Program Evaluation of the Research in Academic Pediatrics Initiative on Diversity (RAPID): Impact on Career Development and Professional Society Diversity.
Despite a demographic surge in U.S. minority children, pediatric workforce diversity has failed to keep pace. The study aim was to evaluate the Research in Academic Pediatrics Initiative on Diversity (RAPID), a research-education program aimed at recruiting, retaining, and professionally advancing diverse early-career faculty in general pediatrics who are pursuing research careers. RAPID includes the following components: small research grants, mentoring by nationally renowned senior investigators, mentoring and networking at an annual breakfast, an annual career-development conference, and monthly mentoring conference calls. Outcomes data from the first 5 years (2012-2017) of RAPID were analyzed. Data sources were Academic Pediatric Association (APA) membership data and postconference, baseline, and end-of-program/follow-up surveys. Outcome measures included mentoring quality, presentations, publications, subsequent grants, impact on career success, conference ratings, and APA membership diversity. For the 10 Scholars from the first 4 cohorts, mean scores were 4.5 (5 = strongly agree) for RAPID fostering mentoring, developing research skills, and helping Scholars feel more comfortable as underrepresented minority (URM) faculty; 78% delivered platform or poster presentations on their project. They published 56 total articles and received a mean of 2.5 subsequent grants. Their mean score for RAPID "advancing my career by facilitating promotion or getting a job" was 4.6. The first 4 RAPID Conferences were highly rated (mean scores = 4.2-4.8) and brought in 33 additional URM young investigators. Pre-RAPID, URM APA membership stagnated at 6%-7% for 5 years. In RAPID's first year, URM APA membership rose to 8%, then to 10% by 2017 (43% increase; P < .001). RAPID Scholars generated multiple presentations and publications. RAPID mentoring and Conferences were highly rated. RAPID was associated with career advancement and increased professional society diversity. RAPID could serve as a national model for enhancing URM career development and professional society diversity.


[The possibility of prediction of cholesterol saturation of gallbladder bile].
Using stepwise regression we studied the possibility to determine the cholesterol saturation index (CSI) of gallbladder bile from analysis of fasting serum bile acid, 24 hour urine bile acid or serum lipids (cholesterol and triglyceride) in 31 gallstone patients. Two multiple regression equations were obtained to predict the CSI of bile from fasting serum bile acid compositions based on absolute concentration and relative concentration. The CSI of the gallbladder bile could not be predicted from 24 hour bile acid or serum lipids. Four critical values were calculated from regression equations, which predicted the CSI of bile with the efficiency above 70 percent. This study indicated for the first time that the prediction of CSI of gallbladder bile can be obtained from an analysis of fasting serum bile acid and hence it is possible to prevent gallstone formation at the stage of cholesterol supersaturated bile production.


Inert gas washout: theoretical background and clinical utility in respiratory disease.
Inert gas washout was first described more than 60 years ago and 2 principal tests have been developed from it: the single breath and multiple breath washout (MBW) techniques. The invention of fast responding gas analysers almost 60 years ago and small computers 30 years later have facilitated breath-by-breath analysis and the development of sophisticated analysis techniques. It is now possible to detect not only the degree of pulmonary ventilation inhomogeneity, but also to gain important insight into the location of the underlying disease process. While single breath washout requires a full vital capacity effort, tidal breathing during the multiple breath test requires minimal co-operation and co-ordination, and is feasible in subjects of all ages. Available MBW normative data from parameters, such as the lung clearance index, appears to vary minimally with age, making MBW particularly useful to follow children longitudinally. Multiple breath inert gas washout has demonstrated improved sensitivity, in comparison to spirometry, in the early detection of a number of important disease processes, including cystic fibrosis. Despite this, these important techniques remain under-utilised in the clinical setting and there is a lack of commercially available devices currently available. The recent resurgence of research in this area has produced a large number of important studies and a pronounced international interest has developed in these techniques. This review article will provide an overview of the theoretical background of inert gas washout and analysis indices, review important physiological and clinical insights gained from research to date (as well as from our own experience) to illustrate its utility, and outline the challenges that lie ahead in incorporating these techniques into the mainstream clinical setting.


[Determination of heat stable salt anions in alkanolamine desulphurization solution by ion chromatography].
To control the potential risk of natural gas purification plants, an ion chromatographic method has been developed to determine the heat stable salts (HSS) in alkanolamine desulphurization solution. Seven HSS anions, including CH3COO(-), HCOO(-), Cl(-), SO4(2-), C2O4(2-), S2O3(2-), SCN(-), were determined in a single injection. Before the chromatographic analysis, these industrial samples were pretreated by three steps, i.e. filtration, solid phase extraction and dilution. Using the gradient elution with KOH solution, all of the seven anions have been separated and determined by a conductivity detector. As the calibration results, the linear range of this method was 0.01 - 0.5 mmol/L for the 7 anions. The limit of detection (LOD, S/N = 3) was 0. 1 mg/L for each anion. By spiked standard solutions in the samples, the recoveries were in the range of 80.0% - 100.3%. The repeatability of this method was evaluated at five different concentrations. The relative standard deviations (RSD, n = 10) of the peak areas were in the range of 0.94% to 3.99%. Moreover, the reproducibility of the method was also tested in three different laboratories and it was acceptable with the RSD <5%. The proposed method has been applied to the determination of HSS in eight gas purification plants, three oil refineries and one coal gas plant and to monitor a gas purification plant continuously in 15 days. It's shown that the accuracy and precision of this method are satisfactory.


Mice infer probabilistic models for timing.
Animals learn both whether and when a reward will occur. Neural models of timing posit that animals learn the mean time until reward perturbed by a fixed relative uncertainty. Nonetheless, animals can learn to perform actions for reward even in highly variable natural environments. Optimal inference in the presence of variable information requires probabilistic models, yet it is unclear whether animals can infer such models for reward timing. Here, we develop a behavioral paradigm in which optimal performance required knowledge of the distribution from which reward delays were chosen. We found that mice were able to accurately adjust their behavior to the SD of the reward delay distribution. Importantly, mice were able to flexibly adjust the amount of prior information used for inference according to the moment-by-moment demands of the task. The ability to infer probabilistic models for timing may allow mice to adapt to complex and dynamic natural environments.


Prenatal alcohol exposure induces long-term changes in dendritic spines and synapses in the mouse visual cortex.
To study the long-term changes of dendritic spine and synapse taking place in a mouse model of fetal alcohol spectrum disorders (FASDs). Pregnant mice were intubated daily with ethanol (EtOH) from E5 to parturition. A DiI diolistic method was used to label dendritic spines of pyramidal cells in the visual cortex of EtOH-exposed and control pups over the period from postnatal (P) day P0 to P30; synaptic ultrastructure was also analyzed using transmission electron microscopy. Prenatal alcohol exposure was associated with a significant decrease in the number of dendritic spines of pyramidal neurons in the visual cortex and an increase in their mean length. The changes were dose dependent and persisted to P30. Ultrastructural changes were also observed, with decreased numbers of synaptic vesicles, narrowing of the synaptic cleft and thickening of the postsynaptic density compared to controls; ultrastructural changes also persisted to P30. Prenatal alcohol exposure is associated with long-term changes in dendritic spines and synaptic ultrastructure; these alterations probably reflect the developmental retardation of dendritic spines and synapses in visual cortex. These long-term changes are likely to contribute to lifelong mental retardation associated with childhood FASDs.


Roles of lipid turnover in transmembrane signal transduction.
Cells of higher organisms respond to external stimuli with a cascade of intracellular biochemical events initiated by binding of a hormone, growth factor, or neurotransmitter to a specific cell surface receptor. Previously well-characterized signal transduction pathways involve cyclic nucleotides as intracellular second messengers. Over the past decade, increasing attention has been focused on other signaling pathways in which membrane lipids serve as second messengers or their precursors. This review describes current understanding of these pathways and points to recent discoveries likely to open new frontiers in the coming decade.


Keratectasia following laser in situ keratomileusis in a low-risk patient with benign joint hypermobility syndrome.
Here we present the case of a 27-year-old woman with benign joint hypermobility (BJHS) syndrome who developed keratectasia after laser in situ keratomileusis (LASIK) in both eyes. Both eyes had identical low Randleman risk factor scores. To our knowledge, this is the first report of such a complication in a patient with BJHS. It highlights our incomplete knowledge of the risk factors for keratectasia following LASIK and suggests that BJHS should be considered as a risk factor for keratectasia.


Laparoscopic left hepatectomy for mucinous cystic neoplasm of the liver.
Among liver cystic lesions, mucinous cystic neoplasm of the liver (MCN-L) constitutes a challenging issue in terms of management: preoperative diagnosis is often unachievable and this may mislead to inappropriate treatment [1-3]. We present the case of an otherwise healthy 29-year-old female who underwent laparotomic cyst unroofing in segment 4 and cholecystectomy in another institution. Post-operative course was complicated by biliary leakage that was endoscopically treated. Short term follow-up showed early recurrence with a volumetric enlargement of the cyst occupying most of the left hepatic lobe and new satellite cyst in Sg5. The doubt of MCN-L arose, and the patient was scheduled for laparoscopic removal at our Centre, despite the previous laparotomic procedure. An optic port was placed into right upper abdominal quadrant and 3 further ports were placed. A long and difficult adhesiolysis was performed and Pringle's manoeuver was settled. Intraoperative US confirmed the anatomic limits of the cysts in Sg5 and in the left hepatic lobe. The cyst on Sg5 was resected first and frozen section was suspicious for MCN-L. In order to prevent recurrence, left laparoscopic hepatectomy was performed. The specimen was extracted through the previous midline laparotomy. Post-operative course was uneventful and the patient was discharged on POD 5. Pathology and immunochemistry confirmed the diagnosis of MCN-L. Hepatic cystic lesions may be insidious and preoperative biopsy is not always possible due to lack of solid tissue. In unclear settings, an intraoperative frozen section is mandatory to guide intraoperative decisions. In the suspicion of malignancy, resection with oncologic criteria must be chosen as the most appropriate treatment, as well as the retrieving of MCN-L requires hepatic resection to avoid early recurrence [4, 5]. Despite of previous laparotomy, we consider a laparoscopic approach could be attempted in selected cases, in institution with particular expertise in laparoscopic liver surgery.


