and 23% versus 10%, respectively; both p<0.01). In multivariable analysis, the development of CIN was associated with a 4.2-fold increase in postoperative mortality after cardiac procedures (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.3-13.7; p=0.02). CIN was also associated with increased risk of postoperative AKI according to the Acute Kidney Network and RIFLE definitions (p<0.0001 for all). The development of CIN at diagnostic angiography is an independent predictor of postoperative AKI and mortality after cardiac procedures.


Developmental changes and water status in tulip bulbs during storage: visualization by NMR imaging.
Magnetic Resonance Imaging (MRI) and light and scanning electron microscopy (SEM) were used to follow time-dependent morphological changes and changes in water status of tulip bulbs (Tulipa gesneriana L., cv. 'Apeldoorn') during bulb storage for 12 weeks at 20 degrees C (non-chilled) or 4 degrees C (chilled) and after planting. MR images reflecting the water content, the relaxation times T1 and T2 (or their reciprocal values, the relaxation rates R1 and R2), and the apparent self-diffusion coefficient of water molecules (ADC), were obtained for intact bulbs. After planting, scape elongation and flowering occurred only in chilled bulbs, while elongation in non-chilled bulbs was retarded. Microscopic observations showed different structural components and high heterogeneity of the bulb tissues. MRI revealed the elongation of the flower bud during storage, which was significantly faster in the chilled bulbs. In addition, MRI demonstrated a redistribution of water between different bulb organs, as well as significant differences in the pattern of this redistribution between the chilled and non-chilled bulbs. Generally, R2 relaxation rates became faster in all bulb organs during storage. At the same time, ADC values remained constant in the chilled bulbs, while exhibiting a significant increase in the non-chilled bulbs.


US organ donation breakthrough collaborative increases organ donation.
More than 92000 Americans are on waiting lists for organ transplants, and an average of 17 of them die each day while waiting. The US Organ Donation Breakthrough Collaborative (ODBC), which began in 2003 at the request of the Secretary of the US Department of Health and Human Services, was a formal, concerted effort of the donation and transplantation community to bring about a major change to improve the organ donation system. The nationwide Collaborative was housed within a Health and Human Services agency, the Health Resources and Services Administration (HRSA) Division of Transplantation, and included participation of the organ procurement organizations (OPOs) throughout the United States and the American hospitals with the largest organ-donor potential. HRSA leaders used the Breakthrough Series Collaborative method, originally developed by the Institute for Healthcare Improvement, as the model for the intervention. Expert practitioners drawn from hospitals and OPOs that had already demonstrated their ability to achieve and sustain high organ donation rates were chosen as faculty for the collaborative and best practices were gleaned from their institutions. The number of organ donors in Collaborative hospitals increased 14.1% in the first year, a 70% greater increase than the 8.3% increase experienced by non-Collaborative hospitals. Moreover, the increased organ recovery continued into the post-Collaborative periods. Between October 2003 and September 2006, the number of total US organ donors increased 22.5%, an increase 4-fold greater than the 5.5% increase measured over the same number of years in the immediate pre-Collaborative period. The study did not involve a randomized design, but time-series analysis using statistical process control charts shows a highly significant discontinuity in the rate of increase in participating hospitals concurrent with the Collaborative program, and strongly suggests that the activities of the Collaborative were a major contributor to this increase. Given the stable nature of the historical increases over many years, the HRSA estimates that more than 4000 annual additional transplants have occurred in association and apparently as a result of these increases in organ donation.


A global perspective on tropical montane rivers.
Tropical montane rivers (TMR) are born in tropical mountains, descend through montane forests, and feed major rivers, floodplains, and oceans. They are characterized by rapid temperature clines and varied flow disturbance regimes, both of which promote habitat heterogeneity, high biological diversity and endemism, and distinct organisms' life-history adaptations. Production, transport, and processing of sediments, nutrients, and carbon are key ecosystem processes connecting high-elevation streams with lowland floodplains, in turn influencing soil fertility and biotic productivity downstream. TMR provide key ecosystem services to hundreds of millions of people in tropical nations. In light of existing human-induced disturbances, including climate change, TMR can be used as natural model systems to examine the effects of rapid changes in abiotic drivers and their influence on biodiversity and ecosystem function.


Mixibius parvus sp. nov. and Diphascon (Diphascon) ziliense sp. nov., two new species of Eutardigrada from Sicily.
Two new species, Mixibius parvus sp. nov. and Diphascon (Diphascon) ziliense sp. nov. are described from Sicily. Mixibius parvus sp. nov. has three macroplacoids and a microplacoid and differs from M. tibetanus, the only other known species of the genus with those characteristics, in having a wrinkled cuticle without true small tubercles, a shorter microplacoid, smaller claw pt index values, and in lacking a cuticular bar on the first three pairs of the legs.Diphascon (Diphascon) ziliense sp. nov. lacks eye spots, has a pharyngeal bulb with two macroplacoids and a septulum, and possesses lunules and cuticular bars on the legs. It is similar to D. (D.) ramazzottii and D. (D.) procerum but differs from them in characters of the cuticular ornamentation and, in addition, from D. (D.) ramazzottii in having lunules and slightly longer claws in proportion to the body size and to the buccal tube. The new species differs from D. (D.) procerum in having stouter claws with a wider common portion and with the main branches shorter in proportion to the total length of the respective claws.


