The association between obstructive sleep apnea and neurocognitive performance--the Apnea Positive Pressure Long-term Efficacy Study (APPLES).
To determine associations between obstructive sleep apnea (OSA) and neurocognitive performance in a large cohort of adults. Cross-sectional analyses of polysomnographic and neurocognitive data from 1204 adult participants with a clinical diagnosis of obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES), assessed at baseline before randomization to either continuous positive airway pressure (CPAP) or sham CPAP. Sleep and respiratory indices obtained by laboratory polysomnography and several measures of neurocognitive performance. Weak correlations were found for both the apnea hypopnea index (AHI) and several indices of oxygen desaturation and neurocognitive performance in unadjusted analyses. After adjustment for level of education, ethnicity, and gender, there was no association between the AHI and neurocognitive performance. However, severity of oxygen desaturation was weakly associated with worse neurocognitive performance on some measures of intelligence, attention, and processing speed. The impact of OSA on neurocognitive performance is small for many individuals with this condition and is most related to the severity of hypoxemia.


The impact of MMR vaccine on mumps infection in England and Wales.
In the absence of an immunisation programme, epidemics of mumps have occurred at three-yearly intervals in England and Wales. Mumps has been the commonest cause of viral meningitis in children. Routine immunisation (as part of combined measles/mumps/rubella vaccine) was introduced in 1988 and has had a substantial impact on the disease. There has been a 79% reduction in notified cases over two years and the epidemic cycle has been interrupted. Prospects for elimination are good.


Paroxysmal disorders in infancy and their risk factors in a population-based cohort: the Generation R Study.
To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort. This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth. Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p<0.001) and low Apgar score at 1 minute (p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05). Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations.


Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells.
Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-β-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-β-CyD (FA-HP-β-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-β-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-β-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-β-CyD against AML cells was stronger than that of HP-β-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-β-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-β-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-β-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.


REG-O3 chimeric peptide combining growth hormone and somatostatin sequences improves joint function and prevents cartilage degradation in rat model of traumatic knee osteoarthritis.
REG-O3 is a 24-aminoacid chimeric peptide combining a sequence derived from growth hormone (GH) and an analog of somatostatin (SST), molecules displaying cartilage repair and anti-inflammatory properties, respectively. This study aimed to investigate the disease-modifying osteoarthritis drug (DMOAD) potential of REG-O3 by analyzing its effect on pain, joint function and structure, upon injection into osteoarthritic rat knee joint. Osteoarthritis was induced in the right knee of mature male Lewis rats (n = 12/group) by surgical transection of the anterior cruciate ligament (ACLT) combined with partial medial meniscectomy (pMMx). Treatments were administered intra-articularly from fourteen days after surgery through three consecutive injections one week apart. The effect of REG-O3, solubilized in a liposomal solution and injected at either 5, 25 or 50 μg/50 μL, was compared to liposomal (LIP), dexamethasone and hyaluronic acid (HA) solutions. The study endpoints were the pain/function measured once a week throughout the entire study, and the joint structure evaluated eight weeks after surgery using OARSI score. ACLT/pMMx surgery induced a significant modification of weight bearing in all groups. When compared to liposomal solution, REG-O3 was able to significantly improve weight bearing as efficiently as dexamethasone and HA. REG-O3 (25 μg) was also able to significantly decrease OARSI histological global score as well as degeneration of both cartilage and matrix while the other treatments did not. This study provides evidence of a remarkable protecting effect of REG-O3 on pain/knee joint function and cartilage/matrix degradation in ACLT/pMMx model of rat osteoarthritis. REG-O3 thus displays an interesting profile as a DMOAD.


Pharmacist's identity development within multidisciplinary primary health care teams in Ontario; qualitative results from the IMPACT project.
Multidisciplinary team development generates changes in roles, responsibilities, and identities of individual health care providers. The Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics (IMPACT) project introduced pharmacists into family practice teams across Ontario, Canada, to provide medication assessments, drug information, and academic detailing and to develop office system enhancements to improve drug therapy. To analyze pharmacists' narrative accounts during early integration to study identity development within emerging team-based care. Qualitative design using 63 pharmacist narrative reports of pharmacists' experiences over a 9-month integration period. Four independent researchers with varied professional backgrounds used immersion and crystallization to identify codes and iterative grounded theory to determine and debate process and content themes relevant to identity development. The pharmacists' narratives spoke of the daily experiences of integrating into a family practice setting: feeling valued and contributing concretely to patient care; feeling underutilized; feeling like a nuisance, or feeling as though working too slowly. Pharmacist mentors helped deal with uncertainty and complexity of care. Pharmacists perceived that complementary clinical contributions enhanced their status with physicians and motivated pharmacists to take on new responsibilities. Changes in perspective, clinic-relevant skill development, and a new sense of professionalism signaled an emerging pharmacist family practice identity. Pharmacists found that the integration into team-based primary health care provided both challenges and fresh opportunities. Pharmacists' professional identities evolved in relation to valued role models, emerging practice-level opportunities, and their patient-related contributions.


The T Cell Immunoscore as a Reference for Biomarker Development Utilizing Real-World Data from Patients with Advanced Malignancies Treated with Immune Checkpoint Inhibitors.
We aimed to determine the prognostic value of an immunoscore reflecting CD3+ and CD8+ T cell density estimated from real-world transcriptomic data of a patient cohort with advanced malignancies treated with immune checkpoint inhibitors (ICIs) in an effort to validate a reference for future machine learning-based biomarker development. Transcriptomic data was collected under the Total Cancer Care Protocol (NCT03977402) Avatar® project. The real-world immunoscore for each patient was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells utilizing CIBERSORTx and the LM22 gene signature matrix. Then, the immunoscore association with overall survival (OS) was estimated using Cox regression and analyzed using Kaplan-Meier curves. The OS predictions were assessed using Harrell's concordance index (C-index). The Youden index was used to identify the optimal cut-off point. Statistical significance was assessed using the log-rank test. Our study encompassed 522 patients with four cancer types. The median duration to death was 10.5 months for the 275 participants who encountered an event. For the entire cohort, the results demonstrated that transcriptomics-based immunoscore could significantly predict patients at risk of death (p-value < 0.001). Notably, patients with an intermediate-high immunoscore achieved better OS than those with a low immunoscore. In subgroup analysis, the prediction of OS was significant for melanoma and head and neck cancer patients but did not reach significance in the non-small cell lung cancer or renal cell carcinoma cohorts. Calculating CD3+ and CD8+ T cell immunoscore using real-world transcriptomic data represents a promising signature for estimating OS with ICIs and can be used as a reference for future machine learning-based biomarker development.


Homozygosity for the SCN10A Polymorphism rs6795970 Is Associated With Hypoalgesic Inflammatory Bowel Disease Phenotype.
Background: Hypoalgesic inflammatory bowel disease (IBD), a condition in which patients with active disease do not perceive and/or report abdominal pain, is associated with serious complications and there is a lack of cost-effective, reliable diagnostic methods to identify "at-risk" patients. The voltage-gated sodium channels (VGSC's), Nav1.7, Nav1.8, and Nav1.9, are preferentially expressed on nociceptive neurons, and have been implicated in visceral inflammatory pain. At least 29 VGSC single nucleotide polymorphisms (SNPs) have been implicated in chronic somatic pain syndromes, but little is known about their role in human visceral sensation. We hypothesized that disruptive VGSC polymorphisms result in anti-nociceptive behavior in IBD. Methods and Findings: We performed targeted exome sequencing and/or TaqMan genotyping to evaluate the Nav1.7, Nav1.8, and Nav1.9 genes (SCN9A, SCN10A and SCN11A) in 121 IBD patients (including 41 "hypoalgesic" IBD patients) and 86 healthy controls. Allelic and genotypic frequencies of polymorphisms were compared among study groups who had undergone characterization of intestinal inflammatory status and abdominal pain experience. Forty-nine total exonic SNPs were identified. The allelic frequency of only one non-synonymous SNP (rs6795970 [SCN10A]) approached significance in hypoalgesic IBD patients when compared to other IBD patients (p = 0.096, Fisher's exact test). Hypoalgesic IBD patients were more likely to be homozygous for this polymorphism (46 vs. 22%, p = 0.01, Fisher's exact test). Conclusions: This is the first human study to demonstrate a link between a genetic variant of SCN10A and abdominal pain perception in IBD. These findings provide key insights into visceral nociceptive physiology and new diagnostic and therapeutic targets to consider in IBD and other gastrointestinal conditions associated with chronic abdominal pain. Further studies are required to elucidate the precise pathophysiological impact of the rs6795970 polymorphism on human gastrointestinal nociception.