Using sequence motifs for enhanced neural network prediction of protein distance constraints.
Correlations between sequence separation (in residues) and distance (in Angstrom) of any pair of amino acids in polypeptide chains are investigated. For each sequence separation we define a distance threshold. For pairs of amino acids where the distance between C alpha atoms is smaller than the threshold, a characteristic sequence (logo) motif, is found. The motifs change as the sequence separation increases: for small separations they consist of one peak located in between the two residues, then additional peaks at these residues appear, and finally the center peak smears out for very large separations. We also find correlations between the residues in the center of the motif. This and other statistical analysis are used to design neural networks with enhanced performance compared to earlier work. Importantly, the statistical analysis explains why neural networks perform better than simple statistical data-driven approaches such as pair probability density functions. The statistical results also explain characteristics of the network performance for increasing sequence separation. The improvement of the new network design is significant in the sequence separation range 10-30 residues. Finally, we find that the performance curve for increasing sequence separation is directly correlated to the corresponding information content. A WWW server, distanceP, is available at http://www.cbs.dtu.dk/services/distanceP/.


Hypertension in diabetes: treatment considerations.
Treatment of blood pressure in the patient with diabetes remains a challenge. While data extrapolated from many trials seemed to imply that lower blood pressures leads to more favorable cardiovascular outcomes, this paper reviews newer trials designed to treat to blood pressure targets below 130/80 mmHg in patients with long term established diabetes, which showed that this goal may prove more harmful than helpful. In clinical practice this may be less relevant due to the fact that less than half of patients are even at the goal of 130/80. The interaction between glucose control and blood pressure control are also discussed, emphasizing the importance of multifactorial treatment.


Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis.
In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.


Infection does not increase long-term mortality in patients with acute severe alcoholic hepatitis treated with corticosteroids.
To determine whether infection in patients with acute severe alcoholic hepatitis (AAH) treated with corticosteroids is associated with increased mortality. Consecutive patients with AAH were treated with steroids and recruited to the study. Clinically relevant infections (body temperature > 38 °C or < 36 °C for more than 4 h, ascitic neutrophil count > 0.25 ×109/L, consolidation on chest radiograph or clinically relevant positive microbiological culture of bodily fluid) were recorded prospectively. Clinical and laboratory parameters were recorded and survival at 90 d and 6 mo was determined. Univariate analysis of factors associated with 90-d mortality was performed and significant variables included in a multivariate analysis. Seventy-two patients were included in the final analysis (mean age 47.9 years, 26% female, mean discriminant function 53.0). Overall mortality in the group occurred in 15 (21%), 23 (32%) and 31 (43%) at day 28, day 90 and 1 year respectively. 36 (50%) had a clinically relevant infection during their hospitalisation (23 after initiation of steroids). The median time to development of incident infection after commencement of steroids was 10 d. The commonest site of infection was ascites (31%) and bacteraemia (31%) followed by urinary tract (19%) and respiratory tract (8%). Forty-one separate organisms were isolated in 33 patients; the most frequent genus was Escherichia (22%) and Enterococcus (20%). Infection was not associated with 90-d or 1 year mortality but was associated with higher creatinine, model for end-stage liver disease and Lille score. Baseline urea was the only independent predictor of 90-d mortality. Clinically relevant infections are common in patients with AAH but are not associated with increased 90-d or 1 year mortality.


Disparities in cancer mortality and incidence among American Indians and Alaska Natives in the United States.
We used improved data on American Indian and Alaska Native (AI/AN) ancestry to provide an updated and comprehensive description of cancer mortality and incidence among AI/AN populations from 1990 to 2009. We linked the National Death Index and central cancer registry records independently to the Indian Health Service (IHS) patient registration database to improve identification of AI/AN persons in cancer mortality and incidence data, respectively. Analyses were restricted to non-Hispanic persons residing in Contract Health Service Delivery Area counties in 6 geographic regions of the United States. We compared age-adjusted mortality and incidence rates for AI/AN populations with White populations using rate ratios and mortality-to-incidence ratios. Trends were described using joinpoint analysis. Cancer mortality and incidence rates for AI/AN persons compared with Whites varied by region and type of cancer. Trends in death rates showed that greater progress in cancer control was achieved for White populations compared with AI/AN populations over the last 2 decades. Spatial variations in mortality and incidence by type of cancer demonstrated both persistent and emerging challenges for cancer control in AI/AN populations.


Reynolds numbers influence the directionality of self-propelled microjet engines in the 10(-4) regime.
The motion directionality of self-propelled bubble-jet microengines is influenced by their velocities and/or viscosity of the media in which they move. The influence of the fuel concentration from 1 to 3 wt% of H2O2 in 0.5% steps and of the glycerol fraction from 0 to 64% in aqueous solution on the directionality of the microjets motions is examined systematically. We show that with decreasing Reynolds numbers of the system (that is, with increasing viscosity or decreasing velocity of the microjets), the directionality of the motion shifts from circular to linear motion. This translates to a shorter travel time towards a designated target for the microjets despite moving at a slower speed, since the movements are linear instead of circular. We show that such dependence of trajectories of microjets on Re is a general issue. This observation has a strong implication for the real-world applications of microjets.


Experimental hindlimb ischemia leads to neutrophil-mediated increases in gastrocnemius MMP-2 and -9 activity: a potential mechanism for ischemia induced MMP activation.
Matrix metalloproteinases (MMP)-2 and -9 are Type 4 collagenases instrumental in basement membrane degradation, a process necessary for angiogenesis to occur. Polymorphonuclear leukocytes (PMNs) contain MMP-9, and in the presence of both PMN-derived serine protease and membrane type 1 (MT1)-MMP, are able to activate pro-MMP-2 following hindlimb ischemia. We hypothesized that neutrophil depletion (ND) of animals prior to hindlimb ischemia (HI) would abrogate the activation of pro-MMP-2 and decrease the level of MMP-9 12 FVB/N Tie2/LacZ-182 SATO female mice were randomly divided into four blinded groups; HI + PBS, HI + anti-PMN antibody (GR-1), HI + isotype matched control antibody (IgG(2b,K)), and no HI + PBS. PMN depletion was achieved prior to the time of ischemia and maintained until sacrifice. HI was achieved by unilateral femoral artery ligation. Three days postligation the animals were sacrificed and the gastrocnemius muscle from each hindlimb was harvested. MMP-2 and -9 (gelatin zymography) and MT1-MMP (Western blot) expression and activation were quantified by densitometry and NIH Image Analysis software. MMP values were expressed as a ratio of ischemic-to-nonischemic hindlimbs and compared between groups. Statistical significance was determined with analysis of variance (ANOVA) RESULTS: Zymograms revealed a greater than 10-fold increase in active MMP-9 and greater than 4-fold increase in active MMP-2 from HI + PBS compared to no HI + PBS (P < 0.05). HI + anti-PMN antibody demonstrated reduction of both active MMP-2 and -9 levels to that of the nonischemic group. Pro-MMP-2 was constitutively expressed in all four groups with no significant differences between any group (P = NS). There was no difference between the HI + isotype-matched antibody group and the HI + PBS group throughout the experiments (P = NS). ND did not affect MT1-MMP activation or expression Limb ischemia causes activation of MMP-2 and -9, which is eliminated by ND. ND animals undergoing hindlimb ischemia exhibit identical levels of active MMP-2 and -9 as animals that did not have hindlimb ischemia. Neutrophils may be an important activator of MMP-2 and the suppliers of MMP-9 in the ischemic hindlimb and may be essential for tissue remodeling, basement membrane degradation, and angiogenesis in ischemic limbs


Unicompartmental Knee Arthroplasty Provides Significantly Greater Improvement in Function than Total Knee Arthroplasty Despite Equivalent Satisfaction for Isolated Medial Compartment Osteoarthritis.
While some advocate for unicompartmental knee arthroplasty (UKA) for isolated medial compartment osteoarthritis (OA), others favor total knee arthroplasty (TKA). The purpose of this study was to compare the functional outcomes of UKA and TKA performed for patients with unicompartmental arthritis (OA). A study was performed on 133 patients that met strict criteria for UKA, but who underwent either medial UKA or TKA for isolated medial compartment OA based upon physician equipoise. The primary outcome-New Knee Society Score (KSS)-was assessed preoperatively and at 2 years postoperatively. A propensity score weighted regression was used to balance the groups on several key covariates, including age, gender, body mass index, and baseline KSS. After propensity weighting, there were no significant differences between UKA and TKA in overall baseline KSS or KSS after 2 years postoperatively. While TKA patients had demonstrated a significantly greater improvement in the symptoms KSS subscale, UKA patients had a significantly greater improvement in the function subscale. Expectations were significantly more likely to be met after UKA, but there were no differences in patient satisfaction. UKA and TKA are both highly successful options for treating patients with medial compartment OA, although functionality increased more, and expectations were more likely to be met, after UKA in this study. Given equivalent patient satisfaction after both TKA and UKA, surgeons should consider factors such as clinical experience, individual preference, cost of care, surgical risk, and recovery needs, when making treatment decisions regarding this clinical entity.


