H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells.
Influenza A virus can induce nasal inflammation by stimulating the death of nasal mucosa epithelium, however, the mechanism is not clear. In this study, to study the causes and mechanisms of nasal mucosa epithelial cell death caused by Influenza A virus H1N1, we isolated and cultured human nasal epithelial progenitor cells (hNEPCs) and exposed them to H1N1 virus after leading differentiation. Then we performed high-resolution untargeted metabolomics and RNAseq analysis of human nasal epithelial cells (hNECs) infected with H1N1 virus. Surprisingly, H1N1 virus infection caused the differential expression of a large number of ferroptosis related genes and metabolites in hNECs. Furthermore, we have observed a significant reduction in Nrf2/KEAP1 expression, GCLC expression, and abnormal glutaminolysis. By constructing overexpression vector of GCLC and the shRNAs of GCLC and Keap1, we determined the role of NRF2-KEAP1-GCLC signaling pathway in H1N1 virus-induced ferroptosis. In addition, A glutaminase antagonist, JHU-083, also demonstrated that glutaminolysis can regulate the NRF2-KEAP1-GCLC signal pathway and ferroptosis. According to this study, H1N1 virus can induce the ferroptosis of hNECs via the NRF2-KEAP1-GCLC signal pathway and glutaminolysis, leading to nasal mucosal epithelial inflammation. This discovery is expected to provide an attractive therapeutic target for viral-induced nasal inflammation.


Barrier methods: renewed interest, but more research needed.
At a recent major international workshop held in Guatemala, the state of the art of barrier contraception was examined. While there are promising leads to new methods, none is likely to be available in the near future.


Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line.
It has been shown that some types of tumour cells produce activated transforming growth factor beta-1 (TGF-beta 1). However, the mechanism for the activation of TGF-beta 1 derived from tumour cells has not been fully elucidated. The present study was undertaken to characterise an activator of latent TGF-beta 1 secreted from a human gastric cancer cell line, KATO-III. Western blot analyses using antibodies for TGF-beta 1, latency associated peptide (LAP) and latent TGF-beta 1-binding protein (LTBP) revealed that, in the cell lysate of KATO-III, TGF-beta 1 protein was expressed as a small latent complex of TGF-beta 1 and LAP. This was also confirmed by a gel chromatographic analysis of the cell lysate obtained from KATO-III. A 2.5 kb transcript of TGF-beta 1 mRNA was detected in KATO-III cells by Northern blot analysis. A gel chromatographic analysis of the conditioned medium from KATO-III cells revealed, in addition to the active form of TGF-beta 1, a factor which activated latent TGF-beta 1 from NRK-49F cells at fractions near a molecular size of 65,000. This factor was inactivated by heat (100 degrees C), acidification, trypsin and serine protease inhibitors. TGF-beta 1 activity in KATO-III cell lysate was not detected in the untreated state, but potent TGF-beta 1 activity was detected after acid treatment. These results suggest that KATO-III releases not only a latent TGF-beta 1 complex but also a type of serine protease, different from plasmin, plasminogen activator, cathepsin D, endoglycosidase F or sialidase, which activates the latent TGF-beta 1 complex as effectively as acid treatment.


Viability of spores after repeated freezing and thawing shocks.
Survival of spores of the fungus Rhizopus nigricans after repeated freezing and thawing was investigated. The cooling rate was 10(4) degrees C/min. Dry spores were fully inactive after 32 repeated shocks. About one-half of spores were killed after 8 repetitions. The water content did not change the resistance, swollen spores reacted to shocks much like dry ones. The sensitivity of spores to freezing-thawing shocks increased considerably when the spores changed from the dormant to the active state. Already after a 30 min cultivation of spores in the nutrient medium two freezing and thawings were sufficient for inactivation of 60% spores. After a 90 min cultivation one freezing and one thawing were sufficient to inactivate practically all spores.


Bond durability when applying phosphate ester monomer-containing primers vs. self-adhesive resin cements to zirconia: Evaluation after different aging conditions.
This study aimed to evaluate bond durability when applying 2 phosphate ester monomer-containing self-adhesive resin cements alone, versus a combination of phosphate ester monomer-containing primer conditioning plus 2 conventional resin cements requiring primers, to zirconia after different artificial aging methods. We cemented air-abraded zirconia plates to composite resin cylinders with self-adhesive resin cements (MS; RU) alone or cemented them with traditional resin cements (ZRV; ZVN) after pre-conditioning with a zirconia primer. A shear bond strength (SBS) test were performed after subjecting them to 19 different aging conditions (n = 15) comprising 30,000× thermocycles, air storage at room temperature (RT), water storage at RT, or at 37 °C for 24 h, 1 week, 1, 3, 6, and 12 months. Zirconia powders mixed with zirconia primer or 2 self-adhesive resin cements were characterized by X-ray photoelectron spectroscopy. Groups MS and ZVN obtained the highest SBS after all of aging methods. SBS after 6 months of storage was similar to SBS after 24 h of storage, while both were higher than SBS after 1 year of storage. Water storage at 37 °C provided higher SBS than RT water storage did. We detected a Zr-O-P bond in both self-adhesive resin cement/zirconia powder mixtures. Application of self-adhesive resin cements alone could be an alternative to pre-conditioning with a zirconia primer followed by the application of conventional resin cements. Formation of Zr-O-P bonds contributed to the bonding improvement of self-adhesive resin cements. Different aging conditions affected SBS values.


Relationship between Adenosine Deaminase Activity in the Cerebral Cortex and the Stimulating Effect of Caffeine in Adult Wistar Rats of Different Ages.
The aim of this study was to test the hypothesis that the higher the activity of adenosinedeaminase (ADA) in the brain, the greater should be the motor activity of animals, and possibly the stronger the psychostimulant effect of caffeine. We studied the effect of caffeine (10 and 20 mg/kg) on the motor activity and ADA activity in the frontal cortex of the brain in 2- and 5-month-old rats with different levels of spontaneous motor activity. Total motor activity significantly decreased with age, which was accompanied by a decrease in ADA activity. Administration of caffeine in a dose of 10 mg/kg stimulated motor activity in both 2- and 5-month-old animals, while ADA activity decreased in 2-month-old rats and increased in 5-month-old animals. Administration of caffeine in a dose of 20 mg/kg did not change the motor activity, however, in 5-month-old animals it led to an even greater increase in ADA activity. Thus, the age-related decrease in motor activity can be due to a decrease in ADA activity. However, the effect of caffeine on motor activity is not directly related to ADA activity in the cerebral cortex.


Visual disturbance by lymphocytic hypophysitis in a non-pregnant woman with systemic lupus erythematosus.
The authors present the case of a patient with systemic lupus erythematosus who developed visual disturbance and amenorrhea. Though the clinical and radiological findings resembled those of pituitary adenoma, the patient was finally diagnosed as having lymphocytic hypophysitis after the operation. We briefly describe this relatively rare entity in relation to its autoimmune pathogenesis.


Recent strategies for electrochemical sensing detection of miRNAs in lung cancer.
MicroRNAs (miRNAs) associated with lung cancer are diversifying. MiR-21, Let-7, and miR-141 are common diagnostic targets. Some new lung cancer miRNAs, such as miR-25, miR-145, and miR-126, have received increasing attention. Although various techniques are available for the analysis of lung cancer miRNAs, electrochemistry has been recognized for its high sensitivity, low cost, and rapid response. However, how to realize the signal amplification is one of the most important contents in the design of electrochemical biosensors. Herein, we mainly introduce the amplification strategy based on enzyme-free amplification and signal conversion, including non-linear HCR, catalytic hairpin assembly (CHA), electrochemiluminescence (ECL), and Faraday cage. Furthermore, new progress has emerged in the fields of nanomaterials, low oxidation potential, and simultaneous detection of multiple targets. Finally, we summarize some new challenges that electrochemical techniques may encounter in the future, such as improving single-base discrimination ability, shortening electrochemical detection time, and providing real body fluid samples assay.


The effects of cardiolipin on the structural dynamics of the mitochondrial ADP/ATP carrier in its cytosol-open state.
Cardiolipin (CL) has been shown to play a crucial role in regulating the function of proteins in the inner mitochondrial membrane. As the most abundant protein of the inner mitochondrial membrane, the ADP/ATP carrier (AAC) has long been the model of choice to study CL-protein interactions, and specifically bound CLs have been identified in a variety of crystal structures of AAC. However, how CL binding affects the structural dynamics of AAC in atomic detail remains largely elusive. Here we compared all-atom molecular dynamics simulations on bovine AAC1 in lipid bilayers with and without CLs. Our results show that on the current microsecond simulation time scale: 1) CL binding does not significantly affect overall stability of the carrier or structural symmetry at the matrix-gate level; 2) pocket volumes of the carrier and interactions involved in the matrix-gate network become more heterogeneous in parallel simulations with membranes containing CLs; 3) CL binding consistently strengthens backbone hydrogen bonds within helix H2 near the matrix side; and 4) CLs play a consistent stabilizing role on the domain 1-2 interface through binding with the R30:R71:R151 stacking structure and fixing the M2 loop in a defined conformation. CL is necessary for the formation of this stacking structure, and this structure in turn forms a very stable CL binding site. Such a delicate equilibrium suggests the strictly conserved R30:R71:R151stacking structure of AACs could function as a switch under regulation of CLs. Taken together, these results shed new light on the CL-mediated modulation of AAC function.


Patient preference attributes in eHealth interventions for cancer-related fatigue: A scoping review.
Cancer-related fatigue (CRF) is one of the most reported long-term effects breast cancer patients experience after diagnosis. Many interventions for CRF are effective, however, not for every individual. Therefore, intervention advice should be adjusted to patients' preferences and characteristics. Our aim was to develop an overview of eHealth interventions and their (preference sensitive) attributes. eHealth interventions were identified using a scoping review approach. Eligible studies included breast cancer patients and assessed CRF as outcome. Interventions were categorised as physical activity, mind-body, psychological, 'other' or 'combination'. Information was extracted on various (preference sensitive) attributes, like duration, intensity, peer support and costs. Thirty-five interventions were included and divided over the intervention categories. (Preference sensitive) attributes varied both within and between these categories. Duration varied from 4 weeks to 6 months, intensity from daily to own pace. Peer support was present in seven interventions and costs were known for six. eHealth interventions exist in various categories, additionally, there is much variation in (preference sensitive) attributes. This provides opportunities to implement our overview for personalised treatment recommendations for breast cancer patients struggling with CRF. Taking into account patients' preferences and characteristics suits the complexity of CRF and heterogeneity of patients.