Molecular and Low-Resolution Structural Characterization of the Na+-Translocating Glutaconyl-CoA Decarboxylase From Clostridium symbiosum.
Some anaerobic bacteria use biotin-dependent Na+-translocating decarboxylases (Bdc) of β-keto acids or their thioester analogs as key enzymes in their energy metabolism. Glutaconyl-CoA decarboxylase (Gcd), a member of this protein family, drives the endergonic translocation of Na+ across the membrane with the exergonic decarboxylation of glutaconyl-CoA (ΔG 0' ≈-30 kJ/mol) to crotonyl-CoA. Here, we report on the molecular characterization of Gcd from Clostridium symbiosum based on native PAGE, size exclusion chromatography (SEC) and laser-induced liquid bead ion desorption mass spectrometry (LILBID-MS). The obtained molecular mass of ca. 400 kDa fits to the DNA sequence-derived mass of 379 kDa with a subunit composition of 4 GcdA (65 kDa), 2 GcdB (35 kDa), GcdC1 (15 kDa), GcdC2 (14 kDa), and 2 GcdD (10 kDa). Low-resolution structural information was achieved from preliminary electron microscopic (EM) measurements, which resulted in a 3D reconstruction model based on negative-stained particles. The Gcd structure is built up of a membrane-spanning base primarily composed of the GcdB dimer and a solvent-exposed head with the GcdA tetramer as major component. Both globular parts are bridged by a linker presumably built up of segments of GcdC1, GcdC2 and the 2 GcdDs. The structure of the highly mobile Gcd complex represents a template for the global architecture of the Bdc family.


[A method of choosing the extractant for the recovery of tin from the internal organs of a human cadaver].
The analysis of naphthenic acid revealed that they may be used for tin detection in the cadaveric material due to their high complex-forming ability. Method of extraction-atomic absorption tin determination in human organs was developed on the basis of naphthenic acid use. Modified method which differs from the common one by higher sensitivity and selectivity is presented.


Changes in genetic and environmental effects on growth during infancy.
Accelerated infant growth is a possible explanation for the relation between birth weight and adult diseases. The aim of this study was to estimate the heritability of infant growth and to examine whether the genetic contribution changes with increasing or decreasing birth weight and gestational age. Growth (change in weight z score) was analyzed in 522 infants from the East Flanders Prospective Twin Survey for age windows of 0-1, 1-6, 6-12, and 12-24 mo. Structural equation modeling was performed to estimate the relative importance of additive genetic, shared environmental, and unique environmental sources of variance. We showed no genetic contribution to growth in the 0-1-mo growth period. However, at later ages, the heritability of growth was high at 94% (95% CI: 90%, 96%) from 1 to 6 mo, 85% (95% CI: 80%, 89%) from 6 to 12 mo, and 86% (95% CI: 77%, 91%) in the 12-24-mo growth period. Nevertheless, in the last age window, a model without genetic factors was also statistically plausible. From 0 to 1 mo, the genetic contribution to growth was low in the average birth weight range but higher at both extremes of birth weight. The genetic contribution from 0 to 1 mo increased with increasing gestational age from 36 wk of gestation onward. This study shows that genetic factors are not important in early infant growth (0-1 mo), whereas heritability is high after 1 mo. Because many (nutritional) interventions are aimed at influencing early postnatal growth, to target long-term health, these interventions may be most successful if implemented in the first month of postnatal growth.


Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival.
Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV small intestinal neuroendocrine tumors (SI-NETs) are controversial. To determine the association of locoregional surgery (LRS) performed at diagnosis with outcomes in patients with asymptomatic SI-NETs and distant metastases. This cohort study included asymptomatic patients with stage IV SI-NETs diagnosed from January 1, 1985, through December 31, 2015, and identified using the prospective database of SI-NETs from Uppsala University Hospital, Uppsala, Sweden. Patients included were treated at a tertiary referral center and followed up until May 31, 2016, with data from the Swedish National Patient Register. The 363 patients with stage IV SI-NETs without abdominal symptoms were divided between those who underwent prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment (hereafter referred to as LRS group [n = 161]) and those who underwent nonsurgical treatment or delayed surgery as needed combined with oncologic treatment (hereafer referred to as delayed LRS group [n = 202]). Prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment vs nonsurgical treatment or delayed surgery as needed combined with oncologic treatment. Overall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality, and reoperation rates measured from baseline. Propensity score matching was performed between the 2 groups. The 363 patients included 173 women (47.7%) and 190 men (52.3%), with a mean (SD) age at diagnosis of 62.4 (11.1) years. Two isonumerical groups with 91 patients in each resulted after propensity score matching. The LRS and delayed LRS groups were comparable in median OS (7.9 years [range, 5.1-10.7 years] vs 7.6 years [range, 5.8-9.5 years]; hazard ratio [HR], 0.98; 95% CI, 0.70-1.37; log-rank P = .93) and cancer-specific survival (7.7 years [range, 4.5-10.8 years] vs 7.6 years [range, 5.6-9.7 years]; HR, 0.99; 95% CI, 0.71-1.40; log-rank P = .99). No difference was found in 30-day mortality (0 patients in both matched groups) or postoperative morbidity (2 [2.2%] vs 1 [1.1%]; P > .99), median LOS (73 days [range, 2-270 days] vs 76 days [range, 0-339 days]; P = .64) or LOS due to local tumor-related symptoms (7.0 days [range, 0-90 days] vs 11.5 days [range, 0-69 days]; P = .81), or incisional hernia repairs (4 patients [4.4%] in both groups; P > .99). Patients in the LRS group underwent more reoperative procedures (13 [14.3%]) compared with those in the delayed LRS group (3 [3.3%]) owing to intestinal obstruction (P < .001). Prophylactic up-front LRS conferred no survival advantage in asymptomatic patients with stage IV SI-NETs. Delayed surgery as needed was comparable in all examined outcomes and was associated with fewer reoperations for intestinal obstruction. The value of a priori LRS in the presence of distant metastases is challenged and needs to be elucidated in a randomized clinical study.


Potassium currents inhibition by gambierol analogs prevents human T lymphocyte activation.
Gambierol is a marine polycyclic ether toxin, produced along with ciguatoxin congeners by the dinoflagellate Gambierdiscus toxicus. We have recently reported that two truncated skeletal analogs of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound showed similar potency to gambierol on voltage-gated potassium channels (Kv) inhibition in neurons. Gambierol and its truncated analogs share the main crucial elements for biological activity, which are the C28=C29 double bond within the H-ring and the unsaturated side chain. Since Kv channels are critical for the regulation of calcium signaling, proliferation, secretion and migration in human T lymphocytes, we evaluated the activity of both the tetracyclic and heptacyclic analogs of gambierol on potassium currents in resting T lymphocyte and their effects on interleukin-2 (IL-2) release and gene expression in activated T lymphocytes. The results presented in this work clearly demonstrate that both truncated analogs of gambierol inhibit Kv channels present in resting T lymphocytes (Kv1.3) and prevented lymphocyte activation by concanavalin A. The main effects of the heptacyclic and tetracyclic analogs of gambierol in human T cells are: (1) inhibition of potassium channels in resting and concanavalin-activated T cells in the nanomolar range, (2) inhibition of IL-2 release from concanavalin-activated T cells and (3) negatively affect the expression of genes involved in cell proliferation and immune response observed in concanavalin-activated lymphocytes. These results together with the lack of toxicity in this cellular model, indicates that both analogs of gambierol have additional potential for the development of therapeutic tools in autoimmune diseases.


Variation in the flavonolignan composition of fruits from different Silybum marianum chemotypes and suspension cultures derived therefrom.
Mature fruits collected from different milk thistle (Silybum marianum (L.) Gaertn.) plants, grown in various habitats in Europe, were analysed for silymarin content and variation in component composition. Two different German and Polish cultivars each, as well as fruits from Hungary and Bulgaria have been compared with respect to their ratio of flavonolignan regioisomers. Besides differences in total silymarin content (0.8%-4.9%), three distinct chemotypical variations in fruit flavonolignan regioisomer composition in the cultivars have been observed. Although the differences in the diastereomer ratios of silybin A/B and isosilybin A/B were not significant, they never appeared in a 1:1 ratio. In vitro cultures have been established from seedlings of three typical chemotypes for further insights into flavonolignan content and composition in suspension cultures and the release of these specialized compounds to the extracellular space. The differences in the three Silybum marianum chemotypes were also observed in the composition of the intracellular silymarin of suspension-cultured cells. Silymarin components released to the cell culture medium, however, showed a highly differing composition with only low amounts of silychristin and silydianin. Assays with crude protein extracts prepared from suspension cells or habituated medium of these three chemotypes did not result in differences in silymarin content or composition. In in vitro assays the formation of the regioisomers silydianin and silychristin were strongly influenced by the taxifolin:coniferyl alcohol concentration ratio.