Compatibility of recombinant tissue plasminogen activator (rtPA) and aflibercept or ranibizumab coapplied for neovascular age-related macular degeneration with submacular haemorrhage.
Subretinal coapplication of recombinant tissue plasminogen activator (rtPA) and vascular endothelial growth factor (VEGF)-antagonists is a new treatment option for age-related macular degeneration complicated by submacular haemorrhage. Here, we investigate the compatibility of rtPA and aflibercept or ranibizumab in vitro because intraoperatively, rtPA or rtPA-induced plasmin may cleave aflibercept or ranibizumab. Aflibercept and ranibizumab, respectively, were incubated with rtPA or plasmin, separated in gel electrophoresis and stained with Coomassie or silver. The antiangiogenic activity of the VEGF-antagonists was quantified by VEGF-ELISA after incubation with the supernatant of primary porcine retinal pigment epithelium cell cultures. In electrophoresis, ranibizumab displayed no additional fragments when it was coapplied with rtPA or plasmin. Its VEGF-inhibiting efficacy remained unchanged in coapplication with rtPA with or without blood, or plasmin. rtPA did not cleave or functionally compromise aflibercept. When aflibercept was coapplied with plasmin, electrophoresis displayed additional bands in Coomassie (30 kDa, 27 kDa, 19 kDa, 15 kDa) and silver staining (31 kDa, 26 kDa, 21 kDa, 19 kDa, 15 kDa). While at a clinical dosage (800 µg/mL) VEGF was inhibited by aflibercept when coapplied with plasmin, at borderline concentrations (400 ng/mL) VEGF-binding ability of aflibercept was abolished. Ranibizumab is not cleaved or functionally compromised by rtPA or plasmin. Aflibercept is cleaved and its VEGF-binding ability is reduced when coapplied with plasmin. In clinical practice, rtPA and ranibizumab can be coapplied as a treatment for neovascular age-related macular degeneration with submacular haemorrhage while the antiangiogenic activity of aflibercept may be compromised when coapplied with rtPA in the presence of plasmin.


Multiple loci with different cancer specificities within the 8q24 gene desert.
Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.


Evaluating the effectiveness of using PROs in clinical practice: a role for cluster-randomised trials.
Many of us believe there are major benefits to be gained by using patient-reported outcomes (PROs) in routine clinical practice. However, demonstrating tangible benefits has frequently proved elusive. Although randomised clinical trials (RCTs) have become accepted as the standard for comparing alternative forms of clinical interventions, when evaluating the effectiveness of PROs there are a number of challenges both in terms of study design and the subsequent analysis. Despite this, to date, of those investigators who have used RCTs, relatively few have used anything other than simple two-group randomisation and comparisons. Most of these trials have also failed to demonstrate convincing benefits to patient outcomes. We suggest that the use of PROs may result in modest yet important improvements to patient outcomes, and that these benefits may be obscured in conventional individual patient trials because of contamination effects. The advantages of alternative designs such as cross-over studies and in particular cluster-randomised trials are illustrated.


Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids.
Pancreatic organoid systems have recently been described for the in vitro culture of pancreatic ductal cells from mouse and human. Mouse pancreatic organoids exhibit unlimited expansion potential, while previously reported human pancreas organoid (hPO) cultures do not expand efficiently long-term in a chemically defined, serum-free medium. We sought to generate a 3D culture system for long-term expansion of human pancreas ductal cells as hPOs to serve as the basis for studies of human pancreas ductal epithelium, exocrine pancreatic diseases and the development of a genomically stable replacement cell therapy for diabetes mellitus. Our chemically defined, serum-free, human pancreas organoid culture medium supports the generation and expansion of hPOs with high efficiency from both fresh and cryopreserved primary tissue. hPOs can be expanded from a single cell, enabling their genetic manipulation and generation of clonal cultures. hPOs expanded for months in vitro maintain their ductal morphology, biomarker expression and chromosomal integrity. Xenografts of hPOs survive long-term in vivo when transplanted into the pancreas of immunodeficient mice. Notably, mouse orthotopic transplants show no signs of tumorigenicity. Crucially, our medium also supports the establishment and expansion of hPOs in a chemically defined, modifiable and scalable, biomimetic hydrogel. hPOs can be expanded long-term, from both fresh and cryopreserved human pancreas tissue in a chemically defined, serum-free medium with no detectable tumorigenicity. hPOs can be clonally expanded, genetically manipulated and are amenable to culture in a chemically defined hydrogel. hPOs therefore represent an abundant source of pancreas ductal cells that retain the characteristics of the tissue-of-origin, which opens up avenues for modelling diseases of the ductal epithelium and increasing understanding of human pancreas exocrine biology as well as for potentially producing insulin-secreting cells for the treatment of diabetes.


Modulatory role of endothelial calcium level in vascular tension of canine depolarized coronary arteries.
The vascular tension in the coronary artery is modulated by factors released by endothelial cells. We investigated the relationship between the Ca2+ level in endothelium and endothelium-mediated changes in smooth muscle tone in high K(+)-depolarized canine coronary arteries by measuring intracellular Ca2+ concentration fluorimetrically with the Ca2+ indicator fura 2. Addition of Ca2+ (1 mM) caused an increase in endothelial Ca2+ and relaxed the 30 mM K(+)-depolarized arteries following inhibition of Ca2+ influx in the smooth muscle with diltiazem. This relaxation was inhibited by NG-monomethyl-L-arginine. As extracellular K+ concentration was decreased, increases of endothelial Ca2+ were augmented, whereas the relaxation was decreased. Basal muscle tone was found to be decreased in low K+ by measuring relaxation by sodium nitroprusside. These results suggest the importance of Ca2+ level in the endothelium in playing a modulatory role in coronary tension through the production of nitric oxide. The correlation of extracellular K+ to Ca2+ level in the endothelium indicates a typical characteristic of the passive Ca2+ entry pathway in the endothelium, whereas the resultant relaxation appears to be restricted by the basal muscle tone.


Robust Fusion of LiDAR and Wide-Angle Camera Data for Autonomous Mobile Robots.
Autonomous robots that assist humans in day to day living tasks are becoming increasingly popular. Autonomous mobile robots operate by sensing and perceiving their surrounding environment to make accurate driving decisions. A combination of several different sensors such as LiDAR, radar, ultrasound sensors and cameras are utilized to sense the surrounding environment of autonomous vehicles. These heterogeneous sensors simultaneously capture various physical attributes of the environment. Such multimodality and redundancy of sensing need to be positively utilized for reliable and consistent perception of the environment through sensor data fusion. However, these multimodal sensor data streams are different from each other in many ways, such as temporal and spatial resolution, data format, and geometric alignment. For the subsequent perception algorithms to utilize the diversity offered by multimodal sensing, the data streams need to be spatially, geometrically and temporally aligned with each other. In this paper, we address the problem of fusing the outputs of a Light Detection and Ranging (LiDAR) scanner and a wide-angle monocular image sensor for free space detection. The outputs of LiDAR scanner and the image sensor are of different spatial resolutions and need to be aligned with each other. A geometrical model is used to spatially align the two sensor outputs, followed by a Gaussian Process (GP) regression-based resolution matching algorithm to interpolate the missing data with quantifiable uncertainty. The results indicate that the proposed sensor data fusion framework significantly aids the subsequent perception steps, as illustrated by the performance improvement of a uncertainty aware free space detection algorithm.


Ligand-induced protein mobility in complexes of carbonic anhydrase II and benzenesulfonamides with oligoglycine chains.
This paper describes a biophysical investigation of residual mobility in complexes of bovine carbonic anhydrase II (BCA) and para-substituted benzenesulfonamide ligands with chains of 1-5 glycine subunits, and explains the previously observed increase in entropy of binding with chain length. The reported results represent the first experimental demonstration that BCA is not the rigid, static globulin that has been typically assumed, but experiences structural fluctuations upon binding ligands. NMR studies with (15)N-labeled ligands demonstrated that the first glycine subunit of the chain binds without stabilization or destabilization by the more distal subunits, and suggested that the other glycine subunits of the chain behave similarly. These data suggest that a model based on ligand mobility in the complex cannot explain the thermodynamic data. Hydrogen/deuterium exchange studies provided a global estimate of protein mobility and revealed that the number of exchanged hydrogens of BCA was higher when the protein was bound to a ligand with five glycine subunits than when bound to a ligand with only one subunit, and suggested a trend of increasing number of exchanged hydrogens with increasing chain length of the BCA-bound ligand, across the series. These data support the idea that the glycine chain destabilizes the structure of BCA in a length-dependent manner, causing an increase in BCA mobility. This study highlights the need to consider ligand-induced mobility of even "static" proteins in studies of protein-ligand binding, including rational ligand design approaches.


A reproducible and generalizable software workflow for analysis of large-scale neuroimaging data collections using BIDS Apps.
Neuroimaging research faces a crisis of reproducibility. With massive sample sizes and greater data complexity, this problem becomes more acute. Software that operates on imaging data defined using the Brain Imaging Data Structure (BIDS) - BIDS Apps - have provided a substantial advance. However, even using BIDS Apps, a full audit trail of data processing is a necessary prerequisite for fully reproducible research. Obtaining a faithful record of the audit trail is challenging - especially for large datasets. Recently, the FAIRly big framework was introduced as a way to facilitate reproducible processing of large-scale data by leveraging DataLad - a version control system for data management. However, the current implementation of this framework was more of a proof of concept, and could not be immediately reused by other investigators for different use cases. Here we introduce the BIDS App Bootstrap (BABS), a user-friendly and generalizable Python package for reproducible image processing at scale. BABS facilitates the reproducible application of BIDS Apps to large-scale datasets. Leveraging DataLad and the FAIRly big framework, BABS tracks the full audit trail of data processing in a scalable way by automatically preparing all scripts necessary for data processing and version tracking on high performance computing (HPC) systems. Currently, BABS supports jobs submissions and audits on Sun Grid Engine (SGE) and Slurm HPCs with a parsimonious set of programs. To demonstrate its scalability, we applied BABS to data from the Healthy Brain Network (HBN; n=2,565). Taken together, BABS allows reproducible and scalable image processing and is broadly extensible via an open-source development model.


m5C RNA and m5C DNA methyl transferases use different cysteine residues as catalysts.
A family of RNA m(5)C methyl transferases (MTases) containing over 55 members in eight subfamilies has been identified recently by an iterative search of the genomic sequence databases by using the known 16S rRNA m(5)C 967 MTase, Fmu, as an initial probe. The RNA m(5)C MTase family contained sequence motifs that were highly homologous to motifs in the DNA m(5)C MTases, including the ProCys sequence that contains the essential Cys catalyst of the functionally similar DNA-modifying enzymes; it was reasonable to assign the Cys nucleophile to be that in the conserved ProCys. The family also contained an additional conserved Cys residue that aligns with the nucleophilic catalyst in m(5)U54 tRNA MTase. Surprisingly, the mutant of the putative Cys catalyst in the ProCys sequence was active and formed a covalent complex with 5-fluorocytosine-containing RNA, whereas the mutant at the other conserved Cys was inactive and unable to form the complex. Thus, notwithstanding the highly homologous sequences and similar functions, the RNA m(5)C MTase uses a different Cys as a catalytic nucleophile than the DNA m(5)C MTases. The catalytic Cys seems to be determined, not by the target base that is modified, but by whether the substrate is DNA or RNA. The function of the conserved ProCys sequence in the RNA m(5)C MTases remains unknown.