Substance P-like immunoreactivity in human sympathetic ganglia.
Substance P-like immunoreactive nerve fibres and terminals are found in the human sympathetic paravertebral ganglia in connection with postganglionic neurones. Substance P may act as neurotransmitter or neuromodulator in the autonomic transmission in man.


Surgical treatment and long-term outcomes of thalamic cavernous malformations.
Resection of thalamic cavernous malformations (CMs) is controversial. The goals of this study were to evaluate the outcome of thalamic CMs after surgical resection, assess predictors of prognosis, and review the literature. The authors used the modified Rankin scale (mRS) to retrospectively evaluate the presentation, surgery, and outcomes of 27 consecutive patients who underwent thalamic CMs microresection using six different approaches between 1998 and 2010. Forty-eight hemorrhages occurred in 27 patients (13 men, 14 women; mean age 33.9 years) with a preoperative mRS score of 2.6 ± 1.0 and a preoperative bleeding rate per patient year of 5.2%. Complete resection was achieved in 26 patients (96.3%) without surgical mortality. The postoperative mRS score at discharge was 1.9 ± 1.0. One lesion rebled 1 month after complete surgical resection. After a mean follow-up duration of 48.7 ± 43.2 months, the mean mRS score was 1.2 ± 1.2 and the postoperative rebleeding rate was 0.91% per patient-year. With regard to neurological function, 81.5% of patients improved, 11.1% stabilized, and 7.4% worsened. Good outcomes (mRS score ≤2, living independently) were achieved in 21 patients (77.8%). Long-term surgical morbidity was observed in five patients (18.2%). A multivariate logistic regression analysis identified age (<40 years) as the only predictor of the postoperative mRS score (≤ 2) (odds ratio, 1.24, 95% confidence interval, 1.02-1.52; P = 0.035). To our knowledge, this is the largest case series reported in the literature to date. Patients with thalamic CMs can obtain a favorable prognosis using microsurgery; an appropriate microsurgical approach contributes to an excellent outcome.


Atherosclerosis precursors in Finnish children and adolescents. XIII. Serum and hair copper and zinc concentrations.
The copper and zinc status of 3-18-year-old Finnish children was estimated by analysing 3,480 serum copper and zinc concentrations, 853 hair copper and 868 hair zinc concentrations. Both copper and zinc have been proposed to be connected with the pathogenesis of cardiovascular diseases. In addition, zinc is essential for normal growth and development. The mean serum copper concentration of 3-year-old children was 21.2 mumol/l and the concentration was significantly lower in older age groups. The average serum zinc concentration showed a narrow variation between 14.1 and 15.0 mumol/l in all age groups, nevertheless girls had significantly lower and boys higher values with increasing age. The distribution of hair copper concentration was skewed within the age groups; the median varied between 9.7 micrograms/g and 29.8 micrograms/g for 3-year-old urban girls and 18-year-old rural girls, respectively. Some rural girls had exceptionally high hair copper levels. Hair zinc concentrations increased with age. In the three youngest age groups (3, 6 and 9 years) the distribution was skewed and the levels low compared with results from the USA where a zinc concentration below 30 micrograms/g is found to be associated with the zinc deficiency syndrome.


Protein acetylation sites mediated by Schistosoma mansoni GCN5.
The transcriptional co-activator GCN5, a histone acetyltransferase (HAT), is part of large multimeric complexes that are required for chromatin remodeling and transcription activation. As in other eukaryotes, the DNA from the parasite Schistosome mansoni is organized into nucleosomes and the genome encodes components of chromatin-remodeling complexes. Using a series of synthetic peptides we determined that Lys-14 of histone H3 was acetylated by the recombinant SmGCN5-HAT domain. SmGCN5 was also able to acetylate schistosome non-histone proteins, such as the nuclear receptors SmRXR1 and SmNR1, and the co-activator SmNCoA-62. Electron microscopy revealed the presence of SmGCN5 protein in the nuclei of vitelline cells. Within the nucleus, SmGCN5 was found to be located in interchromatin granule clusters (IGCs), which are transcriptionally active structures. The data suggest that SmGCN5 is involved in transcription activation.


One-for-All Nanoplatform for Synergistic Mild Cascade-Potentiated Ultrasound Therapy Induced with Targeting Imaging-Guided Photothermal Therapy.
Ameliorated therapy based on the tumor microenvironment is becoming increasingly popular, yet only a few methods have achieved wide recognition. Herein, targeting multifunctional hydrophilic nanomicelles, AgBiS2@DSPE-PEG2000-FA (ABS-FA), were obtained and employed for tumor treatment. In a cascade amplification mode, ABS-FA exhibited favorable properties of actively enhancing computed tomography/infrared (CT/IR) imaging and gently relieving ambient oxygen concentration by cooperative photothermal and sonodynamic therapy. Compared with traditional Bi2S3 nanoparticles, the CT imaging capability of the probe was augmented (43.21%), and the photothermal conversion efficiency was increased (33.1%). Furthermore, remarkable ultrasonic dynamic features of ABS-FA were observed, with increased generation of reactive oxygen species (24.3%) being obtained compared to Ce6, a commonly used sonosensitizer. Furthermore, ABS-FA exhibited obvious inhibitory effects on HeLa cell migration at 6 μg/mL, which to some extent, demonstrated its suppressive effect on tumor growth. A lower dose, laser and ultrasonic power, and shorter processing time endowed ABS-FA with excellent photothermal and sonodynamic effects. By mild cascade mode, the hypoxic condition of the tumor site was largely improved, and a suitable oxygen-rich environment was provided, thereby endowing ABS-FA with a superior synergistically enhanced treatment effect compared with the single-mode approach, which ultimately realized the purpose of "one injection, multiple treatment". Moreover, our data showed that ABS-FA was given with a biological safety profile while harnessing in vivo. Taken together, as a synergistically enhanced medical diagnosis and treatment method, the one-for-all nanoplatform will pave a new avenue for further clinical applications.


Apoplastic ascorbate contributes to the differential ozone sensitivity in two varieties of winter wheat under fully open-air field conditions.
We studied leaf apoplastic ascorbates in relation to ozone (O(3)) sensitivity in two winter wheat (Triticum aestivum L.) varieties: Yangfumai 2 (Y2) and Yangmai 16 (Y16). The plants were exposed to elevated O(3) concentration 27% higher than the ambient O(3) concentration in a fully open-air field from tillering stage until final maturity. The less sensitive variety Y16 had higher concentration of reduced ascorbate in the apoplast and leaf tissue by 33.5% and 12.0%, respectively, than those in the more sensitive variety Y2, whereas no varietal difference was detected in the decline of reduced ascorbate concentration in response to elevated O(3). No effects of O(3) or variety were detected in either oxidized ascorbate or the redox state of ascorbate in the apoplast and leaf tissue. The lower ascorbate concentrations in both apoplast and leaf tissue should have contributed to the higher O(3) sensitivity in variety Y2.


Positron computed tomography and its applications in the young.
Positron computed tomography is a new method for the external quantification of regional myocardial blood flow, substrate fluxes and biochemical reaction rates. It takes advantage of positron emitting tracers, metabolically active tracers, tracer kinetic principles and the quantitative imaging capabilities of the tomograph. To date, the technique has been used primarily for the study of ischemic heart disease and cardiomyopathies in adults. However, initial studies in infants and adolescents with regional cardiomyopathies provide evidence for its potential value in detecting disease at the biochemical level or at a stage that antedates clinical manifestations and cardiac dysfunction. Positron computed tomography is likely to contribute to our understanding of metabolic abnormalities associated with cyanotic or congenital heart disease and of the heart's maturation, and may become useful for optimal timing of corrective surgery. It allows the study of intrinsic myocardial disease in children, clarification of disease mechanisms and diagnosis of congenital metabolic disorders. It also might become useful for detecting disease when it is still confined to biochemical derangements and permit institution of therapy that may halt progression or even reversal of disease before irreversible morphologic changes develop. The high cost of equipment purchase and operation has precluded widespread use, but new technologic developments may make it possible to perform these studies at a cost comparable with that of other noninvasive procedures. Positron computed tomography may then become available as a routine diagnostic tool for studying pediatric cardiac disorders.


[Effect of stress on nucleic acid metabolism in the rat spleen and liver after a flight on the Kosmos-1129 biosatellite].
Changes in nucleic acid metabolism of the spleen and liver of rats flown for 18.5 days on Cosmos-112 were investigated. Postflight changes in the liver RNA synthesis after an additional stress effect (immobilization) in the flown rats were expressed to a lesser degree than in the controls. The DNA synthesis remained essentially at the preflight level. The tissue content of nucleic acids suggests that postflight the dystrophic changes induced by the additional stress effect increased. It is very likely that an exposure to space flight effects contributes to the depletion of compensatory mechanisms maintaining the normal level of metabolic processes.


Urinary metabolic signatures reflect cardiovascular risk in the young, middle-aged, and elderly populations.
The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30-50 years (cohort I, young), 50-70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention. KEY MESSAGES: • Cardiovascular risk in the young and elderly is underestimated. • The urinary metabolome reflects cardiovascular risk across all age groups. • Six metabolites constitute a metabolic signature of cardiovascular risk in young adults. • Middle-aged and elderly adults share a cardiovascular risk metabolic signature. • TMAO and glucuronate levels reflect cardiovascular risk across all age groups.