Efficacy and safety of sitosterol in the management of blood cholesterol levels.
Elevated levels of plasma LDL cholesterol (LDL-C) represent a major risk factor for cardiovascular disease. Treatments aimed at reducing levels of circulating LDL are regarded, therefore, as cardioprotective. The cholesterol lowering properties of plant sterols have been known for some time and many clinical studies have confirmed the efficacy of sitosterol in lowering plasma LDL-C concentrations. Animal studies have also shown reductions in LDL by sitosterol. The use of animal models has been useful in facilitating the elucidation of specific mechanisms by which this sterol exerts its hypocholesterolemic action. It is well known that plant sterols compete with cholesterol for space within bile salt micelles in the intestinal lumen thereby reducing cholesterol absorption. The understanding of the function of plant sterols in impeding cholesterol absorption has been clarified with the discovery of the adenosine binding cassette transporters, ABCG5/8, involved in the regulation of sterol absorption and secretion into the enterocyte and hepatocyte. Compared to cholesterol and other sterols, sitosterol is preferentially pumped out to the intestinal lumen by the ABCG5/8 transporters. This selective binding of sitosterol to the transporters ultimately results in significant lowering of plasma cholesterol. However, some findings support the hypothesis that plant sterols might be an additional risk factor for coronary heart disease. From the review of these studies, it is apparent that sitosterol is a useful dietary supplement for the lowering of plasma cholesterol. Nevertheless, this plant sterol should be used with caution in certain individuals who have a higher absorption rate of sitosterol.


[Mechanisms of sexual dysfunction in alloxan diabetic rats].
The hypophysis weight significantly rises in male and female rats suffering from mild alloxan diabetes (prediabetes and the latent disease form). In pronounced diabetes, a decrease in the hypophysis weight is seen. These changes do not correlate with alterations in sex function which is essentially deranged only in pronounced diabetes mellitus when the blood levels of luteinizing hormone (LH), testosterone and estradiol are reduced and the weight of the reproductive organs (prostate and uterus), dependent on the above blood hormone levels, decreases. These indices remain unchanged in prediabetes and the latent diabetes form. In marked diabetes, a rise in gonadotropin-releasing hormone level in the hypothalamic arcuate body is seen that may be indicative of lowering gonadotropin-releasing hormone secretion into the blood rather than of its synthesis reduction in peptiergic neurons. These disturbances are supposed to be primary link in sex dysfunction development in diabetes.


A randomized, double-blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children.
Two hundred and nineteen children (boys: 56%, girls: 44%) were included in a randomized, double-blind, multicentre (4 centres) controlled trial designed to assess the efficacy and safety of ibuprofen (IBU) in the treatment of 1 to 6 year-old children with otoscopically proven acute otitis media (AOM), either unilateral or bilateral. They randomly received 10 mg/kg IBU (n = 71), or acetaminophen (PARA) (n = 73) or placebo (PLA) (n = 75), orally, tid, for 48 hours. All received oral cefaclor (Alfatil, Lilly, France) for seven days. They were evaluated before (D0) and at the end of treatment (D2). The main criterion of response was the aspect (landmarks and color) of the tympanic membrane assessed on a semi-quantitative scale from 0 to 6. Other criteria, assessed on semi-quantitative scales, included relief of pain (0 or 1), rectal temperature (0 to 2), and overall evaluation by parents of the improvement of quality of life on three items: appetite (0 to 2), sleep (0 to 2), and playing activity (0 to 2). The results at D2 were as follows: there was no significant difference between treatment groups as to the main criterion, but only a trend for IBU and PARA to do better than PLA but not for IBU to do better than PARA. From these data there is no argument to emphasize the utility of non-steroidal anti-inflammatory drugs (NSAIDs) in treating the inflammatory signs of the tympanic membrane in otitis. There was a statistically significant difference between treatment groups at D2 for pain, IBU being superior to PLA (P < 0.01): 7%, 10% and 25% of the children were still suffering at D2 in the IBU, PARA and PLA treatment groups, respectively. The difference between PARA and PLA for pain was not statistically significant. There was no significant difference between treatment groups for the other criteria. All treatments were well and equally tolerated. Although no significant difference was found between the treatment groups on the aspect of the tympanic membrane, the efficacy of IBU was evidenced on the relief of pain, the symptom that most disturbs the child.


Using Culture Sensitivity Reports to Optimize Antimicrobial Therapy: Findings and Implications of Antimicrobial Stewardship Activity in a Hospital in Pakistan.
Background: There are concerns with inappropriate prescribing of antibiotics in hospitals especially broad spectrum in Pakistan and the subsequent impact on antimicrobial resistance rates. One recognized way to reduce inappropriate prescribing is for empiric therapy to be adjusted according to the result of culture sensitivity reports. Objective: Using culture sensitivity reports to optimize antibiotic prescribing in a teaching hospital in Pakistan. Methods: A retrospective observational study was undertaken in Ghurki Trust Teaching Hospital. A total of 465 positive cultures were taken from patients during the study period (May 2018 and December 2018). The results of pathogen identification and susceptibility testing from patient-infected sites were assessed. Additional data was collected from the patient's medical file. This included demographic data, sample type, causative microbe, antimicrobial treatment, and whether empiric or definitive treatment as well as medicine costs. Antimicrobial data was assessed using World Health Organization's Defined Daily Dose methodology. Results: A total of 497 isolates were detected from the 465 patient samples as 32 patients had polymicrobes, which included 309 g-negative rods and 188 g-positive cocci. Out of 497 isolates, the most common Gram-positive pathogen isolated was Staphylococcus aureus (Methicillin-sensitive Staphylococcus aureus) (125) (25.1%) and the most common Gram-negative pathogen was Escherichia coli (140) (28.1%). Most of the gram-negative isolates were found to be resistant to ampicillin and co-amoxiclav. Most of the Acinetobacter baumannii isolates were resistant to carbapenems. Gram-positive bacteria showed the maximum sensitivity to linezolid and vancomycin. The most widely used antibiotics for empiric therapy were cefoperazone plus sulbactam, ceftriaxone, amikacin, vancomycin, and metronidazole whereas high use of linezolid, clindamycin, meropenem, and piperacillin + tazobactam was seen in definitive treatment. Empiric therapy was adjusted in 220 (71.1%) cases of Gram-negative infections and 134 (71.2%) cases of Gram-positive infections. Compared with empiric therapy, there was a 13.8% reduction in the number of antibiotics in definitive treatment. The average cost of antibiotics in definitive treatment was less than seen with empiric treatment (8.2%) and the length of hospitalization also decreased. Conclusions: Culture sensitivity reports helped reduced antibiotic utilization and costs as well as helped select the most appropriate treatment. We also found an urgent need for implementing antimicrobial stewardship programs in hospitals and the development of hospital antibiotic guidelines to reduce unnecessary prescribing of broad-spectrum antibiotics.


Factors influencing the immunogenicity of therapeutic proteins.
Several diseases and disorders are treatable with therapeutic proteins, but some of these products may induce an immune response, especially when administered as multiple doses over prolonged periods. Antibodies are created by classical immune reactions or by the breakdown of immune tolerance; the latter is characteristic of human homologue products. Many factors influence the immunogenicity of proteins, including structural features (sequence variation and glycosylation), storage conditions (denaturation, or aggregation caused by oxidation), contaminants or impurities in the preparation, dose and length of treatment, as well as the route of administration, appropriate formulation and the genetic characteristics of patients. The clinical manifestations of antibodies directed against a given protein may include loss of efficacy, neutralization of the natural counterpart and general immune system effects (including allergy, anaphylaxis or serum sickness). An upsurge in the incidence of antibody-mediated pure red cell aplasia (PRCA) among patients taking one particular formulation of recombinant human erythropoietin (epoetin-alpha, marketed as Eprex(R)/Erypo(R); Johnson & Johnson) in Europe caused widespread concern. The PRCA upsurge coincided with removal of human serum albumin from epoetin-alpha in 1998 and its replacement with glycine and polysorbate 80. Although the immunogenic potential of this particular product may have been enhanced by the way the product was stored, handled and administered, it should be noted that the subcutaneous route of administration does not confer immunogenicity per se. The possible role of micelle (polysorbate 80 plus epoetin-alpha) formation in the PRCA upsurge with Eprex is currently being investigated.


Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells.
NK cells in the human lung respond to influenza A virus- (IAV-) infected target cells. However, the detailed functional capacity of human lung and peripheral blood NK cells remains to be determined in IAV and other respiratory viral infections. Here, we investigated the effects of IAV infection on human lung and peripheral blood NK cells in vitro and ex vivo following clinical infection. IAV infection of lung- and peripheral blood-derived mononuclear cells in vitro induced NK cell hyperresponsiveness to K562 target cells, including increased degranulation and cytokine production particularly in the CD56brightCD16- subset of NK cells. Furthermore, lung CD16- NK cells showed increased IAV-mediated but target cell-independent activation compared to CD16+ lung NK cells or total NK cells in peripheral blood. IAV infection rendered peripheral blood NK cells responsive toward the normally NK cell-resistant lung epithelial cell line A549, indicating that NK cell activation during IAV infection could contribute to killing of surrounding non-infected epithelial cells. In vivo, peripheral blood CD56dimCD16+ and CD56brightCD16- NK cells were primed during acute IAV infection, and a small subset of CD16-CD49a+CXCR3+ NK cells could be identified, with CD49a and CXCR3 potentially promoting homing to and tissue-retention in the lung during acute infection. Together, we show that IAV respiratory viral infections prime otherwise hyporesponsive lung NK cells, indicating that both CD16+ and CD16- NK cells including CD16-CD49a+ tissue-resident NK cells could contribute to host immunity but possibly also tissue damage in clinical IAV infection.


[Home mechanical ventilation as a treatment of the sequelae of tuberculosis surgery].
Nasal intermittent positive-pressure ventilation (NIPPV) has been showed useful for the treatment of chronic respiratory failure in patients with chest wall diseases due to sequelae of tuberculosis. We present a report of a patient with a thoracoplasty and a cavernostomy in situation of chronic respiratory failure. Nasal intermittent positive pressure ventilation improved diurnal hypoxaemia and hypercapnia.


Ion-pair chromatography coupled to inductively coupled plasma-mass spectrometry (IPC-ICP-MS) as a method for thiomolybdate speciation in natural waters.
Molybdenum precipitates preferentially under reducing conditions; therefore, its occurrence in sediment records is used as an indicator of paleoredox conditions. Although thiomolybdates (MoO4-xSx(2-) with x = 1-4) supposedly are necessary intermediates in the process of molybdenum precipitation under anoxic conditions, there is no information about their abundance in natural environments, because of a lack of element-specific methods with sufficiently low detection limits. Here, we optimized ion-pair chromatographic separation for coupling to an inductively coupled plasma-mass spectrometry detector (IPC-ICP-MS). 2-Propanol (10%-25% gradient) replaced the previously used acetonitrile (25%-75%) as the solvent, to reduce the carbon load into the plasma. In synthetic solutions, formation of thiomolybdates was found to occur spontaneously in the presence of excess sulfide and the degree of thiolation was highest at pH 7. Excess hydroxyl led to a transformation of thiomolybdates to molybdate. Under acidic to neutral conditions, precipitation of molybdenum and hydrolysis of tetrathiomolybdate were observed. Flash-freezing was found to be suitable to stabilize tetrathiomolybdate, with <4% transformation over more than two months. High ionic strengths matrices (>2 mM) negatively affected the detection of molybdate, which eluted mainly in the dead volume, but had no negative effect on higher thiolated molybdates. Detection limits were ∼10 nM. With the newly developed IPC-ICP-MS method, thiomolybdates were found to form spontaneously in euxinic marine waters after adding a molybdate spike and occur naturally in sulfidic geothermal waters.


Endoscopic sphincterotomy in acute biliary pancreatitis: A question of anesthesiological risk.
Two consecutive surveys of acute pancreatitis in Italy, based on more than 1000 patients with acute pancreatitis, reported that the etiology of the disease indicates biliary origin in about 60% of the cases. The United Kingdom guidelines report that severe gallstone pancreatitis in the presence of increasingly deranged liver function tests and signs of cholangitis (fever, rigors, and positive blood cultures) requires an immediate and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). These guidelines also recommend that patients with gallstone pancreatitis should undergo prompt cholecystectomy, possibly during the same hospitalization. However, a certain percentage of patients are unfit for cholecystectomy because advanced age and presence of comorbidity. We evaluated the early and long-term results of endoscopic intervention in relation to the anesthesiological risk for 87 patients with acute biliary pancreatitis. All patients underwent ERCP and were evaluated according to the American Society of Anesthesiology (ASA) criteria immediately before the operative procedure. The severity of acute pancreatitis was positively related to the anesthesiological grade. There was no significant relationship between the frequency of biliopancreatic complications during the follow-up and the ASA grade. The frequency of cholecystectomy was inversely related to the ASA grade and multivariate analysis showed that the ASA grade and age were significantly related to survival. Finally, endoscopic treatment also appeared to be safe and effective in patients at high anesthesiological risk with acute pancreatitis. These results further support the hypothesis that endoscopic sphincterotomy might be considered a definitive treatment for patients with acute biliary pancreatitis and an elevated ASA grade.


Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?
Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.


Chronotypic action of theophylline and of pentobarbital as circadian zeitgebers in the rat.
In the rat the deep body temperature rhythm, monitored by telemetry, can be reset in a predictable direction by a stimulant (theopylline) and by a depressant (pentobarbital). When the drugs are applied immediately before or during the early active phases of the circadian cycle, the rhythm is set back (phase delay). When applied later, past the thermal peak, theophylline, but not pentobarbital, shifts the rhythm ahead (phase advance). Theophylline and pentobarbital in addition to having a number of already established pharmacological properties are now further identified as chronobiotics: they are drugs that may be used to alter the biological time structure by rephasing a circadian rhythm.


Can laparoscopic surgery be applied in gastric gastrointestinal stromal tumors located in unfavorable sites?: A study based on the NCCN guidelines.
This article investigated the feasibility of laparoscopic surgery in unfavorable site gastric gastrointestinal stromal tumors (GISTs).We identified 214 patients who underwent primary gastric GIST resection at our institution (January 2006-December 2014) from a prospectively collected database. These patients were divided into a Favorable group (140 cases) and an Unfavorable group (74 cases) according to the 2014 version of the National Comprehensive Cancer Network Clinical Guidelines (NCCN guidelines).The wedge resection rate of the Favorable group was higher than that of the Unfavorable group, and most procedures were performed laparoscopically (P < 0.05). In addition, there were no differences in the other clinicopathological features between these groups (P > 0.05). The postoperative stay of the Unfavorable group was longer than that of the Favorable group (P = 0.02). Laparoscopic surgery in both groups resulted in a shorter operative time, lower blood loss, faster time to first flatus, faster time to first fluid diet, and shorter postoperative stay than open surgery (P < 0.05). Although the difference was not significant (P = 0.09), the postoperative complication incidence of the Favorable group was less than that of the Unfavorable group (10% vs 17.6%). Furthermore, in the Unfavorable group, the incidence of postoperative complications from laparoscopic surgery was significantly lower than that of open surgery (P = 0.001). There were no differences in the 5-year overall survival (OS) and recurrence-free survival (RFS) of these groups (P > 0.05). Furthermore, in the Unfavorable group, the 5-year OS and RFS were similar for both laparoscopic and open procedures. Multivariate Cox regression analysis showed that imatinib (IM) treatment was an independent risk factor for poor prognosis.Laparoscopic operation for gastric GISTs located in unfavorable sites can yield similar long-term outcomes compared with an open operation. However, laparoscopic surgery has the obvious advantage of being minimally invasive, and the incidence of postoperative complications was low. Laparoscopic surgery is thus an option for the treatment of localized gastric GISTs.


Personality types revisited-a literature-informed and data-driven approach to an integration of prototypical and dimensional constructs of personality description.
A new algorithmic approach to personality prototyping based on Big Five traits was applied to a large representative and longitudinal German dataset (N = 22,820) including behavior, personality and health correlates. We applied three different clustering techniques, latent profile analysis, the k-means method and spectral clustering algorithms. The resulting cluster centers, i.e. the personality prototypes, were evaluated using a large number of internal and external validity criteria including health, locus of control, self-esteem, impulsivity, risk-taking and wellbeing. The best-fitting prototypical personality profiles were labeled according to their Euclidean distances to averaged personality type profiles identified in a review of previous studies on personality types. This procedure yielded a five-cluster solution: resilient, overcontroller, undercontroller, reserved and vulnerable-resilient. Reliability and construct validity could be confirmed. We discuss wether personality types could comprise a bridge between personality and clinical psychology as well as between developmental psychology and resilience research.