Jellyfish-associated bacterial communities and bacterioplankton in Indonesian Marine lakes.
In the present study, we compared communities of bacteria in two jellyfish species (the 'golden' jellyfish Mastigias cf.papua and the box jellyfish Tripedalia cf.cystophora) and water in three marine lakes located in the Berau region of northeastern Borneo, Indonesia. Jellyfish-associated bacterial communities were compositionally distinct and less diverse than bacterioplankton communities. Alphaproteobacteria, Gammaproteobacteria, Synechococcophycidae and Flavobacteriia were the most abundant classes in water. Jellyfish-associated bacterial communities were dominated by OTUs assigned to the Gammaproteobacteria (family Endozoicimonaceae), Mollicutes, Spirochaetes and Alphaproteobacteria (orders Kiloniellales and Rhodobacterales). Mollicutes were mainly restricted to Mastigias whereas Spirochaetes and the order Kiloniellales were most abundant in Tripedalia hosts. The most abundant OTU overall in jellyfish hosts was assigned to the family Endozoicimonaceae and was highly similar to organisms in Genbank obtained from various hosts including an octocoral, bivalve and fish species. Other abundant OTUs included an OTU assigned to the order Entomoplasmatales and mainly found in Mastigias hosts and OTUs assigned to the Spirochaetes and order Kiloniellales and mainly found in Tripedalia hosts. The low sequence similarity of the Entomoplasmatales OTU to sequences in Genbank suggests that it may be a novel lineage inhabiting Mastigias and possibly restricted to marine lakes.


Can music lessons increase the performance of preschool children in IQ tests?
The impact of music on human cognition has a distinguished history as a research topic in psychology. The focus of the present study was on investigating the effects of music instruction on the cognitive development of preschool children. From a sample of 154 preschool children of Tehran kindergartens, 60 children aged between 5 and 6 were randomly assigned to two groups, one receiving music lessons and the other (matched for sex, age and mother's educational level) not taking part in any music classes. Children were tested before the start of the course of music lessons and at its end with 4 subtests of the Tehran-Stanford-Binet Intelligence Scale (TSB). The experimental group participated in twelve 75-min weekly music lessons. Statistical analysis showed significant IQ increase in participants receiving music lessons, specifically on the TSB verbal reasoning and short-term memory subtests. The numerical and visual/abstract reasoning abilities did not differ for the two groups after lessons. These data support studies that found similar skills enhancements in preschool children, despite vast differences in the setting in which the instruction occurred. These findings appear to be consistent with some neuroimaging and neurological observations which are discussed in the paper.


[Aggregation of C-reactive protein in solutions at acid pH].
The hydrodynamic properties of the C-reactive protein (CRP) at different pH were studied using quasi-elastic light scattering, size-exclusion liquid chromatography, and nonreducing gel electrophoresis. It was shown that a CRP solution at pH 5.0-7.2 presents a polydisperse system the major component of which is the native pentameric CRP. At pH 4.0-4.5, CRP exists in two states having different hydrodynamic properties: the native pentameric form with a molecular mass of 120 kDa and with the hydrodynamic radius of 4.03 nm and high-molecular-weight aggregates with a wide range of their molecular weight distribution. The interaction of the C-reactive protein with monoclonal antibodies to it indicates that conformation-dependent surface epitopes of the protein lose the native structure at pH 5.0-5.5. The aggregation of CRP is an irreversible process, which begins in a narrow pH range of pH 5.0-4.5 and is not accompanied by the dissociation into subunits but is determined by intermolecular interactions of its quasi-native pentamers.


Multislice Computed Tomography Assessment of Tracheobronchial Patterns in Partial Anomalous Left Pulmonary Artery.
The aim of this study was to present relationship between partial anomalous left pulmonary artery (PALPA) and the tracheobronchial tree and patterns of the tracheobronchial tree assessed by multislice computed tomography (MSCT). Nine patients were assessed by MSCT. The relationships between the tracheobronchial tree and PALPA and different tracheobronchial patterns, location of tracheobronchial stenosis, severity of stenosis, and associated cardiac defects were evaluated. The results of MSCT for these patients were compared with the operative findings. The anatomy of PALPA was clearly identified by MSCT in all 9 patients. Three relationships between PALPA and the tracheobronchial tree were noted. In addition, 3 patterns of tracheobronchial tree anatomy were also demonstrated. The PALPA arose from the right pulmonary artery, forming a pulmonary sling (n = 2). The PALPA, which arose from the proximal right pulmonary artery, went below the tracheal bifurcation and passed anterior (n = 1) or inferior-anterior (n = 6) to the proximal left main bronchus. Three patterns of the tracheobronchial tree were presented with normal (n = 5), normal pattern with right tracheal bronchus (n = 3), and bridging bronchus (n = 1). The rate of tracheobronchial stenosis was 56% (5/9).Five patients underwent operation, and at that time, the relationship between PALPA and the tracheobronchial tree defined on MSCT was confirmed. The PALPA can be associated with tracheobronchial anomalies and airway compression depending on its orientation to the airway. Noninvasive imaging modalities such as MSCT will be helpful for making further management decisions.


Improving estimates of diving lung volume in air-breathing marine vertebrates.
The air volume in the respiratory system of marine tetrapods provides a store of O2 to fuel aerobic metabolism during dives; however, it can also be a liability, as the associated N2 can increase the risk of decompression sickness. In order to more fully understand the physiological limitations of different air-breathing marine vertebrates, it is therefore important to be able to accurately estimate the air volume in the respiratory system during diving. One method that has been used to do so is to calculate the air volume from glide phases - periods of movement during which no thrust is produced by the animal - which many species conduct during ascent periods, when gases are expanding owing to decreasing hydrostatic pressure. This method assumes that there is conservation of mass in the respiratory system, with volume changes only driven by pressure. In this Commentary, we use previously published data to argue that both the respiratory quotient and differences in tissue and blood gas solubility potentially alter the mass balance in the respiratory system throughout a dive. Therefore, near the end of a dive, the measured volume of gas at a given pressure may be 12-50% less than from the start of the dive; the actual difference will depend on the length of the dive, the cardiac output, the pulmonary shunt and the metabolic rate. Novel methods and improved understanding of diving physiology will be required to verify the size of the effects described here and to more accurately estimate the volume of gas inhaled at the start of a dive.


HRS mediates tumor immune evasion by regulating proteostasis-associated interferon pathway activation.
By sorting receptor tyrosine kinases into endolysosomes, the endosomal sorting complexes required for transport (ESCRTs) are thought to attenuate oncogenic signaling in tumor cells. Paradoxically, ESCRT members are upregulated in tumors. Here, we show that disruption of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a pivotal ESCRT component, inhibited tumor growth by promoting CD8+ T cell infiltration in melanoma and colon cancer mouse models. HRS ablation led to misfolded protein accumulation and triggered endoplasmic reticulum (ER) stress, resulting in the activation of the type I interferon pathway in an inositol-requiring enzyme-1α (IRE1α)/X-box binding protein 1 (XBP1)-dependent manner. HRS was upregulated in tumor cells with high tumor mutational burden (TMB). HRS expression associates with the response to PD-L1/PD-1 blockade therapy in melanoma patients with high TMB tumors. HRS ablation sensitized anti-PD-1 treatment in mouse melanoma models. Our study shows a mechanism by which tumor cells with high TMB evade immune surveillance and suggests HRS as a promising target to improve immunotherapy.


STIM1 translocation to the plasma membrane enhances intestinal epithelial restitution by inducing TRPC1-mediated Ca2+ signaling after wounding.
Early epithelial restitution is an important repair modality in the gut mucosa and occurs as a consequence of epithelial cell migration. Canonical transient receptor potential-1 (TRPC1) functions as a store-operated Ca2+ channel (SOCs) in intestinal epithelial cells (IECs) and regulates intestinal restitution, but the exact upstream signals initiating TRPC1 activation after mucosal injury remain elusive. Stromal interaction molecule 1 (STIM1) is a single membrane-spanning protein and is recently identified as essential components of SOC activation. The current study was performed to determine whether STIM1 plays a role in the regulation of intestinal epithelial restitution by activating TRPC1 channels. STIM1 translocation to the plasma membrane increased after wounding, which was followed by an increase in IEC migration to reseal wounds. Increased STIM1 levels at the plasma membrane by overexpressing EF-hand mutant STIM1 enhanced Ca2+ influx through SOCs and stimulated IEC migration after wounding. STIM1 interacted with TRPC1 and formed STIM1/TRPC1 complex, whereas inactivation of STIM1 by STIM1 silencing decreased SOC-mediated Ca2+ influx and inhibited epithelial restitution. In cells overexpressing EF-hand mutant STIM1, TRPC1 silencing also decreased STIM1/TRPC1 complex, reduced SOC-mediated Ca2+ influx, and repressed cell migration after wounding. Our findings demonstrate that induced STIM1 translocation to the plasma membrane promotes IEC migration after wounding by enhancing TRPC1-mediated Ca2+ signaling and provide new insight into the mechanism of intestinal epithelial restitution.