Central and peripheral glucocorticoid receptors are involved in the plasma cortisol response to an acute stressor in rainbow trout.
Cortisol, the primary circulating corticosteroid in teleosts, is elevated during stress following activation of the hypothalamus-pituitary-interrenal (HPI) axis. Cortisol exerts genomic effects on target tissues in part by activating glucocorticoid receptors (GR). Despite a well-established negative feedback loop involved in plasma cortisol regulation, the role of GR in the functioning of the HPI axis during stress in fish is still unclear. We used mifepristone (a GR antagonist) to suppress GR signaling in rainbow trout (Oncorhynchus mykiss) and assessed the resultant changes to HPI axis activity. We show for the first time that mifepristone caused a functional knockdown of GR by depleting protein expression 40-75%. The lower GR protein expression corresponded with a compensatory up-regulation of GR mRNA levels across tissues. Mifepristone treatment completely abolished the stressor-induced elevation in plasma cortisol and glucose levels seen in the control fish. A reduction in corticotropin-releasing factor (CRF) mRNA abundance in the hypothalamic preoptic area was also observed, suggesting that GR signaling is involved in maintaining basal CRF levels. We further characterized the effect of mifepristone treatment on the steroidogenic capacity of interrenal tissue in vitro. A marked reduction in cortisol production following adrenocorticotropic hormone stimulation of head kidney pieces was observed from mifepristone treated fish. This coincided with the suppression of steroidogenic acute regulatory protein, but not P450 side chain cleavage mRNA abundances. Overall, our results underscore a critical role for central and peripheral GR signaling in the regulation of plasma cortisol levels during stress in fish.


Correlations between self-rating and observer-rating of psychopathology in at-risk mental state and first-episode psychosis patients: influence of disease stage and gender.
Research findings on the correlations between self-rating and observer-rating of schizophrenic psychopathology are inconsistent and have rarely considered first-episode psychosis (FEP) and at-risk mental state (ARMS) for psychosis patients. This study investigates these correlations in ARMS and FEP patients and how they are moderated by disease stage and gender. In the Basel Früherkennung von Psychosen (FePsy) study, positive and negative psychotic and affective symptoms were rated in 126 ARMS and 94 FEP patients using two observer- and three self-rating scales. The agreement between self-rating and observer-rating and the moderating influence of disease stage and gender was quantified using Pearson correlation and multiple regression models. Correlations between self- and observer-rated subscales covering the same symptom dimension were low and mostly non-significant except for one correlation of positive and one of negative symptoms. There was no moderating influence of disease stage and gender on the correlations between self-rating and observer-rating except for one higher association in positive symptoms in FEP compared to ARMS and in women compared to men. However, these significant interaction effects did not withstand correction for multiple testing. This study suggests that the agreement between self-rating and observer-rating in FEP and ARMS patients is rather low, similar across symptom dimensions, and only partially dependent on disease stage and gender. However, low correlations between self-rating and observer-rating do not necessarily indicate that these patients have difficulties reporting their symptoms. They could also have occurred because the scales did not exactly cover the same symptom dimensions.


Affective reactions to pictures of ingroup and outgroup members.
A pervasive form of social categorization among humans is between us and them. In this study, we assessed emotional reactions when people viewed pictures depicting members of the same or different ethnic group. African American and European American participants viewed a series of pleasant and unpleasant pictures portraying either ingroup or outgroup members, while physiological, behavioral, and evaluative judgments were measured. Two hypotheses were assessed. The outgroup antipathy hypothesis predicts that people will respond to outgroup pictures with more negative affect than to ingroup pictures. In contrast, the ingroup empathy hypothesis predicts that people will show exaggerated (pleasant and unpleasant) affective responses to pictures of ingroup members, due to group identification or personal relevance. The data provided no support for the antipathy hypothesis, whereas facial EMG, skin conductance, rating, and viewing time data lent support to the ingroup empathy hypothesis, in which greater pleasure and displeasure were apparent when viewing ingroup pictures.


Impact of school sports injury.
Most injuries in school occur during sport. To explore the impact of sports injury in supervised school sport. A prospective study of sports injury in children of secondary school age presenting to the accident and emergency department. Each patient was identified on registration, matched with medical records after discharge, and contacted later by telephone to complete a structured interview. Patients were only included if their injury was sustained during supervised school sport. During the study period, 194 patients aged 11-18 attended the accident and emergency department with an injury, 51% of which occurred during school sport. Injuries occurred most commonly in rugby (43%), followed by physical education and games together (17.5%). Most injuries were x rayed (72%). Just over 12% of pupils lost no time from sport, most (71%) were back to sport within three weeks, and 2.7% were injured for more than eight weeks. Almost a third of parents needed to take time off from work to deal with the injured child. School sports injuries are important. They account for just over half of all injuries in secondary school children. They cause significant disruption to school and sport and have important implications for the wider family.


Comparison of the effects of angiotensin II receptor antagonist monotherapy and combination therapy with a diuretic on cardiac function in spontaneously hypertensive rats.
Losartan, an angiotensin II receptor blocker (ARB), has been reported to promote sodium excretion and show an enhanced antihypertensive effect when used in combination with hydrochlorothiazide (HCTZ). We investigated the effects of losartan monotherapy and combination therapy together with HCTZ on cardiac function in hypertensive rats using echocardiography. Spontaneously hypertensive rats (n = 21) fed on high-salt diet (8 % NaCl) for 13 weeks were randomly assigned to rats without medication (HS, n = 7), those medicated with ARB (ARB, losartan 30 mg/kg/day, n = 8), and those with ARB and HCTZ (ARB + HCTZ, losartan 30 mg/kg/day + HCTZ 10 mg/kg/day, n = 6). Blood pressure measurements and echocardiography were performed at 13, 17, and 29 weeks of age. After the end of the protocol, the proportion of cardiac muscle fibrosis was measured histologically. In the HS group, blood pressure and left ventricular mass/body weight (LV mass/BW) increased, and % fractional shortening (%FS) and early diastolic mitral annular velocity (e') decreased significantly with age. In the ARB group, although blood pressure and %FS were maintained, LV mass/BW increased with age as in the HS group, and e' decreased. In the ARB + HCTZ group, blood pressure decreased and LV mass/BW, %FS, and e' were maintained. The progression of myocardial fibrosis was clearly prevented in rats treated with ARB. ARB was shown to inhibit systolic disorder and myocardial fibrosis in hypertensive rats. Combination therapy proved to be more effective than monotherapy and is also effective in inhibiting diastolic disorders.


Broadening students' perspectives on literature review.
Student dietitians, in our experience, have demonstrated a very narrow perspective in using professional literature. The limited scope of reference journals used and the lack of ability to critically review the literature and abstract the essentials of a study were identified as problem areas. An assignment designed to address those inadequacies was developed, implemented, and evaluated. Following scientific guidelines, 11 students from the coordinated program in dietetics each reviewed three to five non-nutrition-specific journals and abstracted all nutrition-related articles published for the current 16-month period. The resulting 339 abstracts were compiled and distributed to faculty and facility preceptors. Improvement was evident in students' ability to critically evaluate and abstract an article. Faculty members, facility preceptors, and students evaluated the project as being worthwhile.


Deformed-helix ferroelectric liquid-crystal spatial light modulator that demonstrates high diffraction efficiency and 370-line pairs/mm resolution.
New liquid-crystal media and photoconductor materials are being utilized in spatial light modulators to increase their resolution, diffraction efficiency, speed, and sensitivity. A prototypical device developed for real-time holography applications has shown an 8% diffraction efficiency from a holographic grating with a spatial frequency of 370 line pairs/mm (lp/mm). At 18 lp/mm the device has demonstrated a 31% diffraction efficiency with a 600-micros hologram write time using 400-nJ/cm(2) write beams.


Potential use of grape and wine polysaccharide extracts as fining agents to modulate the volatile composition of Viura wines.
This paper describes for the first time the use of grape derived polysaccharide extracts as potential fining agents to modulate the volatile composition of Viura white wines. Polysaccharide extracts were obtained from white grape pomace, red wine pomace, white must, red must, white wine, and lees from white wine. Except for higher alcohols, the extracts from white pomace, red pomace and white lees increased the content of most volatile compounds after one and twelve months of bottle aging. They could be used to enhance fruity and floral aromas and reduce unpleasant aromas, showing as good modulators of white wine aroma. The presence of mannoproteins, glucans, non-pectic polysaccharides, and low molecular weight polysaccharides increased the content of most volatile families. Polysaccharides of medium molecular weight showed negative correlations with volatile contents. Our results support the use of winemaking by-products to obtain valuable polysaccharides, contributing to the circular economy.


ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule-associated proteins.
Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155, 2018. © 2017 Wiley Periodicals, Inc.


Introducing pharmacy students to the structure and function of general practice through undergraduate placements.
The aim of this study was to design and evaluate the introduction of a sustainable and feasible structure of placements in general practice for third-year pharmacy students at the University of Sunderland. The national agenda in the United Kingdom (UK) calls for an increased presence of pharmacists within general practice; therefore, development of placements in this is setting is aligned to the development of these new roles. The placements were located in general practice surgeries in the North East of England in the UK. Students engaged in activities which introduced them to the structure and function of general practice and familiarise them with the role of pharmacists and other practice staff. Two cohorts undertook the education activity during the development process. The first cohort was comprised of 213 students, with 193 students the following year. An action research approach was taken to evaluate and revise the design of the placement. The final design and delivery have been shown to have a positive impact on student learning experience, be feasible and sustainable. The placement was also successful at introducing students to potential future roles in general practice for pharmacists. This model of general practice placement provision was found to be a feasible and sustainable delivery model, which was well received by undergraduate students.