[Epidemiological surveillance of HIV/AIDS in Navarra].
More than fifteen years have passed since the first cases of AIDS were diagnosed in Navarra in 1985. According to the notifications received from then until December 2001, 2,400 people have been counted with HIV infection, of whom approximately 700 have developed AIDS, and 565 have died of AIDS or other causes. The incidence of new infections by HIV, cases of AIDS and deaths related to the latter, have shown a clear tendency to decline in Navarra in recent years. The decrease in cases is very important amongst the users of intravenous drugs, while the cases amongst masculine homo/bisexuals and amongst persons infected following a heterosexual encounter have remained fairly stable. For the first time, starting in 1999, persons infected through a sexual encounter are higher than the users of parenteral drugs. There has been an increase in the proportion of cases of AIDS and infection in persons originating from countries where the disease is endemic, accounting for over 23% of new cases of infection in the years 2000 and 2001. The figures for Navarra also reflect the important reduction of cases of AIDS and AIDS-related deaths since the introduction of more efficient anti-retroviral treatments in 1996. The strategies for the detection of HIV infection in persons who have maintained risk practices is important if we consider that in the years 2000 and 2001, there was a simultaneous diagnosis of infection and disease in one in every five patients. This implies that these persons did not benefit from treatments in the same way as they would have if the diagnosis had been made earlier.


Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic?
Temporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary brain injury that occurred a long time before the appearance of neurological symptoms. This type of epilepsy is characterized by refractoriness to drug treatment, so to require surgical resection of mesial temporal regions involved in seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor and channel functioning and modifications in other cellular components. In particular, a growing body of evidence from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive therapies.


Reciprocity among maternal distress, child behavior, and parenting: transactional processes and early childhood risk.
Transactional theories support that parent-child processes are best studied in conjunction with one another, addressing their reciprocal influence and change across time. This study tested a longitudinal, autoregressive model exploring bidirectional relations among maternal symptomatology, child internalizing/externalizing symptoms, and maternal sensitivity during the preschool period (child ages 3 to 5 years), comparing relations among families of typically developing children and children with developmental risk. This study included 250 families, 110 of which had a child with early developmental delay. Analyses utilized data from maternal report, father report, and observational methods. The results indicated significant stability in maternal symptomatology, child internalizing/externalizing symptoms, and maternal sensitivity over time. Support for bidirectional effects between maternal symptomatology and child internalizing symptoms was found specifically for mothers of children with developmental risk. Maternal symptomatology was found to mediate the influence of child internalizing and externalizing symptoms on maternal sensitivity. The findings underscore critical transactional processes within families of children with early developmental risk that connect increased maternal symptomatology to emerging child internalizing symptoms during the preschool period.


Probing the effect of tip pressure on fungal growth: Application to Aspergillus nidulans.
The study of fungal cells is of great interest due to their importance as pathogens and as fermenting fungi and for their appropriateness as model organisms. The differential pressure between the hyphal cytoplasm and the bordering medium is essential for the growth process, because the pressure is correlated with the growth rate. Notably, during the invasion of tissues, the external pressure at the tip of the hypha may be different from the pressure in the surrounding medium. We report the use of a method, based on the micropipette-aspiration technique, to study the influence of this external pressure at the hyphal tip. Moreover, this technique makes it possible to study hyphal growth mechanics in the case of very thin hyphae, not accessible to turgor pressure probes. We found a correlation between the local pressure at the tip and the growth rate for the species Arpergillus nidulans. Importantly, the proposed method allows one to measure the pressure at the tip required to arrest the hyphal growth. Determining that pressure could be useful to develop new medical treatments for fungal infections. Finally, we provide a mechanical model for these experiments, taking into account the cytoplasm flow and the wall deformation.


A decade of progress in lymphoma: advances and continuing challenges.
Our ability to manage patients with non-Hodgkin lymphoma and Hodgkin lymphoma has improved dramatically in the past decade. The survival of patients with the two most frequent lymphomas (ie, diffuse large B-cell lymphoma and follicular lymphoma), have improved significantly with the incorporation of rituximab as a standard treatment regimen. New insights into the biology of lymphomas provided by studying patterns of gene expression have improved our ability to classify these diseases. Identifying the treatments most effective with different patterns of gene expression offers the opportunity to further improve treatment outcomes. We now cure most patients with Hodgkin lymphoma, but the past decade has seen advances in our ability to identify patients who are most likely to be cured with less toxic treatment approaches. Unfortunately, our ability to improve the treatment of patients with peripheral T-cell lymphoma has not kept pace with the management of those suffering from B-cell lymphomas. However, better classification systems, improved understanding of the biology of these disorders, and clinical trials aimed specifically at identifying optimal regimens for patients with aggressive peripheral T-cell lymphomas offer hope to improve treatment results over the next decade.


Inclusion of the equity focus and social determinants of health in health care education programmes in Colombia: a qualitative approach.
The Pan American Health Organization (PAHO) and the Colombian Ministry of Health and Social Protection have determined a need for an approach to include Equity Focus (EF) and Social Determinants of Health (SDH) in health training programmes in Colombia. We studied the incorporation of EF and SDH in the curricula of several universities in Colombia to identify opportunities to strengthen their inclusion. Qualitative methodology was performed in two stages: (i) initial exploration (self-administered questionnaires and review of curricula) and (ii) validation of the information (semi-structured interviews). The inclusion of the EF and SDH in university curricula is regarded as an opportunity to address social problems. This approach addresses a broad cross-section of the curriculum, especially in the subjects of public health and Primary Health Care (PHC), where community outreach generates greater internalization by students. The dominance of the biomedical model of study plans and practice scenarios focusing on disease and little emphasis on community outreach are factors that limit the inclusion of the approach. The inclusion of EF and SDH in university curricula in Colombia has primarily focused on increasing the knowledge of various subjects oriented towards understanding the social dynamics or comprehensiveness of health and disease and, in some programmes, through practical courses in community health and PHC. Increased integration of EF and SDH in subjects or modules with clinical orientation is recommended.


Plasma cell-free DNA methylation combined with tumor mutation detection in prognostic prediction of patients with non-small cell lung cancer (NSCLC).
Lung Cancer is one of the most common cancers with high degree of malignancy, is a devastating disease with a poor prognosis worldwide. prognostic prediction for patients with non small-cell lung cancer (NSCLC) is still challenge. The cohort consisted of 64 consecutive patients with NSCLC identified from June1, 2014, to June 30, 2018. Liquid biopsy samples were collected. Genomic mutation DNA was calculated by including all substitutions and indels over the entire somatic, coding, sequencing length. statistical evaluations were carried out using SPSS software. Quantity of total ctDNA was successfully determined in all 64 patients from whom baseline circulating DNA was available. ctDNA concentration ranged from 4000 to 3,562,000 genome equivalents per milliliter. Treatments induced a significant decrease in cancer specific markers in most patients with response to treatments, while the methylated DNA demonstrated favorable prediction efficiency regardless of the response status. Patients with ctDNA mutation and methylated DNA decreasing have favorable overall survival (P < .05). combination of genetic and methylated DNA decreasing had high reliability in predicting overall survival of patients with NSCLC. We have detected both tumor mutations and methylated DNA in plasma of patients with NSCLC. Combined genetic and methylated DNA decreasing after treatment was an independent risk factor for prognosis of patients with NSCLC. Meanwhile, it had favorable predict value and had potential to be defined as a novel biomarker for patients with NSCLC.


Comparison of three strains of diabetic rats with respect to the rate at which retinopathy and tactile allodynia develop.
We compared three rat strains to determine if different strains develop early-stage diabetic retinopathy or sensory neuropathy at different rates. Sprague Dawley, Lewis, and Wistar rats were made diabetic with streptozotocin. Diabetic and nondiabetic animals had retinal vascular pathology measured at eight months of diabetes. The number of cells in the retinal ganglion cell layer (GCL), retinal function (using electroretinography [ERG]), and retinal levels of inducible nitric oxide synthase (iNOS), cyclooxygenase2 (COX2), and vascular endothelial growth factor (VEGF) were measured at four months of diabetes. Tactile allodynia was assessed in hind paws at two months of diabetes. Diabetes of eight months' duration resulted in a significant increase in retinal degenerate capillaries and pericyte ghosts in Lewis and Wistar rats, but not in Sprague Dawley rats. A significant loss of cells in the GCL occurred only in diabetic Lewis rats, whereas Wistar and Sprague Dawley rats showed little change. Diabetes-induced iNOS and VEGF were statistically significant in all strains. Cyclooxygenase 2 (COX2) was significantly elevated in the Sprague Dawley and Wistar strains. Lewis rats showed a similar trend, however, the results were not statistically significant. All strains tended to show diabetes-induced impairment of dark-adapted b-wave amplitude, but only Sprague Dawley and Lewis strains had a significant reduction in latency. All strains showed significant tactile allodynia in peripheral nerves. At the durations studied, Lewis rats showed accelerated loss of both retinal capillaries and ganglion cells in diabetes, whereas diabetic Wistar rats showed degeneration of the capillaries without significant neurodegeneration, and Sprague Dawley rats showed neither lesion. Identification of strains that develop retinal lesions at different rates should be of value in investigating the pathogenesis of retinopathy.