Validation of a Published Model to Reduce Burden of Retinopathy of Prematurity Screening.
The E-ROP study evaluated 1257 patients screened for retinopathy of prematurity (ROP), and found that no infant born at or after 27 weeks' gestational age and having a birthweight over 750 g developed treatable disease if they had no ROP at 37 weeks' gestational age. The study investigators suggested that there is little value in continued screening of infants meeting these criteria who have no ROP at 37 weeks. We attempted to replicate these published data in a larger multi-center cohort to validate or refute this hypothesis. Retrospective cohort study. We conducted a chart review of every infant treated for ROP from February 2004 through April 2022 at 6 medical centers located in the mid-southern region of the United States. We evaluated gestational age, birthweight, and presence or absence of ROP at 37 weeks' gestational age to determine whether any treated infants would have been "missed" using these screening criteria. Of 6729 infants screened, 298 (4.43%) received treatment. Ten infants who required treatment developed first evidence of ROP after 37 weeks' gestational age. However, only 1 infant was >750 g birthweight and >27 weeks' gestational age. This patient developed zone 2, stage 3 with pre-plus disease and was treated because of limited access to care at a remote hospital; however, ROP was detected at the first examination after 37 weeks, so this infant would have been identified for continued follow-up. Our results, in a cohort 5 times that of the original study, replicated that infants >750 g birthweight and >27 weeks' gestational age did not develop treatable ROP if they had no ROP at 37 weeks, supporting the termination of examination at that time in patients meeting these criteria.


Unlocking the Power of EHRs: Harnessing Unstructured Data for Machine Learning-based Outcome Predictions.
The integration of Electronic Health Records (EHRs) with Machine Learning (ML) models has become imperative in examining patient outcomes due to the vast amounts of clinical data they provide. However, critical information regarding social and behavioral factors that affect health, such as social isolation, stress, and mental health complexities, is often recorded in unstructured clinical notes, hindering its accessibility. This has resulted in an over-reliance on clinical data in current EHR-based research, potentially leading to disparities in health outcomes. This study aims to evaluate the impact of incorporating patient-specific context from unstructured EHR data on the accuracy and stability of ML algorithms for predicting mortality, using the MIMIC III database. Results from the study confirmed the significance of incorporating patient-specific information into prediction models, leading to a notable improvement in the discriminatory power and robustness of the ML algorithms. Furthermore, the findings underline the importance of considering non-clinical factors related to a patient's daily life, in addition to clinical factors, when making predictions about patient outcomes. The advent of advanced generative models, such as GPT-4, presents new opportunities for effectively extracting social and behavioral factors from unstructured clinical notes, further enhancing the accuracy and stability of ML algorithms in predicting patient outcomes. The results of our study have significant ramifications for improving ML in clinical decision support and patient outcome predictions, specifically highlighting the potential role of generative models like GPT-4 in advancing ML-based outcome predictions.


[Changes in the cardiovascular system in adenovirus infection in adults].
The effect of adenovirus infection on the cardiovascular system of 37 adult patients with CHD and without signs of CHD was studied. It was shown that adenovirus infection caused lesion of the cardiovascular system with few clinical signs but with distinct ECG changes. They occurred in the 1st and 2nd weeks and were rather unstable. The most stable and noticeable ECG changes were recorded in CHD patients with a previous history of myocardial infarction and when adenovirus infection was complicated by pneumonia.


Visible-Light-Mediated Oxidative Debenzylation Enables the Use of Benzyl Ethers as Temporary Protecting Groups.
The cleavage of benzyl ethers by catalytic hydrogenolysis or Birch reduction suffers from poor functional group compatibility and limits their use as a protecting group. The visible-light-mediated debenzylation disclosed here renders benzyl ethers temporary protective groups, enabling new orthogonal protection strategies. Using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as a stoichiometric or catalytic photooxidant, benzyl ethers can be cleaved in the presence of azides, alkenes, and alkynes. The reaction time can be reduced from hours to minutes in continuous flow.


[Constitutional chromosome anomalies and acute leukemia].
A review on the association between acute leukemias (AL) and constitutional chromosome abnormalities (CCA) is presented. AL, myeloblastic or lymphoblastic according to age are 18 to 20 times more frequent in Down Syndrome (DS) children than in non DS children. The incidence of acquired chromosome abnormalities is similar in leukemic cells of DS and non DS patients but the type of anomalies, in the leukemic myeloblastic cells of DS, are different : hyperdiploidy, excess of C, F and G. Gain of chromosomes 8, 19 and 22 would characterize leukemic myeloblasts in an early stage of differentiation. Recent data on transient leukemoid reactions show that a 21 in DS appears to be predisposing factor in the development of AL. Association between AL and other balanced or unbalanced CCA appears until now to be fortuitous.


[The acute visual hallucinosis in infancy. Clinical, neurophysiological and psychodevelopmental aspects and differential typology (author's transl)].
By introducing the definition "hallucinosis" (Wernicke) it has become possible to confine the psychoses of organic origin more closely. Therefore, this term should also be used in pediatry and pedopsychiatry in order to designate cases with corresponding clinical aspects. Thus, accordance to the phenomenological characteristics of such syndromes as described in this paper, it is justified to emphasize that the acute hallucinosis in children is a special type of disease as compared to other psychoses caused by exogenic influences in this age group. The 10 case reports deal with visual hallucinoses which turned out to be characteristically different compared to those in adults. Hallucinating children at the age of 3 to 9 years predominantly visualized animals and legendary beings. Contrary to findings in adults, scenic and systematized visions were scarcely noticed, which psychodevelopmentally may be attributed to the fact that creative power in children is still little pronounced. Etiologically intoxications and infectious diseases were the cause for the visual hallucinations of the 10 children described. In the development of visual hallucinations somatic and psychic factors are significant. They have been discussed on the basis of today's knowledge. As today, however, there exists no satisfactory theory concerning the conditions favoring the development of hallucinations. To explain the somatogenesis of visual hallucinations three theories have been outlined, based on the present neurophysiological findings. It has been worked out that especially in children emotion plays an essential role in the origin of hallucinations. In infancy and early school age, while rational control of reality is still suppressed to a great extent, domination of emotional life goes along with lack of differentiation. At the same time the difference between imagination and perception is still little precise; therefore, phenomena, impressing as hallucinations in the adult, occur with greater facility in children.


Opportunity lost? The major in mental health nursing in Australia.
The ongoing difficulty in educating and sustaining an adequate nursing workforce in mental health settings has been identified throughout the world. Different strategies have been implemented internationally to deal with this situation. In Australia major streams in mental health nursing were introduced in some Australian universities to promote mental health nursing as a viable career choice for nursing students. Fourteen universities had implemented or planned to implement a major stream in mental health nursing. From a survey of these programs a lack of consistency in the structure and content of programs was evident. For most programs the intakes had been relatively small, although retention rates appeared promising. To determine the extent majors in mental health nursing introduced in Australia have been sustained since their implementation. Cross-sectional design. A survey instrument used in 2010 was readministered in 2013. Schools of Nursing in Australia where a major in mental health nursing had been implemented or planned. Subject and program coordinators. The survey was administered via email. Of the 14 majors in mental health nursing originally proposed or implemented, only five were remaining, three had never commenced the program despite plans to do so and six programs once operating had now ceased. Numbers of students undertaking the program have tended to be small. Few modification changes in the structure and content in the majors since initial implementation were reported. The findings suggest that the major in mental health nursing has not been a successful or sustainable strategy, and therefore is unlikely to contribute positively to strengthening the mental health nursing workforce. The availability of sufficient graduate nurses with the interest and skills to pursue a career in mental health nursing is becoming urgent. The adequate resourcing of strategies to address this issue needs to be considered as a matter of priority.


Direct adaptive control of wind energy conversion systems using Gaussian networks.
Grid connected wind energy conversion systems (WECS) present interesting control demands, due to the intrinsic nonlinear characteristics of windmills and electric generators. In this paper a direct adaptive control strategy for WECS control is proposed. It is based on the combination of two control actions: a radial basis zfunction network-based adaptive controller, which drives the tracking error to zero with user specified dynamics, and a supervisory controller, based on crude bounds of the system's nonlinearities. The supervisory controller fires when the finite neural-network approximation properties cannot be guaranteed. The form of the supervisor control and the adaptation law for the neural controller are derived from a Lyapunov analysis of stability. The results are applied to a typical turbine/generator pair, showing the feasibility of the proposed solution.


Real-space evidence of the equilibrium ordered bicontinuous double diamond structure of a diblock copolymer.
The ordered bicontinuous double diamond (OBDD) structure has long been believed to be an unstable ordered network nanostructure, which is relative to the ordered bicontinuous double gyroid (OBDG) structure for diblock copolymers. Using electron tomography, we present the first real-space observation of the thermodynamically stable OBDD structure in a diblock copolymer composed of a stereoregular block, syndiotactic polypropylene-block-polystyrene (sPP-b-PS), in which the sPP tetrapods are interconnected via a bicontinuous network with Pn3̄m symmetry. The OBDD structure underwent a thermally reversible order-order transition (OOT) to OBDG upon heating, and the transition was accompanied with a slight reduction of domain spacing, as demonstrated both experimentally and theoretically. The thermodynamic stability of the OBDD structure was attributed to the ability of the configurationally regular sPP block to form helical segments, even above its melting point, as the reduction of internal energy associated with the helix formation may effectively compensate the greater packing frustration in OBDD relative to that in the tripods of OBDG.