Bacterial ventriculoperitoneal shunt infections: changing trends in antimicrobial susceptibility, a 7-year retrospective study from Pakistan.
Ventriculoperitoneal (VP) shunt infections in adults represent a severe complication and make treatment more challenging. Therefore, drug susceptibility patterns are crucial for therapeutic decisions and infection control in neurosurgical centers. This 7-year retrospective study aimed to identify the bacteria responsible for adult VP shunt infections and determine their drug susceptibility patterns. This single-center study was performed from 2015 to 2021 in Lahore, Pakistan, and included CSF cultures from VP shunt infections. Demographic data, causative organisms, and antimicrobial susceptibility testing results were collected. Multivariate analysis of variance (MANOVA) and two-sample t-tests were used to analyze and compare the antibiotic sensitivity trends over the study period. 14,473 isolates recovered from 13,937 CSF samples of VP shunt infections were identified and analyzed for their susceptibility patterns to antimicrobials. The proportion of Gram-negative and Gram-positive bacteria were 11,030 (76%) and 3443 (24)%, respectively. The predominant bacteria were Acinetobacter species (n = 5898, 41%), followed by Pseudomonas species (n = 2368, 16%) and coagulase-negative Staphylococcus (CoNS) (n = 1880, 13%). 100% of Staphylococcus aureus (S.aureus) and CoNS were sensitive to vancomycin and linezolid (n = 2580). However, 52% of S. aureus (719/1,343) were methicillin-resistant Staphylococcus aureus (MRSA). Acinetobacter showed maximum sensitivity to meropenem at 69% (2759/4768). Pseudomonas was 80% (1385/1863 sensitive to piperacillin-tazobactam, Escherichia coli (E. coli) showed 72% to amikacin (748/1055), while Klebsiella spp. was 57% (574/1170) sensitive to piperacillin-tazobactam. The sensitivity of piperacillin-tazobactam and meropenem for Gram-negative bacteria decreased significantly (p < 0.05) over 7 years, with 92.2% and 88.91% sensitive in 2015 and 66.7% and 62.8% sensitive in 2021, respectively. The significant decrease in the effectiveness of carbapenem and beta-lactam/beta-lactamase inhibitor combination drugs for the common Gram-negative causative agents of VP shunt infections suggests that alternative antibiotics such as colistin, fosfomycin, ceftazidime/avibactam, ceftolozane/tazobactam, and tigecycline should be considered and in consequence included in testing panels. Additionally, it is recommended to adopt care bundles for the prevention of VP shunt infection.


Distinct isocomplexes of the TRAPP trafficking factor coexist inside human cells.
The transport protein particle (TRAPP) complex is required for proper vesicular transport from the ER to the Golgi. The composition of yeast TRAPP is well characterized, but the organization of mammalian TRAPP complex remains elusive. Using a tandem affinity purification (TAP) approach, we provide first experimental proof for the association of NIBP (NIK/IKKbeta binding protein) with Bet3 and find two human paralogs of Trs33 (A and B) associated with Bet3. Interaction studies and gel filtration analysis reveal that both proteins are part of human TRAPP and might mark two distinct isocomplexes that exert different functions in the regulation of ER-to-Golgi traffic.


Near-field ptychography: phase retrieval for inline holography using a structured illumination.
Inline holography is a common phase-contrast imaging method which uses free-space propagation to encode the phase signal into measured intensities. However, quantitative retrieval of the sample's image remains challenging, imposing constraints on the nature of the sample or on the propagation distance. Here, we present a way of simultaneously retrieving the sample's complex-valued transmission function and the incident illumination function from near-field diffraction patterns. The procedure relies on the measurement diversity created by lateral translations of the sample with respect to a structured illumination. The reconstruction approach, in essence identical to that employed in ptychography, is applied to hard X-ray synchrotron measurements and to simulations. Compared to other inline holography techniques, we expect near-field ptychography to reduce reconstruction artefacts by factoring out wavefront imperfections and relaxing constraints on the sample's scattering properties, thus ultimately improving the robustness of propagation-based X-ray phase tomography.


Carbonic anhydrase inhibition in glaucoma: hazard or benefit for the chronic lunger?
Carbonic anhydrase inhibitors, of proven value in the longterm management of glaucoma, have a number of troublesome side effects, most of which are well-known. However, their potential hazards to patients with chronic obstructive lung disease have received little attention. The author reviews the physiological effects of carbonic anhydrase inhibition on carbon dioxide metabolism and the implications for the chronic lung patient. The untoward pulmonary complications associated with the use of carbonic anhydrase inhibitors are of particular importance to ophthalmologists, since chronic lung disease and glaucoma, both common disorders in the elderly, frequently coexist in the same patient.


Bioproduction of Antibody-Drug Conjugate Payload Precursors by Engineered Cell Factories.
Antibody-drug conjugates (ADCs), which combine the exquisite specificity of antibodies with the cell-killing ability of cytotoxic drug payloads, have emerged as an attractive means for treating cancers. All (pre)clinical ADCs employ biosynthesized cytotoxins as their ADC payload precursors (APPs). The cost-effective bioproduction of APPs is receiving great interest from both academia and industry. Given the lack of systematic overviews of the topic, we provide the current status of APPs and focus on their state-of-the-art bioproduction strategies, illustrated with typical examples and critical analyses. Challenges in further enhancing the bioproduction efficiency of APPs and other cytotoxins are also discussed. This research has implications for bioprocess and metabolic engineering, systems and synthetic biology, and biopharmaceutical drug discovery, development, and industrialization.


Eating Disorders in Athletes: From Risk Management to Therapy.
Balanced sporting activity should be considered a resource in the treatment of eating disorders (ED), in particular of the BED and in obesity and, if conducted and guided by expert preparers and rehabilitators, in some forms of anorexia and in bulimia. To assess the role of excessive physical activity, predominantly interfering with daily activities by ultimately resulting in greater energy consumption leading to weight loss, and study the diagnostic criteria of bulimia and anorexia nervosa. A number of literature studies also report the presence of ED among athletes. A 2004 study reported that the prevalence of eating disorders in sports would be 13.5% compared to 4.5% of the control subjects. In general, nutrition is used as a tool for improving performance not only of athletes but also of technicians and coaches. But in the presence of factors of vulnerability towards ED, the tendency to manipulate the weight can result in an eating disorder or the so-called athletic anorexia or the RED-S. It is important to emphasize that not only do professional athletes suffer from it, but also good-looking amateurs and laypersons.


ISCEV extended protocol for the S-cone ERG.
The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure for testing generalized retinal function but encourages more extensive testing. This extended protocol describes a method of assessing the function of the short-wavelength-sensitive cone (S-cone) retinal pathway, using a short-wavelength flash superimposed on a background that saturates the rods and adapts the L/M-cones to elicit a response, known as the S-cone ERG. Stimulus parameters such as the strength and luminance of the flash and background, respectively, and their spectral and temporal characteristics are specified. As a complement to the ISCEV standard, testing the S-cone ERG enables further characterization of light-adapted retinal function and may refine diagnosis of some retinal disorders. Typical applications are described including use in the diagnosis of rod monochromacy and S-cone monochromacy, identification and investigation of cone On-bipolar cell dysfunction and use of the technique to confirm the diagnosis of enhanced S-cone syndrome.


Oxygen radicals in cardiovascular-renal disease.
Oxidative stress is associated with diabetes mellitus and hypertension. Recent studies suggest that oxygen radicals contribute to the enhanced basal vascular tone, tubuloglomerular feedback, monocyte/macrophage infiltration and sensitivity of the vasculature and to the impaired endothelium-dependent relaxation in the diseased kidney. Pharmacological antioxidants can decrease oxidative stress, improve renal vascular function and decrease blood pressure in cardiovascular-renal disease.


Carboxypeptidase M: Multiple alliances and unknown partners.
Carboxypeptidase M (EC 18.104.22.168) belongs to the family of the carboxypeptidases. These enzymes remove C-terminal amino acids from peptides and proteins and exert roles in the physiological processes of blood coagulation/fibrinolysis, inflammation, food digestion and pro-hormone and neuropeptide processing. Among the carboxypeptidases CPM is of particular importance because of its constitutive expression in an active form at the surface of specialized cells and tissues in the human body. Despite the fact that the function(s) of this enzyme is not fully understood several suggestions have been made since its discovery more than two decades ago. Based on potential substrates and its presence, often on the boundary between the host and environment, a role in inflammation was proposed. This review describes how recent discoveries affected the insights in the cellular and physiological functions of CPM. A critical analysis of the potential endogenous peptide and protein substrates is provided. The distribution of CPM on different cell types and tissues and its expression in states of disease are discussed. There is evidence that CPM functions not only as a protease but also as a binding partner in cell-surface protein-protein interactions.


Hippocampal replay contributes to within session learning in a temporal difference reinforcement learning model.
Temporal difference reinforcement learning (TDRL) algorithms, hypothesized to partially explain basal ganglia functionality, learn more slowly than real animals. Modified TDRL algorithms (e.g. the Dyna-Q family) learn faster than standard TDRL by practicing experienced sequences offline. We suggest that the replay phenomenon, in which ensembles of hippocampal neurons replay previously experienced firing sequences during subsequent rest and sleep, may provide practice sequences to improve the speed of TDRL learning, even within a single session. We test the plausibility of this hypothesis in a computational model of a multiple-T choice-task. Rats show two learning rates on this task: a fast decrease in errors and a slow development of a stereotyped path. Adding developing replay to the model accelerates learning the correct path, but slows down the stereotyping of that path. These models provide testable predictions relating the effects of hippocampal inactivation as well as hippocampal replay on this task.