[Etiology of a nephrotic form of primary chronic glomerulonephritis in children].
As many as 91 children with the nephrotic and hematuric forms of primary chronic glomerulonephritis were examined for the presence of streptococcal infection and allergic diseases. It has been shown that as compared to patients with the hematuric form of chronic glomerulonephritis, those with the nephrotic form manifest a higher occurrence of A3, a dramatic rise of serum IgE and its dependence on the activity of glomerulonephritis. The data obtained may attest to the etiological role played by allergy in the development of the nephrotic form of glomerulonephritis. Frequently occurring colonization of hemolytic streptococcus in the fauces and the rise of the ASL-O titer in the blood serum seen in patients with the hematuric form of glomerulonephritis, its dependence on the disease activity suggest the streptococcal etiology in patients with that form in contrast to those with the nephrotic form.


Using and joining a franchised private sector provider network in Myanmar.
Quality is central to understanding provider motivations to join and remain within a social franchising network. Quality also appears as a key issue from the client's perspective, and may influence why a client chooses to use a franchised provider over another type of provider. The dynamic relationships between providers of social franchising clinics and clients who use these services have not been thoroughly investigated in the context of Myanmar, which has an established social franchising network. This study examines client motivations to use a Sun Quality Health network provider and provider motivations to join and remain in the Sun Quality Health network. Taken together, these two aims provide an opportunity to explore the symbiotic relationship between client satisfaction and provider incentives to increase the utilization of reproductive health care services. Results from a series of focus group discussions with clients of reproductive health services and franchised providers shows that women chose health services provided by franchised private sector general practitioners because of its perceived higher quality, associated with the availability of effective, affordable, drugs. A key finding of the study is associated with providers. Provider focus group discussions indicate that a principle determinate for joining and remaining in the Sun Quality Health Network was serving the poor.


Effects of previous noxious stimulus applied to remote areas on noxious stimulus-evoked c-Fos expression in the rat trigeminal nucleus caudalis.
Noxious stimulus-evoked c-Fos expression in the spinal dorsal horn is modulated by noxious stimuli applied previously to remote areas of the body. To confirm the existence of such modulation in c-Fos expression in the trigeminal system, changes in c-Fos expression in the trigeminal nucleus caudalis induced by formalin injection into the rat whisker pad were examined by previously injecting formalin into different areas (contralateral whisker pad, ipsilateral or contralateral forepaw) of the body. Formalin injection-evoked c-Fos expression in this nucleus was significantly reduced by previous formalin injection into the contralateral whisker pad or ipsilateral forepaw but not into the contralateral forepaw. The interval between the two injections of formalin that produced a maximal reduction of formalin injection-evoked c-Fos expression was 1 h, and the reduction of c-Fos expression was less when the interval of the two noxious stimuli was longer or shorter than 1 h. These results suggested that noxious stimulus-evoked c-Fos expression in the trigeminal nucleus caudalis is reduced by noxious stimulus applied previously to remote areas, and the reduction is dependent on the area of previous noxious stimulation and interval between the two noxious stimuli.


Modeling and Observation of Nonlinear Damping in Dissipation-Diluted Nanomechanical Resonators.
Dissipation dilution enables extremely low linear loss in stressed, high aspect ratio nanomechanical resonators, such as strings or membranes. Here, we report on the observation and theoretical modeling of nonlinear dissipation in such structures. We introduce an analytical model based on von Kármán theory, which can be numerically evaluated using finite-element models for arbitrary geometries. We use this approach to predict nonlinear loss and (Duffing) frequency shift in ultracoherent phononic membrane resonators. A set of systematic measurements with silicon nitride membranes shows good agreement with the model for low-order soft-clamped modes. Our analysis also reveals quantitative connections between these nonlinearities and dissipation dilution. This is of interest for future device design and can provide important insight when diagnosing the performance of dissipation dilution in an experimental setting.


Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male mice, but not DBA/2J or A/J male mice.
Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported. The current set of studies further investigates, in three commonly studied mouse strains, the effect of footshock stress on ethanol self-administration. Furthermore, the effect of footshock on plasma corticosterone levels was determined to investigate potential biochemical correlates. Adult male C57BL/6J, DBA/2J, and A/J mice were allowed to self-administer 10% (wt/vol) ethanol for 12 days in a standard 23-h two-bottle paradigm before receiving either 15 min of mild inescapable footshock or no footshock. Shock intensity was equal to the mean intensity at which each strain vocalized as previously determined. Following footshock, animals had the opportunity to self-administer ethanol for an additional 23 h. Separate animals were subjected to either footshock or no shock prior to collection of plasma for corticosterone. Mild footshock stress altered ethanol self-administration and increased plasma corticosterone levels in C57BL/6J mice. Footshock stress did not alter ethanol self-administration or plasma corticosterone levels in DBA/2J or A/J mice. These data demonstrate that mild footshock stress is a suboptimal method of modeling the stress-induced increases in ethanol consumption often reported by humans.


Molecular Insight into Gene Response of Diorcinol- and Rubrolide-Treated Biofilms of the Emerging Pathogen Stenotrophomonas maltophilia.
Stenotrophomonas maltophilia is a multidrug-resistant human opportunistic pathogen. S. maltophilia contributes to disease progression in cystic fibrosis patients and is found in wounds and infected tissues and on catheter surfaces. Due to its well-known multidrug resistance, it is difficult to treat S. maltophilia infections. Strain-specific susceptibility to antimicrobials has also been reported in several studies. Recently, three fungal diorcinols and 14 rubrolides were shown to reduce S. maltophilia K279a biofilm formation. Based on these initial findings, we were interested to extend this approach by testing a larger number of diorcinols and rubrolides and to understand the molecular mechanisms behind the observed antibiofilm effects. Of 52 tested compounds, 30 were able to significantly reduce the biofilm thickness by up to 85% ± 15% and had strong effects on mature biofilms. All compounds with antibiofilm activity also significantly affected the biofilm architecture. Additional RNA-sequencing data of diorcinol- and rubrolide-treated biofilm cells of two clinical isolates (454 and K279) identified a small set of shared genes that were affected by these potent antibiofilm compounds. Among these, genes for iron transport, general metabolism, and membrane biosynthesis were most strongly and differentially regulated. A further hierarchical clustering and detailed structural inspection of the diorcinols and rubrolides implied that a prenyl group as side chain of one of the phenyl groups of the diorcinols and an increasing degree of bromination of chlorinated rubrolides were possibly the cause of the strong antibiofilm effects. This study gives a deep insight into the effects of rubrolides and diorcinols on biofilms formed by the important global pathogen S. maltophilia. IMPORTANCE Combating Stenotrophomonas maltophilia biofilms in clinical and industrial settings has proven to be challenging. S. maltophilia is multidrug resistant, and occurrence of resistance to commonly used drugs as well as to antibiotic combinations, such as trimethoprim-sulfamethoxazole, is now frequently reported. It is therefore now necessary to look beyond conventional and already existing antimicrobial drugs when battling S. maltophilia biofilms. Our study contains comprehensive and detailed data sets for diorcinol and rubrolide-treated S. maltophilia biofilms. The study defines genes and pathways affected by treatment with these different compounds. These results, together with the identified structural elements that may be crucial for their antibiofilm activity, build a strong backbone for further research on diorcinols and rubrolides as novel and potent antibiofilm compounds.


Molecular diagnosis of Ewing's sarcoma/primitive neuroectodermal tumor in formalin-fixed paraffin-embedded tissues by RT-PCR and fluorescence in situ hybridization.
Recent studies have suggested that formalin-fixed paraffin-embedded (FFPE) tissues can be used for molecular analyses by fluorescence in situ hybridization (FISH) and RT-PCR. We analyzed 18 cases of ES/PNET for the t(11;22)(q24;q12) and t(21;22)(q22;q12) fusion transcripts by RT-PCR and analyzed for EWS translocation by interphase FISH with a dual color fusion probe to compare these two approaches directly. RT-PCR detected 13 (72%) EWS-FLI-1 fusions (type I=10, type II=3) and 2 (11%) EWS-ERG fusions. Three cases could not be evaluated because the housekeeping gene phosphoglycerate kinase (internal mRNA control) was not amplified. FISH was diagnostic in 15 of 18 cases (83%). There were three discordant cases between RT-PCR and FISH (concordance of 83%). Using a combination of RT-PCR and FISH, the results were complementary. One advantage of RT-PCR analysis was that subtypes of EWS translocation could be determined specifically (type I, type II and ERG). These findings indicate that because of the difficulties and limitations associated with the molecular analysis of FFPE tissues, a combination of RT-PCR and FISH may be a better approach to enhance the sensitivity and accuracy of detecting ES/PNET translocations in FFPE tissues with suboptimally preserved nucleic acids.