Kyphectomy and Pedicular Screw Fixation with Posterior-Only Approach in Pediatric Patients with Myelomeningocele.
Defective posterior spinal arch and paraspinal musculature lead to progressive kyphosis in patients with myelomeningocele. Kyphosis decreases the patients' functional status and quality of life. To correct or prevent further deterioration, different surgical techniques have been introduced. Our aim is to present our clinical experience in kyphectomy and pedicle screw fixation with a posterior-only approach in pediatric patients with myelomeningocele and to discuss the technique with a review of the literature. Four patients with lumbar and 2 patients with thoracolumbar kyphosis (female:male ratio = 1:5) secondary to myelomeningocele were operated between January 2009 and October 2012. The median age was 5.5 years (range = 3-10 years). The criteria of the patient selection for the procedure were progression of kyphosis angle, impaired truncal balance and cosmetic deformity. In this retrospective study, we performed chart reviews for demographic and clinical data. We measured the pre- and postoperative kyphosis angles by using the Cobb method on lateral x-rays. The mean preoperative kyphosis angle was 114.3° (range = 91-136°). The mean operative time was 171.7 min (range = 110-220 min). The mean intraoperative blood loss was 450 cc (range = 300-700 cc). The postoperative mean kyphosis angle was 28.2° (range = 13-33°). Five patients had skin breakdown. After osteofusion was established, those 5 patients' instrumentations were explanted. No acute or immediate postoperative complications occurred. Other complications were pneumonia and urinary tract infection. In the long term, 2 patients died due to pneumonia and slit-ventricle syndrome, respectively. Kyphectomy and pedicle screw instrumentation with the posterior-only approach dramatically reduces the kyphosis angle that develops in patients with myelomeningocele. The method itself is less time-consuming and leads to less intraoperative blood loss compared to other methods used for this patient population. Skin breakdown is the most common short-term complication.


Buccal fat pad reconstruction for oral submucous fibrosis.
Oral submucous fibrosis is a chronic debilitating disease characterized by gradually increasing fibrosis of the oral cavity and pharynx, mainly the buccal mucosa, resulting in trismus. Prepotency of the disease is seen in the Indian subcontinent, with its highest incidence in South India due to various deleterious habits. In spite of the numerous medical modalities employed in the management of oral submucous fibrosis, occasionally surgical intervention becomes inevitable. Various flaps have been used to reconstruct the surgical defects following excision of fibrous bands. Undoubtedly; the buccal fat pad remains the most versatile because of its excellent blood supply and minimal donor site morbidity. Here we present a case of severe oral submucous fibrosis surgically treated and reconstructed using buccal fat pad.


Losartan reduces albuminuria in patients with essential hypertension. An enalapril controlled 3 months study.
Elevated urinary albumin excretion is a common feature of essential hypertension which may be reduced by ACE-inhibition through independent reductions of both systemic and intraglomerular pressure. A concurrent inhibition of bradykinin breakdown may be involved. A double-blind, randomized, 12 weeks study of the effects on enalapril 20 mg (n = 46) vs losartan 50 mg daily (n = 47) on blood pressure, albuminuria, fasting blood glucose, and lipids in 57 male and 36 female patients with essential hypertension. Blood pressure was similarly reduced during both treatments: enalapril 156/102 (15/5) (mean [SD] to 142/92 [14/7]) mmHg, losartan: 159/103 (17/6) to 149/94 (21/9) mmHg, both P < 0.001. Urinary albumin to creatinine ratio was significantly reduced during losartan (from 1.14(x/divided by 2.48) (geometric mean (x/divided by antilog SD) to 0.81 (x/divided by 2.43) mg/mmol, P < 0.01), as well as during enalapril (from 0.95 (x/divided by 2.45) to 0.73 (x/divided by 2.00) mg/mmol, both P < 0.05). The effect on albuminuria was especially evident in patients with microalbuminuria. Fasting blood glucose, total cholesterol, HDL-cholesterol and triglycerides were unchanged during losartan, whereas minor reductions were found in all lipids during enalapril. No difference was observed between the groups. Enalapril 20 mg and losartan 50 mg daily reduce blood pressure equally in essential hypertensive patients. No adverse effects were seen on glucose and lipid concentrations. Losartan treatment reduces albuminuria at least as effectively as enalapril, suggesting that glomerular leakage of albumin is profoundly affected by the effects angiotensin II.


Viologen-phosphorus dendrimers exhibit minor toxicity against a murine neuroblastoma cell line.
Dendrimers containing viologen (derivatives of 4,4'-bipyridyl) units in their structure have been demonstrated to exhibit antiviral activity against human immunodeficiency virus (HIV-1). It has also recently been revealed that novel dendrimers with both viologen units and phosphorus groups in their structure show different antimicrobial, cytotoxic and hemotoxic properties, and have the ability to influence the activity of cholinesterases and to inhibit α-synuclein fibrillation. Since the influence of viologen-phosphorus structures on basic cellular processes had not been investigated, we examined the impact of such macromolecules on the murine neuroblastoma cell line (N2a). We selected three water-soluble viologen-phosphorus (VPD) dendrimers, which differ in their core structure, number of viologen units and number and type of surface groups, and analyzed several aspects of the cellular response. These included cell viability, generation of reactive oxygen species (ROS), alterations in mitochondrial activity, morphological modifications, and the induction of apoptosis and necrosis. The MTT assay results suggest that all of the tested dendrimers are only slightly cytotoxic. Although some changes in ROS formation and mitochondrial function were detected, the three compounds did not induce apoptosis or necrosis. In light of these results, we can assume that the tested VPD are relatively safe for mouse neuroblastoma cells. Although more research on their safety is needed, VPD seem to be promising nanoparticles for further biomedical investigation.


Experimental double-differential cross sections and derived kerma factors for oxygen at incident neutron energies from reaction thresholds to 65 MeV.
The double-differential cross sections (energy spectra) for the (n, px), (n, dx), (n, tx) and (n, rx) reactions on oxygen have been measured for nine incident neutron energies in the range 25 to 65 MeV at lab angles between 20 degrees and 160 degrees in steps of 10 degrees. From these measurements, the energy differential cross sections have been determined and consequently the partial and total kerma factors. Based on the obtained experimental partial kerma factors in the incident neutron energy range 25-65 MeV, a procedure is proposed for the extrapolation of these values to the reaction threshold energy of each measured reaction channel. Results of the experimental double-differential, energy differential and total cross sections are presented. The deduced partial and total kerma factors of the present work are compared with results of previous measurements and theoretical predictions.


Mean frequency and signal amplitude of the surface EMG of the quadriceps muscles increase with increasing torque--a study using the continuous wavelet transform.
The continuous wavelet transform (CWT), a time-frequency method, was used when calculating mean frequency of the power spectrum (MNF) and signal amplitude (RMS) of the surface EMG to investigate their relationships to force during a gradually increasing knee extension (ramp). Based upon the CWT, MNF was redefined to include time dependence on the EMG signal frequency contents, the short-time MNF (STMNF). Surface EMG was recorded from vastus lateralis, rectus femoris and vastus medialis in 21 clinically healthy subjects during a brief, gradually increasing contraction up to 100% of a maximum voluntary contraction (MVC), with a duration of approximately 10 s. The relationships between the EMG variables and force using linear regression were determined for each subject. For vastus lateralis, we also investigated if certain aspects of the muscle morphology (i.e., proportions and areas of different fibre types) influenced the EMG-force relationship. For the majority of subjects (17-18 out of 21 subjects) there were significant positive correlations between STMNF and force in the three muscles. No sex differences were found in intercepts or regression coefficients of STMNF. The muscle morphology had a significant influence on the STMNF-force intercept and the regression coefficient. Positive and highly significant linear correlations between RMS and force were found for all subjects and all three muscles.In conclusion, time frequency methods can be applied when investigating EMG during brief contractions associated with non-stationarity. In a great majority of the subjects, and in the three muscles, significant linear force dependencies were found for STMNF. Thus, when evaluating muscle fatigue, e.g., in ergonomic situations, it is important to consider the force level as one factor that can influence the results. Morphological variables (fibre proportions and fibre areas) influenced the STMNF-force relationship in vastus lateralis.


Short-term effects of lower oil dried distillers grains with solubles in laying hen rations.
Extraction of oil from dried distillers grains has become a common practice among US ethanol producers. The valuable oil has been diverted to markets other than poultry feed, leaving new dried distillers grains with solubles (DDGS) products higher in fiber and purportedly lower in ME. This study compared 3 DDGS products with 10.3, 7.3, or 5.2% ether extract, respectively, with a corn-soy control ration in young Bovan laying hens for a feeding period from 20 to 33 wk of age. The DDGS was fed at the rate of 20% of the ration. Lower oil content of DDGS had no effect on short-term egg production parameters: feed intake, egg production, egg weight or mass, and hen weight gain. The diets containing lower fat DDGS (5.2%) did have reduced AME and kilocalories per day intake for laying hens. For each percent reduction in oil from a normal DDGS sample (10.3%) to medium oil (7.3%) DDGS, AME decreased 42.3 kcal/kg of diet. However, total kilocalories per day intake did sustain good egg production during this short trial.


Insights into the labeling effect of Kidney Donor Performance Index reporting: The Australian experience.
In 2016, Australia began reporting the Kidney Donor Performance Index (KDPI) with all deceased donor kidney transplant offers despite this not being used in organ allocation rules, offering a unique opportunity to explore the "labeling effect" of KDPI reporting. We reviewed all kidneys retrieved for transplant in Australia from 2015 to 2018 and analyzed the association of KDPI reporting with organ nonutilization, number of offer declines, and donor/recipient age and longevity matching. Analyses were stratified by organ failure risk: higher risk (KDPI > 80%), standard risk (KDPI 20% to 79%), and lower risk (KDPI 0% to 20%). There was no significant difference in organ nonutilization post KDPI reporting either overall or for higher-risk kidneys. KDPI reporting was associated with an increase in offer declines for both higher-risk (incidence risk ratio 1.45, P = .007) and standard-risk (incidence risk ratio 1.22, P = .021) kidneys but not for lower-risk organs. There was a significant increase in recipient age and expected posttransplant survival score for higher-risk kidneys but no differences among other groups. We conclude that although KDPI reporting in Australia has been associated with an increased number of offer declines for higher-risk kidneys, this has not resulted in increased nonutilization and may have contributed to more appropriate use of these organs.