Real-time integration of MDCT-derived coronary anatomy and epicardial fat: impact on epicardial electroanatomic mapping and ablation for ventricular arrhythmias.
This study aimed to evaluate the feasibility and accuracy of real-time integration of multidetector computed tomography (MDCT) derived coronary anatomy and epicardial fat distribution and its impact on electroanatomical mapping and ablation. Epicardial catheter ablation for ventricular arrhythmias (VA) is an important therapeutic option in patients after endocardial ablation failure. However, epicardial mapping and ablation are limited by the presence of coronary arteries and epicardial fat. Twenty-eight patients (21 male, age 59 ± 16 years) underwent combined endo-epicardial electroanatomical mapping. Prior to the procedure, MDCT derived coronary anatomy and epicardial fat meshes were loaded into the mapping system (CARTO XP, Biosense Webster Inc, Diamond Bar, California). Real-time registration of MDCT data was performed after endocardial mapping. The distance between epicardial ablation sites and coronary arteries was assessed by registered MDCT and angiography. After the procedure, mapping and ablation points were superimposed on the MDCT using a reversed registration matrix for head-to-head comparison of mapping data and corresponding fat thickness. Image registration was successful and accurate in all patients (position error 2.8 ± 1.3 mm). At sites without evidence for scar, epicardial bipolar voltage decreased significantly (p < 0.001) with increasing fat thickness. Forty-six VA were targeted; 25 (54%) were abolished by catheter ablation, in 21 (46%) ablation failed. In 5 VA no target site was identified and in 3 VA adhesions prevented mapping. In 2 VA ablation was withheld due to His-bundle vicinity and in 7 VA due to proximity of coronary arteries. In 4 VA catheter ablation was ineffective. At ineffective ablation sites epicardial fat was significantly thicker compared to successful sites (16.9 ± 6.8 mm [range 7.3 to 22.2 mm] and 1.5 ± 2.1 mm [range 0.0 to 6.1 mm], p = 0.002). Real-time image integration of pre-acquired MDCT information is feasible and accurate. Epicardial fat >7 mm and the presence of coronary arteries are important reasons for epicardial ablation failure. Visualization of fat thickness during the procedure may facilitate interpretation of bipolar electrograms and identification of ineffective ablation sites.


Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity.
Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance.


The impact of timing modified natural cycle frozen embryo transfer based on spontaneous luteinizing hormone surge.
To evaluate whether adjusting timing of modified natural cycle frozen embryo transfer (mNC-FET) 1 day earlier in the setting of a spontaneous LH surge has an impact on pregnancy outcomes. This retrospective cohort study evaluated all mNC-FET with euploid blastocysts from May 1, 2016 to March 30, 2019, at a single academic institution. Standard protocol for mNC-FET included ultrasound monitoring and hCG trigger when the dominant follicle and endometrial lining were appropriately developed. Patients had serum LH, estradiol, and progesterone checked on day of trigger. If LH was ≥ 20 mIU/mL, trigger was given that day and FET was performed 6 days after surge (LH/HCG+6), with the intent of transferring 5 days after ovulation. If LH was < 20 mIU/mL, FET was performed 7 days after trigger (hCG+7). Primary outcomes included clinical pregnancy and live birth rates. To account for correlation between cycles, a generalized estimating equation (GEE) method for multivariable logistic regression was used. Four hundred fifty-three mNC-FET cycles met inclusion criteria, of which 205 were in the LH/HCG+6 group and 248 were in the HCG+7 group. The overall clinical pregnancy rate was 64% and clinical miscarriage rate was 4.8%, with similar rates between the two groups. The overall live birth rate was 60.9% (61.0% in LH/HCG+6 group and 60.9% in HCG+7 group). After implementing GEE, the odds of CP (aOR 0.97, 95% CI [0.65-1.45], p = 0.88) and LB (aOR 0.98, 95% CI [0.67-1.45], p = 0.93) were similar in both groups. In our study cohort, mNC-FET based on LH/HCG+6 versus HCG+7 had similar pregnancy outcomes.


A hierarchical approach to model parameter optimization for developmental systems.
In the context of Systems Biology, computer simulations of gene regulatory networks provide a powerful tool to validate hypotheses and to explore possible system behaviors. Nevertheless, modeling a system poses some challenges of its own: especially the step of model calibration is often difficult due to insufficient data. For example when considering developmental systems, mostly qualitative data describing the developmental trajectory is available while common calibration techniques rely on high-resolution quantitative data. Focusing on the calibration of differential equation models for developmental systems, this study investigates different approaches to utilize the available data to overcome these difficulties. More specifically, the fact that developmental processes are hierarchically organized is exploited to increase convergence rates of the calibration process as well as to save computation time. Using a gene regulatory network model for stem cell homeostasis in Arabidopsis thaliana the performance of the different investigated approaches is evaluated, documenting considerable gains provided by the proposed hierarchical approach.


Histone Variants as Stem Cell Biomarkers for Long-Term Injection Medialization Laryngoplasty.
Vocal fold (VF) paralysis by sectioning the recurrent laryngeal nerve dramatically impacts the life of thyroidectomy patients. Volume-expanding materials can temporarily restore VF medialization. To prolong this benefit, adipose mesenchymal stem cells (ADSCs) and micronized acellular dermis (MACD) were co-injected in a rabbit model of injection medialization laryngoplasty. Biomarkers of in situ proliferation were identified by mass spectrometry proteomics and pathway analysis to guide future efforts to increase the length of benefit. ADSCs were expanded and/or differentiated into chondrocytes (CHON) as collagen microspheres. After VF paralysis rabbits received MACD, MACD + undifferentiated ADSC, or MACD+CHON, ADSCs differentiated into chondrocytes. After 12 weeks, animals were sacrificed and 5-µm paraffin-embedded cryosections were prepared from larynges for hematoxylin and eosin visualization and nanoflow liquid chromatography electrospray-ionization tandem-mass spectrometry analysis of tissue collections. Validated proteins were processed by Venn subtraction and gene ontology (GO) overrepresentation analysis to identify unique pathways and biomarkers. Confirmed proteins numbered 147 (MACD), 1,243 (MACD+ADSC), and 1,033 (MACD+CHON). Totally, 333 proteins were uniquely found in the MACD+ADSC group, including mesenchymal surface markers CD9, CD44, fibronectin, and vimentin. Over 70% of proteins belonged to catalytic activity and binding GO categories, with the histone (H) family being overrepresented (P < 0.05). Histone variants H3.3, H2A.V, and H2A.Z (associated with open chromatin states) were overrepresented in the MACD+ADSC group, whereas structural histones H2A, H2B, and H4 were not. Biomarkers, including atypical histones, are associated with in vivo proliferation of ADSCs and an expanded VF medialization volume. NA Laryngoscope, 128:E402-E408, 2018.


Implementation of Coach McLungsSM into primary care using a cluster randomized stepped wedge trial design.
Asthma is a prevalent chronic disease that is difficult to manage and associated with marked disparities in outcomes. One promising approach to addressing disparities is shared decision making (SDM), a method by which the patient and provider cooperatively make a decision about asthma care. SDM is associated with improved outcomes for patients; however, time constraints and staff availability are noted implementation barriers. Use of health information technology (IT) solutions may facilitate the utilization of SDM. Coach McLungsSM is a collaborative web-based application that involves pediatric patients, their caregivers, and providers in a personalized experience while gathering patient-reported data. Background logic provides decision support so both audiences can develop a well-informed treatment plan together. The goal of this study is to evaluate the implementation of the Coach McLungsSM intervention into primary care. Implementation will be evaluated using a stepped wedge randomized control study design at 21 pediatric and family medicine practices within a large, integrated, nonprofit healthcare system. We will measure changes in emergency department visits, hospitalizations, and oral steroid use, which serve as surrogate measures for patient-centered asthma outcomes. We will use a generalized linear mixed models with logit link to test the hypothesis for the reduction in exacerbation rates specifying the fixed effects of intervention and time and random effects for practice and practice*time. This design achieves 84% power to detect the hypothesized effect size difference of 10% in overall exacerbation between control (40%) and intervention (30%) periods (two-sided, p = 0.05). Implementation will be guided using the Expert Recommendations for Implementing Change (ERIC), a compilation of implementation strategies, and evaluated using the CFIR (Consolidated Framework for Implementation Research) and RE-AIM (Reach Effectiveness, Adoption, Implementation, Maintenance). We anticipate that a tailored implementation of Coach McLungsSM across diverse primary care practices will lead to a decrease in emergency department visits, hospitalizations, and oral steroid use for patients in the intervention group as compared to the control condition. Clincaltrials.gov, NCT05059210. Registered 28 September 2021, https://www. gov/ct2/show/NCT05059210.


Human brain leucyl aminopeptidase: isolation, characterization and specificity against some neuropeptides.
In order to obtain a greater understanding of the role of aminopeptidases in the degradation of peptides and proteins in the nervous system, we have isolated and characterized leucyl aminopeptidase (EC 220.127.116.11) from human cerebral cortex and studied its action on some physiologically important neuropeptides. The enzyme has a low specificity constant for the hydrolysis of Leu-7-amido-4-methylcoumarin (69s-1M-1) but the peptides Tyr-Gly-Gly and Tyr-Gly-Gly-Phe-Leu (Leu5-enkephalin) were much better substrates (specificity constants 8300 and 18050s -1M-1 respectively). Optimum activity for the degradation of Leu-enkephalin was obtained at pH10.5 in the presence of 5mM-Mn++. A sharp drop in specificity constant occurred with increasing chain length in the series Leu-enkephalin, dynorphin 1-8, 1-10 and 1-13, suggesting that the enzyme functions only as an oligopeptidase. Other neuropeptides were poor substrates (cholecystokinin octapeptide, angiotensin-I) or not hydrolysed at all (somatostatin, Arg8-vasopressin).


A novel hybrid modeling approach for the evaluation of integrated care and economic outcome in heart failure treatment.
Demographic changes, increased life expectancy and the associated rise in chronic diseases pose challenges to public health care systems. Optimized treatment methods and integrated concepts of care are potential solutions to overcome increasing financial burdens and improve quality of care. In this context modeling is a powerful tool to evaluate potential benefits of different treatment procedures on health outcomes as well as health care budgets. This work presents a novel modeling approach for simulating different treatment procedures of heart failure patients based on extensive data sets from outpatient and inpatient care. Our hybrid heart failure model is based on discrete event and agent based methodologies and facilitates the incorporation of different therapeutic procedures for outpatient and inpatient care on patient individual level. The state of health is modeled with the functional classification of the New York Heart Association (NYHA), strongly affecting discrete state transition probabilities alongside age and gender. Cooperation with Austrian health care and health insurance providers allowed the realization of a detailed model structure based on clinical data of more than 25,000 patients. Simulation results of conventional care and a telemonitoring program underline the unfavorable prognosis for heart failure and reveal the correlation of NYHA classes with health and economic outcomes. Average expenses for the treatment of NYHA class IV patients of €10,077 ± €165 were more than doubled compared to other classes. The selected use case of a telemonitoring program demonstrated potential cost savings within two years of application. NYHA classes II and III revealed most potential for additional treatment measures. The presented model allows performing extensive simulations of established treatment procedures for heart failure patients and evaluating new holistic methods of care and innovative study designs. This approach offers health care providers a unique, adaptable and comprehensive tool for decision making in the complex and socioeconomically challenging field of cardiovascular diseases.