Evidence for the roles of histamine and prostaglandins as mediators in exercise-induced asthma: the inhibitory effect of terfenadine and flurbiprofen alone and in combination.
We investigated the effects of terfenadine, a histamine H1-receptor antagonist, and flurbiprofen, a cyclooxygenase inhibitor, on exercise-induced bronchoconstriction to assess the contribution of the mast cell products histamine and prostaglandins. Eight asthmatics were studied on 4 occasions with treadmill exercise tests. Terfenadine or placebo was administered 3 h prior to exercise, and flurbiprofen or placebo was administered 2 h prior to exercise, in a double-blind randomized trial. Airway calibre was determined by measurement of the forced expiratory volume in one second (FEV1) immediately prior to exercise challenge, and over 30 min post-exercise. Following placebo, the mean maximum percentage fall in FEV1 was 39%. This fell to 25% after terfenadine (p less than 0.05), 27% after flurbiprofen (p less than 0.05), and 30% after the active combination (NS). Analysis of the areas under curves of percentage falls in FEV1 over 30 min showed significant inhibition on all 3 active drug days (p less than 0.05). We conclude that histamine release and prostaglandin generation contribute to exercise-induced bronchoconstriction, although the interaction between these mediators appears complex.


Inferring product healthfulness from nutrition labelling. The influence of reference points.
Despite considerable research on nutrition labelling, it has proven difficult to find a front-of-pack label which is informative about product healthfulness across various situations. This study examines the ability of different types of nutrition labelling schemes (multiple traffic light label, nutrition table, GDA, logo) to communicate product healthfulness (a) across different product categories, (b) between options from the same product category, and (c) when viewed in isolation and in comparison with another product. Results of two experiments in Germany and The Netherlands show that a labelling scheme with reference point information at the nutrient level (e.g., the traffic light label) can achieve all three objectives. Although other types of labelling schemes are also capable of communicating healthfulness, labelling schemes lacking reference point information (e.g., nutrition tables) are less effective when no comparison product is available, and labelling schemes based on overall product healthfulness within the category (e.g., logos) can diminish consumers' ability to differentiate between categories, leading to a potential misinterpretation of product healthfulness. None of the labels affected food preferences.


Effects of Cornus mas L. and Morus rubra L. extracts on penicillin-induced epileptiform activity: an electrophysiological and biochemical study.
Traditionally, Morus rubra L. (Moraceae) (red mulberry) and Cornus mas L. (Cornacea) (cornelian cherry) fruits are eaten fresh and are also used in marmalades, juices, jam, natural dyes in Turkey and are believed to have beneficial effects in case of multiple health issues such as antipyretic, diarrhea and intestinal parasites. However, the effects of M. rubra and C. mas on epilepsy has not been known. This study evaluates the effects of M. rubra and C. mas extracts on penicillin-induced epileptiform activity. Sixty Wistar rats randomly divided into ten groups (n=6): control, sham, penicillin, penicillin+M. rubra extract (2.5, 5, 10, 20 mg/kg) and penicillin+C. mas extract (2.5, 5, 10 mg/kg). Epileptiform activity was induced by using penicillin (500 IU, i.c.) and electrocorticogram records (150 min) were obtained. Also, biochemical analysis in blood samples were evaluated. According to the electrocorticogram analysis, the effective dose was detected as 10 mg/kg for both C. mas and M. rubra. This dose decreased the spike frequencies of convulsions while amplitude wasn't changed by both substances. In erythrocyte studies, there were significant differences regarding nitric oxide in the control, sham and penicillin groups. There were significant differences regarding malondialdehyde in all groups. In the plasma, there were significant differences among groups regarding xanthine oxidase in the penicillin‑C. mas and penicillin‑M. rubra groups. There were differences regarding malondialdehyde in the penicillin-C. mas and M. rubra-C. mas groups. Both extracts reduced the frequency of epileptiform activity. After administration of the extracts malondialdehyde levels decreased also in both erythrocytes and plasma.


Fit for genomic and proteomic purposes: Sampling the fitness of nucleic acid and protein derivatives from formalin fixed paraffin embedded tissue.
The demand for nucleic acid and protein derivatives from formalin-fixed paraffin-embedded (FFPE) tissue has greatly increased due to advances in extraction and purification methods, making these derivatives available for numerous genomic and proteomic platforms. Previously, DNA, RNA, microRNA (miRNA), or protein derived from FFPE tissue blocks were considered "unfit" for such platforms, as the process of tissue immobilization by FFPE resulted in cross-linked, fragmented, and chemically modified macromolecules. We conducted a systematic examination of nucleic acids and proteins co-extracted from 118 FFPE blocks sampled from the AIDS and Cancer Specimen Resource (ACSR) at The George Washington University after stratification by storage duration and the three most common tumor tissue types at the ACSR (adenocarcinoma, squamous cell carcinoma, and papillary carcinoma). DNA, RNA, miRNA, and protein could be co-extracted from 98% of the FFPE blocks sampled, with DNA and miRNA "fit" for diverse genomic purposes including sequencing. While RNA was the most labile of the FFPE derivatives, especially when assessed by RNA integrity number (RIN), it was still "fit" for genomic methods that use smaller sequence lengths, e.g., quantitative PCR. While more than half of the protein derivatives were fit for proteomic purposes, our analyses indicated a significant interaction effect on the absorbance values for proteins derived from FFPE, implying that storage duration may affect protein derivatives differently by tumor tissue type. The mean absorbance value for proteins derived from more recently stored FFPE was greater than protein derived from older FFPE, with the exception of adenocarcinoma tissue. Finally, the fitness of one type of derivative was weakly associated with the fitness of derivatives co-extracted from the same FFPE block. The current study used several novel quality assurance approaches and metrics to show that archival FFPE tissue blocks are a valuable resource for contemporary genomic and proteomic platforms.


Osteocalcin, energy and glucose metabolism.
Osteocalcin is a bone matrix protein that has been associated with several hormonal actions on energy and glucose metabolism. Animal and experimental models have shown that osteocalcin is released into the bloodstream and exerts biological effects on pancreatic beta cells and adipose tissue. Undercarboxylated osteocalcin is the hormonally active isoform and stimulates insulin secretion and enhances insulin sensitivity in adipose tissue and muscle. Insulin and leptin, in turn, act on bone tissue, modulating the osteocalcin secretion, in a traditional feedback mechanism that places the skeleton as a true endocrine organ. Further studies are required to elucidate the role of osteocalcin in the regulation of glucose and energy metabolism in humans and its potential therapeutic implications in diabetes, obesity and metabolic syndrome.


Rapid and accurate direct injection chromatographic method for measuring volatile anesthetics in whole blood of dogs.
A modified rapid, accurate, and relatively simple gas chromatographic procedure was used for the analysis of a single hydrocarbon volatile anesthetic agent in whole arterial blood of dogs. Lengthy extraction procedures and laborious chromatographic separations were avoided. The glassware required was inexpensive and readily available, as were rubber and rubber-laminated Teflon septa which were excellent for making air-tight seals. Variations in blood pH, lipid content, protein concentration, hematocrit, and other components of whole blood will influence the solubility of the anesthetics. However, the procedure described in the present report was corrected for those factors by constructing standard curves with blood from each experimental dog. The arterial concentration of methoxyflurane (MTF) in 25 dogs was determined at 60 and 120 minutes of surgical anesthesia. Arterial concentrations of MTF at 60 minutes of anesthesia ranged from 7.29 to 41.7 mg/dl of blood, and at least 120 minutes, the range was from 9.02 to 55. There was no significant difference in arterial blood concentrations of MTF (P greater than 0.05) at 60 and 120 minutes of anesthesia.