Sample stacking by acetonitrile-salt mixtures.
A new type of sample stacking for capillary zone electrophoresis (CZE), which occurs in mixtures of acetonitrile and high concentrations of inorganic salts in the sample, is described here. It is different from the stacking obtained in low-ionic-strength buffers in the sample since it is improved by the presence of a high concentration of ions while the latter type deteriorates in the presence of such ions. It is based on the addition of acetonitrile to the sample to eliminate proteins by precipitation. From a practical point of view, the stacking in acetonitrile is more useful since it both removes proteins and counteracts the deleterious effects of high concentrations of inorganic ions present in the sample. Furthermore, it allows a larger volume of the sample to be loaded on the capillary. More than one-third of the capillary can be loaded with the sample by this type of stacking, producing a high sample concentration with good resolution and increased sensitivity of detection. It is well suited for analyzing small molecules in serum, urine, food, tissues, and industrial samples. Furthermore, since proteins are eliminated, the capillary does not need thorough washings between samples, speeding up the analysis and extending the capillary life.


Different animal welfare orientations towards some key research areas of current relevance to pastoral dairy farming in New Zealand.
The New Zealand dairy industry needs to meet public expectations regarding animal welfare in order to retain the freedom to operate and achieve market success. Three key orientations towards animal welfare assessment have been identified, namely biological functioning, affective state and natural living, the last two of which are more recent foci for societal concern. Biological functioning was the first and most-studied aspect of animal welfare and continues to be important, but now the contribution of affective state to animal well-being is emphasised much more. Natural living, or naturalness, has received relatively less attention from animal welfare science. It is proposed that increasing the use of naturalness as a contextual reference point for considering species-specific behavioural expressions of affective state will enhance its inclusion in animal welfare assessment. Nevertheless, all three orientations need to be considered in order to evaluate the significance of welfare research findings. On this basis, five key aspects of the New Zealand dairy industry that have been the subject of recent research, due to the risk of them not meeting public expectations, are highlighted and discussed. The aspects are provision of shade and shelter, meeting targets for body condition, provision of comfortable surfaces for rearing calves, and for adult cows while off pasture, and pain relief for disbudding of calves. Research evidence indicates that the industry guidelines on body condition score, if met, would satisfy public expectations across the three orientations to animal welfare, whereas further work is needed on the other aspects. It is concluded that considering these three orientations to animal welfare when planning research and then evaluating the outcomes will help to promote the market success of the dairy industry in New Zealand.


Extracellular Vesicles (EVs) from Lung Adenocarcinoma Cells Promote Human Umbilical Vein Endothelial Cell (HUVEC) Angiogenesis through Yes Kinase-associated Protein (YAP) Transport.
Yes kinase-associated protein (YAP) plays an important role in angiogenesis and can promote the occurrence and development of many tumor types. However, whether YAP affects tumor angiogenesis in lung cancer, and its potential mechanism in lung cancer, are unknown. In this study, we explored the role of YAP in the angiogenesis of lung adenocarcinoma, and further illustrated its possible mechanism. The expression levels of YAP and the vascular endothelial marker protein CD31 were examined by immunohistochemistry and immunofluorescence in human lung adenocarcinoma tissues, revealing a possible positive correlation between YAP and CD31 in lung adenocarcinoma. The results of the western blotting (WB) of Human Umbilical Vein Endothelial Cells (HUVECs) after coculture with lung adenocarcinoma H1975 cells, H1975 cell-supernatants and H1975-derived EVs showed that YAP derived from H1975 cells can enter HUVECs via EVs. These results were confirmed by immunofluorescence. Finally, we generated H1975 low-YAP expression cells by transfecting the cells with a shYAP lentivirus, and confirmed that the low expression of YAP in H1975 cells inhibits HUVEC angiogenesis by reducing the amount of YAP that enters HUVECs. We found, for the first time, that YAP promotes angiogenesis in lung adenocarcinoma via EVs, at least partially. Our work may provide a promising method for lung cancer treatment by targeting angiogenesis in the future.


Correlation of electroretinographic findings and peripheral retinal nonperfusion in patients with sickle cell retinopathy.
This study examined the relationship between the proportion of peripheral retinal nonperfusion and electroretinogram measures in one untreated eye of 44 patients with sickle cell retinopathy. The proportion of peripheral retinal nonperfusion was derived from fluorescein angiographic frames covering 180 degrees of the temporal periphery. The extent of peripheral retinal capillary nonperfusion was greater in patients with peripheral retinal neovascularization compared with those without neovascularization. Reductions in electroretinogram a- and b-wave amplitudes were found in patients with and without neovascularization. However, such reductions were of greater frequency and magnitude in patients with neovascularization. Electroretinogram abnormalities were restricted to reductions in amplitude; implicit times were generally normal. In terms of the variables of the b-wave luminance-response function, abnormalities were restricted to reductions in the amplitude variable Rmax; values of logK and n were generally within the normal range. Across all patients, there was a significant negative correlation between electroretinogram amplitude measures and capillary nonperfusion, indicating that the electroretinogram provides information about the functional consequences of peripheral capillary nonperfusion in sickle cell retinopathy.


CD30 plays a role in T-dependent immune response and T cell proliferation.
CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily and expressed in both normal and malignant lymphoid cells. However, the role of CD30 in lymphopoiesis is not known. In this study, we showed CD30 was expressed both in T and B cells, but its deficiency in mice had no effect on T- and B-cell development. In fact, CD30 deficiency attenuated B-cell response to T-cell-dependent antigens. The impaired B cell response in CD30-deficient mice is caused by the reduction of activation-induced cytidine deaminase (AID) expression. Moreover, CD30-deficient mice exhibited decreased TCR-mediated T cell proliferation and slightly impaired TCR signaling. High-throughput RNA sequencing analysis revealed that CD30 deficiency led to a decrease of FOXO-autophagy axis in T cells upon TCR stimulation. Thus, CD30 positively regulates T-cell-dependent immune response and T cell proliferation.


Discovery of Potent Disheveled/Dvl Inhibitors Using Virtual Screening Optimized With NMR-Based Docking Performance Index.
Most solid tumors have their own cancer stem cells (CSCs), which are resistant to standard chemo-therapies. Recent reports have described that Wnt pathway plays a key role in self-renewal and tumorigenesis of CSCs. Regarding the Wnt/β-catenin pathway, Dvl (mammalian Disheveled) is an attractive target of drug discovery. After analyzing the PDZ domain of human Dvl1 (Dvl1-PDZ) using NMR, we subjected it to preliminary NMR titration studies with 17 potential PDZ-binding molecules including CalBioChem-322338, a commercially available Dvl PDZ domain inhibitor. Next, we performed virtual screening (VS) using the program GOLD with nine parameter sets. Results were evaluated using the NMR-derived docking performance index (NMR-DPI). One parameter set of GOLD docking showing the best NMR-DPI was selected and used for the second VS against 5,135 compounds. The second docking trial identified more than 1,700 compounds that exhibited higher scores than CalBioChem-322338. Subsequent NMR titration experiments with five new candidate molecules (NPL-4001, 4004, 4011, 4012, and 4013), Dvl1-PDZ revealed larger chemical shift changes than those of CalBioChem-322338. Finally, these compounds showed partial proliferation inhibition activity against BT-20, a triple negative breast cancer (TNBC) cell. These compounds are promising Wnt pathway inhibitors that are potentially useful for anti-TNBC therapy.


Effects of sodium cyanide upon swimming performance in guinea-pigs and the conferment of protection by pretreatment with p-aminopropiophenone.
The swimming performance of guinea-pigs was degraded following administration of sodium cyanide (NaCN) at doses which were not lethal for individual animals. Decrements in performance were observed two minutes following subcutaneous administration of NaCN, were maximal at 8-16 minutes and, at the highest dose tested, did not return to control levels until 64-128 minutes. Pretreatment with p-aminopropiophenone (PAPP) at a dose inducing 7-15% methemoglobinemia (met.Hb), 15-90 minutes after administration, protected animals against the effects of NaCN upon swimming performance. However, the protection decreased as the interval between PAPP and NaCN was increased from 15 to 75 minutes. These data suggested that NaCN may affect both motor and cognitive function in guinea-pigs. The relevance of this animal model for predicting the behavioural effects of cyanide poisoning for assessing the protective efficacy of pretreatment with PAPP in humans is discussed.


Computed tomography evaluation of residual root thickness after pre-flaring using gates Glidden drills: The sequence effect.
The aim of the present study is to evaluate the residual root thickness in mesiolingual (ML) canals of mandibular molars after pre-flaring using different sequences of Gates-Glidden (GG) drills. Computed tomography (CT) scans of the ML canals of 60 mandibular first molars were provided from areas within 1, 2, 3 and 4 mm of the furcation area and minimum initial root thickness (MIRT) of concave areas was measured at each level. The samples were divided into two groups (G1 and G2) which were prepared by the step-back and crown-down techniques, respectively. In both groups, anti-curvature filing was used. On secondary CT images of the samples in the same position, the minimum residual root thickness (MRRT) and the amount of removed dentin were analyzed by t-test and ANOVA. There was no significant difference for MIRT between the two groups. The MRRT was greater in the G2 group in all the sections, with no significant difference between them. The average of MRRT was not <0.5 mm in any of the groups or sections. Based on the results of this study when the appropriate root thickness is present initially, GG drills used in any sequence may be suitable, safe and cost effective for pre-flaring of mesial canals of mandibular first molars with preserving the root thickness of furcation areas.