Angiotensin II stimulates phosphatidylinositol turnover in adrenal glomerulosa cells by a calcium-independent mechanism.
Angiotensin II enhances phosphatidylinositol turnover in isolated adrenal glomerulosa cells. In the present experiments we examined whether this effect required the presence of extracellular Ca2+. It was found that neither the stimulation of phosphatidylinositol breakdown nor the stimulation of incorporation of [32P]phosphate into phosphatidic acid and phosphatidylinositol required the presence of extracellular Ca2+. These observations suggest that the enhancement of phosphatidylinositol turnover may precede, but does not depend on, angiotensin-induced Ca2+ influx.


Molecular magneto-ionic proton sensor in solid-state proton battery.
High proton conductivity originated from its small size and the diffusion-free Grotthuss mechanism offers immense promise for proton-based magneto-ionic control of magnetic materials. Despite such promise, the realization of proton magneto-ionics is hampered by the lack of proton-responsive magnets as well as the solid-state sensing method. Here, we report the proton-based magneto-ionics in molecule-based magnet which serves as both solid-state proton battery electrode and radiofrequency sensing medium. The three-dimensional hydrogen-bonding network in such a molecule-based magnet yields a high proton conductivity of 1.6 × 10-3 S cm-1. The three-dimensional printed vascular hydrogel provides the on-demand proton stimulus to enable magneto-ionics, where the Raman spectroscopy shows the redox behavior responsible for the magnetism control. The radiofrequency proton sensor shows high sensitivity in a wide proton concentration range from 10-6 to 1 molar under a low working radiofrequency and magnetic field of 1 GHz and 405 Oe, respectively. The findings shown here demonstrate the promising sensing application of proton-based magneto-ionics.


[Celebrating 33 years of the DRFZ: Epidemiology and Health Services Research].
The scientific focus of the DRFZ's Programme Area Epidemiology and Health Services Research is, on the one hand, investigating the health care situation of people with rheumatic diseases in Germany, including its deficits, progress and trends. On the other hand, an essential goal is to uncover risk factors for unfavourable disease trajectories, but also protective factors, through the long-term observation of disease courses in large cohorts. With the approval of innovative, targeted therapies at the beginning of this millennium, the question of the real-world safety and effectiveness of the various anti-rheumatic therapies became a key issue for doctors and patients. The biologics registers have developed into central instruments of the programme area, which enable questions on comparative drug safety, but also on therapy effectiveness and risk reduction through effective therapy, to be answered in a robust manner.In this article, selected results of epidemiological research at the DRFZ are presented. The overall goal of the research was and is to contribute to improving the quality of life of children and adults with rheumatic and musculoskeletal diseases. This is the purpose of clinical-evaluative health services research as well as the acquisition of knowledge that supports effective, individualised therapy. Large, long-term patient cohorts and a stable network with clinical rheumatologists and those affected have proven to be indispensable instruments.


Hysteroscopy as a standard procedure for assessing endometrial lesions among postmenopausal women.
Endometrial cancer is the most prevalent type of malignant neoplasia of the genital tract. The objective of this study was to calculate the sensitivity, specificity, accuracy and positive and negative predictive values for diagnostic hysteroscopy, in comparison with histopathological tests, for all lesions of the endometrial cavity. Retrospective descriptive study at the public tertiary-level university hospital of Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. Diagnostic hysteroscopy was indicated in the following instances: endometrial thickness > 4 mm in asymptomatic patients; postmenopausal bleeding; and irregular endometrium or endometrium difficult to assess from ultrasound, with or without vaginal bleeding. Ultrasound evaluations were carried out no more than three months prior to hysteroscopy. There were 510 patients, with a mean age of 61.1+/-2.0 years and mean time elapsed since the menopause of 12.7+/-2.5 years. Endometrial biopsies were performed on 293 patients (57.5%). Histopathological analysis showed that 18 patients presented endometrial carcinoma or typical or atypical hyperplasia, and none of them presented endometrial thickness of less than 8 mm. No significant differences were found between the median thicknesses of the various benign lesions (p > 0.05). In our data, the sensitivity, specificity, accuracy and positive and negative predictive values for cancer or hyperplasia were 94.4%, 97.0%, 96.8%, 68% and 99.6%, respectively. Our results suggest that hysteroscopy is valuable as a diagnostic tool for malignant/hyperplastic and benign lesions, except for submucous myomas, for which the sensitivity was only 52.6%.


The neural basis of phantom limb pain.
A recent study suggests that brain changes in amputees may be pain-induced, questioning maladaptive plasticity as a neural basis of phantom pain. These findings add valuable information on cortical reorganization after amputation. We suggest further lines of research to clarify the mechanisms that underlie phantom pain.


A small molecule inhibits and misdirects assembly of hepatitis B virus capsids.
Hepatitis B virus (HBV) capsids play an important role in viral nucleic acid metabolism and other elements of the virus life cycle. Misdirection of capsid assembly (leading to formation of aberrant particles) may be a powerful approach to interfere with virus production. HBV capsids can be assembled in vitro from the dimeric capsid protein. We show that a small molecule, bis-ANS, binds to capsid protein, inhibiting assembly of normal capsids and promoting assembly of noncapsid polymers. Using equilibrium dialysis to investigate binding of bis-ANS to free capsid protein, we found that only one bis-ANS molecule binds per capsid protein dimer, with an association energy of -28.0 +/- 2.0 kJ/mol (-6.7 +/- 0.5 kcal/mol). Bis-ANS inhibited in vitro capsid assembly induced by ionic strength as observed by light scattering and size exclusion chromatography. The binding energy of bis-ANS for capsid protein calculated from assembly inhibition data was -24.5 +/- 0.9 kJ/mol (-5.9 +/- 0.2 kcal/mol), essentially the same binding energy observed in studies of unassembled protein. These data indicate that capsid protein bound to bis-ANS did not participate in assembly; this mechanism of assembly inhibition is analogous to competitive or noncompetitive inhibition of enzymes. While assembly of normal capsids is inhibited, our data suggest that bis-ANS leads to formation of noncapsid polymers. Evidence of aberrant polymers was identified by light scattering and electron microscopy. We propose that bis-ANS acts as a molecular "wedge" that interferes with normal capsid protein geometry and capsid formation; such wedges may represent a new class of antiviral agent.


Systematic review with network meta-analysis: comparative efficacy and tolerability of different intravenous iron formulations for the treatment of iron deficiency anaemia in patients with inflammatory bowel disease.
Iron deficiency anaemia (IDA) is a common complication of inflammatory bowel disease (IBD) associated with reduced quality of life and increased hospitalisation rates. While the best way of treating IDA in IBD patients is not clearly established, current European guidelines recommend intravenous iron therapy in IBD patients with severe anaemia or intolerance to oral iron compounds. To compare the efficacy and tolerability of different intravenous iron formulations used to treat IDA in IBD patients in a systematic review and Bayesian network meta-analysis (NMA), PROSPERO registration number: 42016046565. In June 2016, we systematically searched for studies analysing efficacy and safety of intravenous iron for IDA therapy in IBD. Primary outcome was therapy response, defined as Hb normalisation or increase ≥2 g/dL. Five randomised, controlled trials (n = 1143 patients) were included in a network meta-analysis. Only ferric carboxymaltose was significantly more effective than oral iron [OR=1.9, 95% CrI: (1.1;3.2)]. Rank probabilities showed ferric carboxymaltose to be most effective, followed by iron sucrose, iron isomaltose and oral iron. Pooled data from the systematic review (n = 1746 patients) revealed adverse event rates of 12.0%, 15.3%, 12.0%, 17.0% for ferric carboxymaltose, iron sucrose, iron dextran and iron isomaltose respectively. One drug-related serious adverse event (SAE) each was reported for ferric carboxymaltose and iron isomaltoside, and one possibly drug-related SAE for iron sucrose. Ferric carboxymaltose was the most effective intravenous iron formulation, followed by iron sucrose. In addition, ferric carboxymaltose tended to be better tolerated. Thus, nanocolloidal IV iron products exhibit differing therapeutic and safety characteristics and are not interchangeable.


Major emerging vector-borne zoonotic diseases of public health importance in Canada.
In Canada, the emergence of vector-borne diseases may occur via international movement and subsequent establishment of vectors and pathogens, or via northward spread from endemic areas in the USA. Re-emergence of endemic vector-borne diseases may occur due to climate-driven changes to their geographic range and ecology. Lyme disease, West Nile virus (WNV), and other vector-borne diseases were identified as priority emerging non-enteric zoonoses in Canada in a prioritization exercise conducted by public health stakeholders in 2013. We review and present the state of knowledge on the public health importance of these high priority emerging vector-borne diseases in Canada. Lyme disease is emerging in Canada due to range expansion of the tick vector, which also signals concern for the emergence of human granulocytic anaplasmosis, babesiosis, and Powassan virus. WNV has been established in Canada since 2001, with epidemics of varying intensity in following years linked to climatic drivers. Eastern equine encephalitis virus, Jamestown Canyon virus, snowshoe hare virus, and Cache Valley virus are other mosquito-borne viruses endemic to Canada with the potential for human health impact. Increased surveillance for emerging pathogens and vectors and coordinated efforts among sectors and jurisdictions will aid in early detection and timely public health response.