Pelvic exenterations for primary rectal cancer: Analysis from a 10-year national prospective database.
To identify short-term and oncologic outcomes of pelvic exenterations (PE) for locally advanced primary rectal cancer (LAPRC) in patients included in a national prospective database. Few studies report on PE in patients with LAPRC. For this study, we included PE for LAPRC performed between 2006 and 2017, as available, from the Rectal Cancer Registry of the Spanish Association of Surgeons [Asociación Española de Cirujanos (AEC)]. Primary endpoints included procedure-associated complications, 5-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS). A propensity-matched comparison with patients who underwent non-exenterative surgery for low rectal cancers was performed as a secondary endpoint. Eight-two patients were included. The mean age was 61.8 ± 11.5 years. More than half of the patients experienced at least one complication. Surgical site infections were the most common complication (abdominal wound 18.3%, perineal closure 19.4%). Thirty-three multivisceral resections were performed, including two hepatectomies and four metastasectomies. The long-term outcomes of the 64 patients operated on before 2013 were assessed. The five-year LR was 15.6%, the distant recurrence rate was 21.9%, and OS was 67.2%, with a mean survival of 43.8 mo. R+ve resection increased LR [hazard ratio (HR) = 5.58, 95%CI: 1.04-30.07, P = 0.04]. The quality of the mesorectum was associated with DFS. Perioperative complications were independent predictors of shorter survival (HR = 3.53, 95%CI: 1.12-10.94, P = 0.03). In the propensity-matched analysis, PE was associated with better quality of the specimen and tended to achieve lower LR with similar OS. PE is an extensive procedure, justified if disease-free margins can be obtained. Further studies should define indications, accreditation policy, and quality of life in LAPRC.


Effects of thickened feeding on gastroesophageal reflux in infants: a placebo-controlled crossover study using intraluminal impedance.
Thickening of formula feedings is part of the therapeutic approach for gastroesophageal reflux (GER) in infants. However, its mechanism of action, especially regarding the occurrence of nonacid (pH >4) GER, has not yet been clearly described. The aim of this randomized, placebo-controlled crossover study was to examine the influence of formula thickened with carob (St. John's bread) bean gum on acid and nonacid GER. Infants with recurrent regurgitation and without other symptoms were fed alternately (A-B-A-B-A-B) with thickened (A) and nonthickened (B) but otherwise identical formula. Documentation of GER episodes during the study was performed by simultaneous intraesophageal impedance measurement (intraluminal electrical impedance; IMP) and pH monitoring. The IMP technique is able to detect bolus movements inside a luminal organ. The use of multiple measuring segments on a single catheter allowed the analysis of direction, height, and duration of the bolus transport. Continuous videorecording and visual surveillance of regurgitation frequency and amount resulted in a severity score. Fourteen infants (42 +/- 32 days old) were examined during 6 feeding intervals each for a total measuring time of 342 hours. A total of 1183 GER episodes and 83 episodes of regurgitation were registered. Regurgitation frequency (15 vs 68 episodes) and amount (severity score 0.6 vs 1.8) were significantly lower after feedings with thickened formula. The difference regarding the occurrence of GER documented by IMP was also pronounced (536 vs 647 episodes). Although not statistically significant, maximal height reached by the refluxate in the esophagus was decreased after thickened feedings. Mean GER duration and the frequency of acid (pH <4) GER were not altered. Thickened feeding has a significant effect on the reduction of regurgitation frequency and amount in otherwise healthy infants. This effect is caused by a reduction in the number of nonacid (pH >4) GER episodes, but also because of a decrease of mean reflux height reached in the esophagus. However, the occurrence of acid GER is not reduced. The combination of IMP and pH monitoring allows the complete registration and description of these GER episodes. Thickening of formula feedings with carob bean gum is an efficient therapy for uncomplicated GER in infants.


Replacement of acetate with citrate in dialysis fluid: a randomized clinical trial of short term safety and fluid biocompatibility.
The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid. Twenty four (24) patients on maintenance dialysis three times per week, 13 on on-line hemodiafiltration (HDF) and 11 on hemodialysis (HD), were randomly assigned to start with either citrate dialysis fluid (1 mM citrate, 1.5 mM calcium) or control fluid (3 mM acetate, 1.5 mM calcium) in an open-labeled cross-over trial (6 + 6 weeks with 8 treatments wash-out in between). Twenty (20) patients, 11 on HDF and 9 on HD were included in the analyses. Main objective was short term safety assessed by acid-base status, plasma ionized calcium and parathyroid hormone (PTH). In addition, biocompatibility was assessed by markers of inflammation (pentraxin 3 (PTX-3), CRP, IL-6, TNF-α and IL-1β) and thrombogenicity (activated partial thromboplastin time (APTT) and visual clotting scores). No differences dependent on randomization order or treatment mode (HD vs. HDF) were detected. Citrate in the dialysis fluid reduced the intra-dialytic shift in pH (+0.04 week 6 vs. +0.06 week 0, p = 0.046) and base excess (+3.9 mM week 6 vs. +5.6 mM week 0, p = 0.006) over the study period. Using the same calcium concentration (1.5 mM), citrate dialysis fluid resulted in lower post-dialysis plasma ionized calcium level (1.10 mM vs. 1.27 mM for control, p < 0.0001) and higher post-dialysis PTH level (28.8 pM vs. 14.7 pM for control, p < 0.0001) while pre-dialysis levels were unaffected. Citrate reduced intra-dialytic induction of PTX-3 (+1.1 ng/ml vs. +1.4 ng/ml for control, p = 0.04) but had no effect on other markers of inflammation or oxidative stress. Citrate reduced visual clotting in the arterial air chamber during HDF (1.0 vs. 1.8 for control, p = 0.03) and caused an intra-dialytic increase in APTT (+6.8 s, p = 0.003) without affecting post-dialysis values compared to control. During this small short term study citrate dialysis fluid was apparently safe to use in HD and on-line HDF treatments. Indications of reduced treatment-induced inflammation and thrombogenicity suggest citrate as a biocompatible alternative to acetate in dialysis fluid. However, the results need to be confirmed in long term studies. ISRCTN28536511.