Equity in digital healthcare - the case of Denmark.
As digital healthcare services are expanding in use and purpose in a Danish context so are the functionalities embedded in these, constituting citizens' access to healthcare services and personal health data. In Denmark, the impact of inequalities in digital healthcare remains largely unexplored, making it crucial to pay close attention to this aspect as the digital transformation of the sector progresses. According to the Danish Health Act (2019), the Danish healthcare system is required to ensure easy and equal access to healthcare, high-quality treatment, coherent patient pathways, freedom of choice, easy access to information, transparency, and short waiting times for every citizen. These are focal law-based requirements influenced by the digitalisation of healthcare. Hence, based on insights from a highly digitalised country, in this case, Denmark, this paper aims to initiate a discussion on inequities in digital healthcare, address current challenges, and consider future directions by elaborating on conceptual, ethical, evidence-informed, and methodological issues linked to inequities in digital healthcare. Specifically, this paper discusses why inequities in digital healthcare in a Danish context need increased attention, how health equity is embedded in Danish legislation and how it can be approached from an ethical perspective. The central focus revolves around the essential principles of empowerment, emancipation, and equity, which are being highlighted to emphasise that the digitalisation of healthcare should actively work towards preventing and avoiding the perpetuation of healthcare inequalities. The paper concludes by discussing future directions for ensuring a more sustainable, robust, and equitable digital healthcare system.


Plasticity in transmission strategies of the malaria parasite, Plasmodium chabaudi: environmental and genetic effects.
Parasites may alter their behaviour to cope with changes in the within-host environment. In particular, investment in transmission may alter in response to the availability of parasite resources or host immune responses. However, experimental and theoretical studies have drawn conflicting conclusions regarding parasites' optimal (adaptive) responses to deterioration in habitat quality. We analyse data from acute infections with six genotypes of the rodent malaria species Plasmodium chabaudi to quantify how investment in transmission (gametocytes) is influenced by the within-host environment. Using a minimum of modelling assumptions, we find that proportional investment in gametocytogenesis increases sharply with host anaemia and also increases at low parasite densities. Further, stronger dependence of investment on parasite density is associated with greater virulence of the parasite genotype. Our study provides a robust quantitative framework for studying parasites' responses to the host environment and whether these responses are adaptive, which is crucial for predicting the short-term and evolutionary impact of transmission-blocking treatments for parasitic diseases.


Variation between centers in technique and guidelines for liver biopsy.
Hospitals have few published guidelines to follow when performing a liver biopsy. In 1992, we began revising our protocol in an effort to institute new guidelines for our teaching hospitals. To assess the current practice of liver biopsy, we sent 500 multilingual questionnaires to international academic centers, and 85 U.S. centers were surveyed by telephone. The survey assessed: 1) patient preparation, 2) technical aspects of the biopsy, and 3) post-procedural care. One hundred and eighty international centers and 85 U.S. centers responded (total = 265). We found a wide variation in the practice of this surgical procedure at both national and international centers. Many Asian centers (73%) performed a bleeding time prior to liver biopsy. This practice was seen in only 36% of the U.S. centers. Most centers preferred platelet counts of 50,000/mm3 and above. The aspiration needle was more widely used in the U.S. (74%) and in many international centers, but Asian centers (61%) preferred a cutting needle. Thirty percent of Japanese centers performed more than 50% of their liver biopsies laparoscopically. Few laparoscopies were done at other centers. While about a quarter of the reported U.S., European, Asian, and South American centers observed patients for 4-6 hours after a biopsy, the majority of centers observed patients 10 hours or more. In addition to the wide variation seen, this survey provided us with an academic view of the contemporary practice of liver biopsy and an insight into how to redefine our present guidelines.


Vaccination induces rapid protection against bacterial pneumonia via training alveolar macrophage in mice.
Vaccination strategies for rapid protection against multidrug-resistant bacterial infection are very important, especially for hospitalized patients who have high risk of exposure to these bacteria. However, few such vaccination strategies exist due to a shortage of knowledge supporting their rapid effect. Here, we demonstrated that a single intranasal immunization of inactivated whole cell of Acinetobacter baumannii elicits rapid protection against broad A. baumannii-infected pneumonia via training of innate immune response in Rag1-/- mice. Immunization-trained alveolar macrophages (AMs) showed enhanced TNF-α production upon restimulation. Adoptive transfer of immunization-trained AMs into naive mice mediated rapid protection against infection. Elevated TLR4 expression on vaccination-trained AMs contributed to rapid protection. Moreover, immunization-induced rapid protection was also seen in Pseudomonas aeruginosa and Klebsiella pneumoniae pneumonia models, but not in Staphylococcus aureus and Streptococcus pneumoniae model. Our data reveal that a single intranasal immunization induces rapid and efficient protection against certain Gram-negative bacterial pneumonia via training AMs response, which highlights the importance and the possibility of harnessing trained immunity of AMs to design rapid-effecting vaccine.


ORCA3, a jasmonate-responsive transcriptional regulator of plant primary and secondary metabolism.
Biosynthesis of many classes of secondary metabolites in plants is induced by the stress hormone jasmonate. The gene for ORCA3, a jasmonate-responsive APETALA2 (AP2)-domain transcription factor from Catharanthus roseus, was isolated by transferred DNA activation tagging. Orca3 overexpression resulted in enhanced expression of several metabolite biosynthetic genes and, consequently, in increased accumulation of terpenoid indole alkaloids. Regulation of metabolite biosynthetic genes by jasmonate-responsive AP2-domain transcription factors may link plant stress responses to changes in metabolism.


Incretins and SGLT-2i Therapy of Type 2 Diabetes - Real Life Study of Their Therapeutic and Economic Effects.
Incretins [dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide 1 RA (GLP-1 RA)] and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) groups are now routinely used for type 2 diabetes therapy and comprise a large number of medicinal products. The long term therapeutic and economic effect of the incretins' and SGLT-2i in real life setting is not well documented. The goal of the current study is to analyze the cost and results of incretins and SGLT-2i based therapy for type 2 diabetes in Bulgaria. The study uses information about the changes in glycated hemoglobin (HbA1c) level from the National diabetes register for 6122 patients and cost paid by the National Health Insurance Fund (NHIF) for diabetes complications, and medicine prices. The results show that after the therapy patients achieved excellent diabetes control. There were no HbA1c values less than 6% before treatment. After the therapy, 3356 people showed values less than 7% HbA1c. It is considered very good diabetic control. The number of people with HbA1c above 8% is decreasing significantly. The number of people with values above 9% is decreasing by almost four times. HbA1c level decreases with the highest percentage for the patients treated with GLP-1 RA, followed by those treated with DPP-4i and SGLT-2i. For a year NHIF reimbursed 5.25 million BGN for incretins and SGLT-2i therapy. NHIF can save between 306 and 510 thousand BGN from incidents that have not occurred as a result of 5 years of therapy. Incretins [dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA)] and sodium-glucose linked transporter-2 inhibitors (SGLT-2i) therapy steadily decreases the HbA1c level, and risk of developing diabetic incidents is reduced to between 333 and 465 cases among 6122 treated patients. Avoided cost for therapy of diabetes incidents account for between 305 and 510 thousand BGN.


A century of research into the cause of cancer: is the new oncogene paradigm revolutionary?
Contemporary oncological research is predominantly characterised by genetic explanations, a situation which may be briefly denoted as the oncogene paradigm. This essay discusses why the new paradigm was perceived so attractive that it could take over the whole field of oncology within a time-span of less than two decades. It is argued that the revolutionary character of the oncogene paradigm stems from the fact that it transcends a dichotomy which has kept experimental cancer research divided for more than three quarters of a century. This concerns the dichotomy between so-called exogenous and endogenous explanations of cancer causation. This essay mainly focuses on the role of the exogenous/endogenous dichotomy in the reception of research on oncogenic viruses, especially discussing the work of Nobel laureate Peyton Rous on cancer viruses at the Rockefeller Institute. Rous was severely criticised by James Ewing, director of the Memorial Hospital for Cancer and Allied Diseases in New York, who held the idea that the origin of cancer was based in the cell. The twentieth century controversy over oncogenic viruses is placed in the context of the intense discussion over causality in medicine during the first decades of the twentieth century in Germany. It is argued that the oncogene paradigm may be seen as revolutionary because it succeeded in uniting the exogenous and endogenous explanations of cancer in a single paradigm.


Solitary rectal ulcer syndrome in children: a literature review.
Solitary rectal ulcer syndrome (SRUS) is a benign and chronic disorder well known in young adults and less in children. It is often related to prolonged excessive straining or abnormal defecation and clinically presents as rectal bleeding, copious mucus discharge, feeling of incomplete defecation, and rarely rectal prolapse. SRUS is diagnosed based on clinical symptoms and endoscopic and histological findings. The current treatments are suboptimal, and despite correct diagnosis, outcomes can be unsatisfactory. Some treatment protocols for SRUS include conservative management such as family reassurance, regulation of toilet habits, avoidance of straining, encouragement of a high-fiber diet, topical treatments with salicylate, sulfasalazine, steroids and sucralfate, and surgery. In children, SRUS is relatively uncommon but troublesome and easily misdiagnosed with other common diseases, however, it is being reported more than in the past. This condition in children is benign; however, morbidity is an important problem as reflected by persistence of symptoms, especially rectal bleeding. In this review, we discuss current diagnosis and treatment for SRUS.


High levels of plasma cortisol and impaired hypoosmoregulation in a mutant medaka deficient in P450c17I.
scl is a spontaneous medaka mutant deficient in P450c17I, which is required for production of sex steroids, but not of cortisol, the major role of which is osmoregulation in teleost fish. The scl mutant provides a new model to study the functions of these hormones. We first found that fish homozygous for this mutation have plasma cortisol constitutively at a high physiological level (1000 nM). Since we previously showed that this level reversed the seawater-type differentiation of the medaka gastrointestinal tract, hypoosmoregulation of the scl mutant was analyzed. Muscle water contents in freshwater were normal in scl homozygotes, but the contents were lower than those of the wild type (WT) after seawater transfer. There were no differences in gill mRNA levels of corticosteroid receptors or ion transporters between scl homozygotes and WT. In the intestine, expression of glucocorticoid receptors and Na(+)/K(+)/2Cl(-) cotransporter were induced in WT during seawater acclimation, but not in scl homozygotes. The high plasma cortisol may prevent hypoosmoregulation by inhibition of increased intestinal water absorption, essentially by the Na(+)/K(+)/2Cl(-) cotransporter, in seawater.