Impact of antibiotics for children presenting to general practice with cough on adverse outcomes: secondary analysis from a multicentre prospective cohort study.
Clinicians commonly prescribe antibiotics to prevent major adverse outcomes in children presenting in primary care with cough and respiratory symptoms, despite limited meaningful evidence of impact on these outcomes. To estimate the effect of children's antibiotic prescribing on adverse outcomes within 30 days of initial consultation. Secondary analysis of 8320 children in a multicentre prospective cohort study, aged 3 months to <16 years, presenting in primary care across England with acute cough and other respiratory symptoms. Baseline clinical characteristics and antibiotic prescribing data were collected, and generalised linear models were used to estimate the effect of antibiotic prescribing on adverse outcomes within 30 days (subsequent hospitalisations and reconsultation for deterioration), controlling for clustering and clinicians' propensity to prescribe antibiotics. Sixty-five (0.8%) children were hospitalised and 350 (4%) reconsulted for deterioration. Clinicians prescribed immediate and delayed antibiotics to 2313 (28%) and 771 (9%), respectively. Compared with no antibiotics, there was no clear evidence that antibiotics reduced hospitalisations (immediate antibiotic risk ratio [RR] 0.83, 95% confidence interval [CI] = 0.47 to 1.45; delayed RR 0.70, 95% CI = 0.26 to 1.90, overall P = 0.44). There was evidence that delayed (rather than immediate) antibiotics reduced reconsultations for deterioration (immediate RR 0.82, 95% CI = 0.65 to 1.07; delayed RR 0.55, 95% CI = 0.34 to 0.88, overall P = 0.024). Most children presenting with acute cough and respiratory symptoms in primary care are not at risk of hospitalisation, and antibiotics may not reduce the risk. If an antibiotic is considered, a delayed antibiotic prescription may be preferable as it is likely to reduce reconsultation for deterioration.


Relationship between the persistence of mer operon sequences in Escherichia coli and their resistance to mercury.
Studies related to geographic distribution of E. coli carrying mer operon sequences were carried out on the Indian subcontinent. Out of the 80 E. coli isolates, collected from five geographically distinct regions of India, 68 were found to be resistant to one or the other heavy metal used in the study. Among these isolates, 36 were found to be resistant to the inorganic form (HgCl2) and only 5 to resist both the inorganic and organic forms of mercury. Colony hybridization studies revealed 35 isolates out of 68 to hybridize with the probe. Interestingly, some of the mercury-sensitive isolates (Hgs), especially from the Dal Lake, were found positive in hybridization studies. These findings, supported by mercury volatilization studies, indicate the presence of nonfunctional/vestigial mer sequences in the isolates collected from different environments. On the other hand, few of the mercury-resistant isolates (Hgr) from the Yamuna River did not show any sign of hybridization. Further, volatilization studies also indicated an alternate mode of resistance mechanism operating in them. The studies demonstrate that the mer operon sequences share very high homology among the E. coli isolates collected from different geographical locations, and this metal resistance may be a genetic character that arose from a common ancestral background.


Object detection and recognition: using deep learning to assist the visually impaired.
Deep learning systems have improved performance of devices through more accurate object detection in a significant number of areas, for medical aid in general, and also for navigational aids for the visually impaired. Systems addressing different needs are available, and many manage effectively the detection of static obstacles. This research provides a review of deep learning systems used with navigational tools for the visually Impaired and a framework for guidance for future research. We compare current deep learning systems used with navigational tools for the visually impaired and compile a taxonomy of indispensable features for systems. Challenges to detection. Our taxonomy of improved navigational systems shows that it is sufficiently robust to be generally applied. This critical analysis is, to the best of our knowledge, the first of its kind and will provide a much-needed overview of the field.Implication for RehabilitationDeep learning systems can provide lost cost solutions for the visually impaired.Of these, convolutional neural networks (CNN) and fully convolutional neural networks (FCN) show great promise in terms of the development of multifunctional technology for the visually impaired (i.e., being less specific task oriented).CNN have also potential for overcoming challenges caused by moving and occluded objects.This work has also highlighted a need for greater emphasis on feedback to the visually impaired which for many technologies is limited.


A pilot study comparing treatments for severe attacks of neuromyelitis optica spectrum disorders: Intravenous methylprednisolone (IVMP) with add-on plasma exchange (PLEX) versus simultaneous ivmp and PLEX.
Our previous retrospective study demonstrated that NMOSD patients with an acute attack who did not respond to IVMP alone, however, showed further significant improvement after treatment with PLEX at 6 month-follow-up. To compare the efficacy between treatments with intravenous methylprednisolone (IVMP) with subsequent add-on plasma exchange (PLEX) and a combination of simultaneous IVMP and PLEX in neuromyelitis optica spectrum disorders (NMOSD) patients with a severe acute attack. We conducted a prospective, randomized, controlled, pilot study of the treatments for a severe acute attack in NMOSD patients. There were eleven AQP4-positive NMOSD patients in the study. One received only IVMP, five received IVMP with subsequent add-on PLEX treatment, and the other five received simultaneous IVMP and PLEX treatment. The attacks comprised myelitis (57.1%) and optic neuritis (42.9%). Both treatments with IVMP followed by subsequent add-on PLEX when needed (not-respond to IVMP treatment) and a combination treatment of simultaneous IVMP+PLEX from the outset showed clinical improvement measured by EDSS at 6 months follow-up, compared to those at the attacks (p-value = 0.07 in IVMP add-on PLEX group and p-value = 0.05 in IVMP+PLEX group), respectively. Although, a trend of a better outcome stratified by EDSS toward early PLEX initiation with IVMP+PLEX treatment was observed at 6 months follow-up, however not significantly. Early treatment with PLEX should be encouraged especially in NMOSD with a severe acute attack.


Characteristics of early versus late in-stent restenosis in second-generation drug-eluting stents: an optical coherence tomography study.
In-stent restenosis (ISR) is an important cause of drug-eluting stent (DES) failure and target vessel revascularisation. In this study we aimed to evaluate differences between early and late-presenting restenosis in second-generation DES using optical coherence tomography (OCT). Overall, 171 cases of second-generation DES ISR with a follow-up OCT minimum lumen area <3.0 mm2 were included: 33.3% of patients (n=57) had early ISR, and 66.7% (n=114) had late ISR (duration from stent implantation >1 year). Minimum stent area (MSA) <4.0 mm2, neointimal thickness <100 µm, and heterogeneous neointimal hyperplasia (NIH) were more prevalent in early ISR, whereas NIH with neoatherosclerosis trended towards being more frequent for late ISR (28.9% vs. 15.8%, p=0.06). Multivariable analysis revealed that duration from implantation >2 years, absence of statin use, and NIH >50% were independent predictors for neoatherosclerosis (all p<0.05). OCT morphological characteristics of second-generation DES ISR differ between early and late presentation. Early ISR was associated with MSA <4.0 mm2, while neoatherosclerosis contributed more commonly to late ISR.


Relationships between ultrastructural scrapie pathology and patterns of abnormal prion protein accumulation.
On immunohistochemical examination several morphological types of disease-specific prion protein (PrP(d)) accumulation are recognised in the brain of sheep suffering from scrapie. The present study examined the relationship between the type of PrP(d) deposits seen by light microscopy and ultrastructural changes in the olivary nuclei and the dorsal motor nucleus of the vagus (DMNV) in naturally infected sheep with clinical scrapie. The nature and magnitude of sub-cellular morphological changes found in the olivary nuclei differed from the patterns of degeneration previously described in the DMNV. In the olivary nuclei, lamellar bodies in the neuronal perikaryon were found to correlate with marked intraneuronal PrP(d) accumulation. Bizarre, coated, spiral invaginations of the plasmalemma were only found in A(136) homozygous sheep in this nucleus, where few coated pits were usually observed. Neuropil vacuolation in the olivary nuclei was mild and correlated with sparse extracellular PrP(d) deposition. In the DMNV, the magnitude of extracellular immunolabelling in the neuropil was prominent. These extracellular PrP(d )aggregates coincided with intense neuropil vacuolation, increased numbers of coated pits, and with the presence of pre-amyloid changes and infrequent short fibrils in the extracellular space. Scrapie-infected neurons in the two neuroanatomic sites examined, therefore, appear to process and respond to the presence of PrP(d) differently. We hypothesise that vacuolation, coated pits and spiral invaginations of the plasmalemma may be responses to extracellular PrP(d) molecules, and that lamellar bodies are changes associated with the high levels of intraneuronal PrP(d).


Investigation of the molecular interactions in a pMDI formulation by atomic force microscopy.
The forces of interaction between inhalable formoterol fumarate dihydrate particles, and the various components of a pressurised Metered Dose Inhaler (pMDI) (e.g. aluminium container, other drug particles and stabilising excipients) were investigated in isolation and combination in the model propellant 2H, 3H perfluoropentane (HPFP). The results obtained offer conclusive proof that the model systems tested have a degree of instability both in the presence and absence of polymer(s). The attractive forces measured following the addition of a mixed homopolymer solution may well be weak enough to be overcome by shaking. The use of homopolymers has inherent difficulties associated with it in the form of bridging interaction. Block or comb copolymers may well be a better option therefore, as they will reduce the possibility of bridging interactions. AFM offers great insight into the behaviour of HFA drug suspensions, and could play a vital role in the future development of suspension formulations.


Methylxanthines and the kidney.
This chapter describes the effects of the natural methylxanthines caffeine and theophylline on kidney function. Theophylline in particular was used traditionally to increase urine out put until more potent diuretics became available in the middle of the last century. The mildly diuretic actions of both methylxanthines are mainly the result of inhibition of tubular fluid reabsorption along the renal proximal tubule. Based upon the use of specific adenosine receptor antagonists and the observation of a complete loss of diuresis in mice with targeted deletion of the A1AR gene, transport inhibition by methylxanthines is mediated mainly by antagonism of adenosine A1 receptors (A1AR) in the proximal tubule. Methylxanthines are weak renal vasodilators, and they act as competitive antagonists against adenosine-induced preglomerular vasoconstriction. Caffeine and theophylline stimulate the secretion of renin by inhibition of adenosine receptors and removal of the general inhibitory brake function of endogenous adenosine. Since enhanced intrarenal adenosine levels lead to reduced glomerular filtration rate in several pathological conditions theophylline has been tested for its therapeutic potential in the renal impairment following administration of nephrotoxic substances such as radiocontrast media, cisplatin, calcineurin inhibitors or following ischemia-reperfusion injury. In experimental animals functional improvements have been observed in all of these conditions, but available clinical data in humans are insufficient to affirm a definite therapeutic efficacy of methylxanthines in the prevention of nephrotoxic or postischemic renal injury.


Inhibition of TGF-β1/Smad signal pathway is involved in the effect of Cordyceps sinensis against renal fibrosis in 5/6 nephrectomy rats.
The present study aimed to investigate the effects of Cordyceps sinensis on renal fibrosis and its possible mechanisms. Sprague-Dawley rats were randomly divided into three groups: sham operation (SHAM) group, 5/6 subtotal nephrectomy (SNx) untreated group, and 5/6 subtotal nephrectomy treated with C. sinensis (2.0 g/kg d) (CS) group. Rats were studied 12 weeks after the surgery, and the CS group presented with significantly lower proteinuria, and better renal function compared with the SNx group (p<0.05). Pathological study showed that the glomerulosclerosis tubulointerstitial injury score was significantly reduced in the CS group compared with the SNx group. Furthermore, the mRNA expression of TGF-β1, Smad2 and Smad3 and the protein expression of TGF-β1, TβRI, TβRII and p-Smad2/3 were attenuated by the C. sinensis treatment. In constrast, the mRNA and protein expression of Smad7 was upregulated. Furthermore, the expression of α-SMA and FSP1 was also significantly attenuated, accompanied by the increasing expression of E-cadherin, suggesting the inhibition of the epithelial-mesenchymal transition (EMT). C. sinensis exerted its antifibrotic effect on the SNx rats through the inhibition of the TGF-β1/Smad pathway.


Management of encounters related to subfertility and infertility in Australian general practice: a focus on Aboriginal and Torres Strait Islander females.
To investigate the management of subfertility and infertility among Aboriginal and Torres Strait Islander females attending Australian general practice. Cross-sectional study of 1,258,581 women (18-49 years) attending general practice between January 2011 and June 2019, utilising data from NPS MedicineWise MedicineInsight, a national general practice database in Australia. The prevalence of subfertility/infertility encounters was lower for Aboriginal and Torres Strait Islander females (12.37 per 1,000) than for non-Indigenous females (16.62 per 1,000). Aboriginal and Torres Strait Islander females with a subfertility/infertility encounter were younger and more likely to live outside Major cities and in areas of socioeconomic disadvantage than non-Indigenous females. Rates of prescribed infertility medications were not different between groups, however Aboriginal and Torres Strait Islander females were more likely to receive a pelvic ultrasound (24.30% vs. 19.90%); tests for luteinizing hormone (31.89% vs. 25.65%); testosterone (14.93% vs. 9.96%) and; glycated haemoglobin (HbA1c) (6.32% vs. 3.41%),but less likely to receive an anti-müllerian hormone test (2.78% vs. 7.04%). Lower encounter rates for infertility/subfertility among Aboriginal and Torres Strait Islander peoples may indicate access issues, preferred use of Aboriginal community-controlled health centres or younger average age at first birth and thus less age-related infertility. Future efforts should focus on maximising the inclusiveness of infertility surveillance. There is also a need for further research into the experiences of and preferences for infertility care and associated barriers among Aboriginal and Torres Strait Islander people.


COVID-19 IgG/IgM antibody testing in Los Angeles County, California.
Evidence suggests that asymptomatic and mild SARS-CoV-2 infections comprise > 95% of all cases. Developing a test that indicates past infection and possible immunity against the virus is important. We administered 244 antibody tests to three groups of high-risk population. The test consisted of an IgG component and an IgM component. The overall IgM/IgG positivity for patients with none, mild, moderate, and severe symptoms were 21.1%, 21.8%, 14.2%, and 26.9%, respectively. Those with moderate or severe symptoms were no more or less likely to have positive antibody tests than those with no or mild symptoms.


Effect of 5-thio-D-glucose on food and water intakes and on the acquisition and performance of maze tasks in the rat.
A potent inhibitor of D-glucose transport across the membrane, 5-thio-D-glucose (5-TDG) was examined with respect to its effect on runway and maze performance as well as on food and water intakes and body weight. In an initial experiemnt, three groups of Sprague-Dawley rats were matched in terms of their performance to learn a runway taks with Noyes pellets serving as the reinforcement. After extinction, two groups of rats were given 5-TDG in their food for 14 days, in doses of 20 and 100 mg/kg/day, which exerts potent effects on other functions. Retesting in the runway task showed no significant differences in the time required for the controls and for the 5-TDG treated rats to reach the goal box. Nonfed controls and the same two groups were again fed 500 ant 100 mg/kg/day 5-TDG and were tested on the 12 problems of the Hebb-Williams maze. Again, no significant differences were found in the number of erros made on the 12 problems by the 5-TDG treated animals or by the controls. Thus, this sugar analogue, administered in doses that affect spermatogenesis and other processes, has no effect on the ability of the rats to perform these tasks. Similarly, the intakes of food and water were unaffected by the systemic administration of 5-TDG.


Primary delayed onset craniosynostosis in a child demonstrated by serial computed tomography imaging.
Primary delayed onset craniosynostosis is a rarely reported phenomenon. The unique case of a 2-year-old boy who had computed tomography (CT) scans performed 20 months apart demonstrating the post-gestational development of sagittal suture craniosynostosis is presented. The otherwise healthy male initially presented to the emergency department at age 7 months with soft tissue swelling over his left parietal region secondary to a fall. A CT scan revealed a possible left parietal skull fracture without intracranial pathology and patent cranial sutures with a normocephalic calvarial configuration. Twenty months later, his paediatrician referred the boy to the craniofacial service for evaluation of progressive dolichocephaly. A new CT scan showed complete fusion of the sagittal suture with resultant biparietal narrowing, frontal bossing, and occipital prominence. The patient subsequently underwent uncomplicated frontoparietal craniotomy with calvarial vault reconstruction. Prior reports in the literature of cases of non-syndromic primary delayed onset craniosynostosis all lack 'pre-synostosis' CT imaging that proves post-birth patency of the cranial sutures. This case report documents CT demonstrating true primary delayed onset craniosynostosis.


Cytidine deaminase activity in Penicillium politans NRC-510.
Cell-free extracts of nitrate-grown Penicillium politans NRC-510 catalyzes the hydrolytic deamination of cytidine to uridine. Uridine was chromatographically identified in cell-free extracts. The enzyme exhibited optimum pH and temperature activities at 6.5 and 80 degrees C respectively. Thermal stability experiments indicated that the enzyme restored its activity at 80 degrees C for at least 60 minutes. When cell-free extracts were incubated at 90 degrees C for 5 minutes enzyme activity was inhibited by about 33%. The involvement of sulfhydryl group(s) in the catalytic site of the enzyme was shown. HgCl2 (5 x 10(-3) M) and CuSO4 (10(-2) M) caused a complete inhibition of enzyme activity. Ethylene diamine tetraacetate at a concentration of 5 x 10(-3) M and 10(-2) M inhibited the enzyme as well. Whereas, MgCl2, CoSO2 and MnCl2 had a remarkable activating effect. Dialysis of the cell-free extracts resulted to an increase in enzyme activity by about 30%. To our knowledge the thermophilic nature of the cytidine deaminase of P. politans NRC-510 is unique.


Long-term significance of Killip class and left ventricular systolic dysfunction.
Killip classification is an independent predictor of early mortality after myocardial infarction, and the presence of left ventricular systolic dysfunction (left ventricular ejection fraction <50%) and high Killip class predicts poor short-term prognosis. The long-term prognostic significance of Killip class and left ventricular systolic dysfunction, however, is unknown. We studied the impact of Killip class and left ventricular systolic dysfunction on all-cause mortality (assessed in May 2007 using the Social Security Death Index) in myocardial infarction patients admitted from July 1995 to December 1996. Of 282 patients, 60% (n=168) were Killip class 1, 23% (n=64) were Killip class 2, and 17% (n=50) were Killip class 3 or 4. Patients with higher Killip class were older and more likely to have diabetes, a non-Q-wave myocardial infarction, renal insufficiency, chronic obstructive pulmonary disease, and left ventricular systolic dysfunction. There were 152 deaths at 10 years after myocardial infarction, and patients with Killip class 2, 3, or 4 had higher mortality compared with Killip class 1 in unadjusted analyses. Patients with left ventricular systolic dysfunction and Killip class of 2 or more had significantly higher 10-year mortality (70 deaths or 76.9%) compared with Killip class 1 patients without left ventricular systolic dysfunction (29 deaths or 34.5%, P <.001). This risk persisted after adjusting for demographics, cardiovascular risk factors, and co-morbidities. Much of the risk was explained by deaths in the first 5 years after myocardial infarction. Killip class is a strong predictor of long-term mortality, and patients with high Killip class and left ventricular systolic dysfunction are at highest risk.


Tibial artery autografts: alternative conduits for high flow cerebral revascularizations.
Extracranial-to-intracranial (EC-IC) bypass is a valuable tool in treating intracranial diseases requiring flow replacement or parent vessel sacrifice. Radial artery grafts (RAGs) and saphenous vein grafts (SVGs) have been used as conduits to provide adequate high flow revascularizations. It is a therapeutic challenge when these grafts are unavailable. All EC-IC high flow cerebral revascularizations performed using conduits other than RAGs or SVGs were identified from a prospective cerebrovascular registry. These patients were retrospectively reviewed for surgical technique, graft patency, graft flow, and clinical outcomes. Three patients (all women) underwent EC-IC bypass surgery using tibial artery grafts (two anterior tibial artery and one posterior tibial artery) because of the nonavailability of RAG or SVG. The two anterior tibial artery graft bypasses were patent with good flow at 8 and 3 months. The posterior tibial artery graft occluded intraoperatively. None of the patients developed vascular complications in the lower extremity due to tibial artery harvest. Tibial arteries are safe, contingent alternatives to conventional conduits for performing high flow cerebral revascularizations and conduit reconstructions.