Gadd45a inhibits cell migration and invasion by altering the global RNA expression.
Gadd45a, the first well-defined p53 downstream gene, can be induced by multiple DNA-damaging agents, which plays important roles in the control of cell cycle checkpoint, DNA repair process and signaling transduction. Our previous findings suggested that Gadd45a maintains cell-cell adhesion and cell contact inhibition. However, little is known about how Gadd45a participates in the suppression of malignancy in human cancer cells. To examine the functions of Gadd45a in cell invasion and metastasis, we performed the adhesion, wound-healing and transwell assays in Gadd45a (+/+) and Gadd45a (-/-) MEF cell lines. We found the adhesion, migration and invasive abilities were much higher in Gadd45a deficient cells. We furthermore applied high-throughput cDNA microarray analysis and bioinformatics analysis to analyze the mechanisms of Gadd45a gene in invasion and metastasis. Compared with the Gadd45a wild type cells, the Gadd45a deficient cells showed a wide range of transcripts alterations. The altered gene pathways were predicted by the MAS software, which indicated focal adhesion,cell communication,ECM-receptor interaction as the three main pathways. Real-time PCR was employed to validate the differentially expressed genes. Interestingly, we figured out that the deregulations of these genes are caused neither by genomic aberrations nor methylation status. These findings provided a novel insight that Gadd45a may involve in tumor progression by regulating related genes expressions.


Optical Monitoring of Breathing Patterns and Tissue Oxygenation: A Potential Application in COVID-19 Screening and Monitoring.
The worldwide outbreak of the novel Coronavirus (COVID-19) has highlighted the need for a screening and monitoring system for infectious respiratory diseases in the acute and chronic phase. The purpose of this study was to examine the feasibility of using a wearable near-infrared spectroscopy (NIRS) sensor to collect respiratory signals and distinguish between normal and simulated pathological breathing. Twenty-one healthy adults participated in an experiment that examined five separate breathing conditions. Respiratory signals were collected with a continuous-wave NIRS sensor (PortaLite, Artinis Medical Systems) affixed over the sternal manubrium. Following a three-minute baseline, participants began five minutes of imposed difficult breathing using a respiratory trainer. After a five minute recovery period, participants began five minutes of imposed rapid and shallow breathing. The study concluded with five additional minutes of regular breathing. NIRS signals were analyzed using a machine learning model to distinguish between normal and simulated pathological breathing. Three features: breathing interval, breathing depth, and O2Hb signal amplitude were extracted from the NIRS data and, when used together, resulted in a weighted average accuracy of 0.87. This study demonstrated that a wearable NIRS sensor can monitor respiratory patterns continuously and non-invasively and we identified three respiratory features that can distinguish between normal and simulated pathological breathing.


Enhancement of dengue virus translation: role of the 3' untranslated region and the terminal 3' stem-loop domain.
An essential step for a productive infection by the dengue flavivirus (DEN) is translation of the m(7)G-capped, nonpolyadenylated positive-sense RNA genome. We have recently identified sequences within the DEN 3' untranslated region (UTR) that modulate viral translation. Here, we show that the DEN type 2 (DEN2) 3'UTR stimulated translation of m(7)G-capped DEN2 5'UTR-containing reporter mRNAs in baby hamster kidney (BHK) cells compared to a 3' vector sequence. Analogous to the 3' poly(A) tail, the DEN2 3'UTR also enhanced translation of reporter mRNAs containing (i) a nonfunctional A cap, (ii) the 5'UTR of human beta-globin, or (iii) a viral internal ribosome entry site (IRES). In all cases, approximately half of the translation efficiency was due to the terminal 3' stem-loop (3'SL) domain. In addition, the 3'SL domain increased the association of mRNAs with polysomes. Together, these results indicate that the DEN2 3'UTR, mediated in part by the 3'SL domain, enhances translation initiation, possibly after recognition of the 5' cap structure.


Attributions and perceptions of criticism: An examination of patients with anxiety and normal control participants.
Perceived criticism from relatives predicts poor clinical outcomes for patients with a variety of psychological disorders. Research indicates the attributions individuals make about motives for relatives' criticism are linked to perceived criticism from this relative. Accordingly, attributions may be an important target of intervention to reduce perceived criticism and improve clinical outcomes, but this association requires testing in a clinical sample. We examined relationships among attributions of criticism, perceived criticism, and upset due to criticism among individuals with anxiety disorders (n = 53) and with no psychopathology (n = 52). Participants completed measures of global attributions, perceived criticism, and upset due to criticism regarding criticism from a romantic partner/spouse or parent. After a 10-min problem-solving interaction with their relative, they completed measures of attributions, perceived criticism, and upset with regard to this relative's critical behavior during the interaction, and observers reliably coded interactions for relatives' criticism. Results showed that negative attributions were related to greater perceived criticism and upset for both global and interaction-specific measures. In analyses of interaction-specific measures, negative attributions added to prediction of perceived criticism and upset over and above the contribution of observed criticism. Positive attributions were not significantly related to global or interaction-specific upset in any analyses. Relationships were consistent across patients and normal controls. Our findings suggest that negative attributions of relatives' motives for their criticism are important predictors of perceived criticism and upset. Thus, interventions targeting these attributions may be helpful in mitigating the negative effect of perceived criticism for individuals with psychopathology. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions.
Telomeres and adjacent subtelomeric regions are packaged as heterochromatin in many organisms. The heterochromatic features include DNA methylation, histones H3-Lys9 (Lysine 9) and H4-Lys20 (Lysine 20) methylation and heterochromatin protein1 alpha binding. Subtelomeric DNA is hypomethylated in human sperm and ova, and these regions are subjected to de novo methylation during development. In mice this activity is carried out by DNA methyltransferase 3b (Dnmt3b). Mutations in DNMT3B in humans lead to the autosomal-recessive ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome. Here we show that, in addition to several satellite and non-satellite repeats, the subtelomeric regions in lymphoblastoid and fibroblast cells of ICF patients are also hypomethylated to similar levels as in sperm. Furthermore, the telomeres are abnormally short in both the telomerase-positive and -negative cells, and many chromosome ends lack detectable telomere fluorescence in situ hybridization signals from either one or both sister-chromatids. In contrast to Dnmt3a/b(-/-) mouse embryonic stem cells, increased telomere sister-chromatid exchange was not observed in ICF cells. Hypomethylation of subtelomeric regions was associated in the ICF cells with advanced telomere replication timing and elevated levels of transcripts emanating from telomeric regions, known as TERRA (telomeric-repeat-containing RNA) or TelRNA. The current findings provide a mechanistic explanation for the abnormal telomeric phenotype observed in ICF syndrome and highlights the link between TERRA/TelRNA and structural telomeric integrity.


Autometrically and automatically monitored, iatrogenous, inhalant-decongestant-associated high blood pressure quantified by rhythmometry.
Blood pressure and heart rate were oscillometrically monitored with an automatic Nippon Colin instrument (Komaki, Japan) and were also self-measured by a 20-year-old man treated with an inhalant-decongestant containing an adrenergic and a corticosteroid analog. The subject also collected 24-hr urines for aldosterone determination. An elevation of urinary aldosterone excretion was observed compared to the usual value range of a peer group. After removal of the drug, urinary aldosterone dropped as did urinary potassium, whereas plasma potassium rose. Chronobiologic serial sections, carried out to follow the time course of blood pressure and heart rate, showed decreasing trends in MESOR after discontinuance of treatment. A decrease in the hyperbaric index, a measure of blood pressure excess over 24 hr, was also observed. Another subject treated with the same and a third treated with a similar inhalant-decongestant, who also monitored their blood pressures automatically and/or with self-measurements, showed similar effects: a decrease in blood pressure after removal of treatment and an increase in blood pressure when (for testing only) treatment was briefly resumed.


New cytotoxic prenylated isoflavonoids from Bituminaria morisiana.
Using cytotoxicity against KB cancer cells as a lead, bioguided-fractionation of the petroleum ether and ethyl acetate extracts of Bituminaria morisiana leaves led to the isolation of two new pterocarpans, namely 3,9-dihydroxy-4-(3,3-dimethylallyl) [6a R, 11a R]-pterocarpan, 3-hydroxy-4-(3,3-dimethylallyl)-4'',5''-dehydropyrano[8,9:2'',3''][6a R,11a R]-pterocarpan and one new isoflavone identified as 4',5''-dihydroxy-6''-methoxy-4'',4''-dimethyl-4'',5''-dihydro-6'' H-pyrano[2'',3'':7,8]-isoflavone. Moreover, two known pterocarpans, erybraedin C and bitucarpin A, three known isoflavones, daidzein, 8-prenyldaidzein and bidwillon C, one known furocoumarin, pseudoisopsoralen and one known coumestan, coumestrol were isolated. The structures of the isolated compounds were established by means of 1D and 2D NMR spectroscopy, as well as mass spectrometry. Further cytotoxicity tests against cells related to the immune system (Jurkat T, Mono-Mac-6 and polymorphonuclear cells) showed a moderate activity of the known pterocarpan erybraedin C against all cell lines used (IC (50) values between 17.6-28.8 microM). In addition, erybraedin C was found to induce necrosis in leukaemia Jurkat T cells.


REC-NN: A reconstruction error compensation neural network for Magnetic Resonance Electrical Property Tomography (MREPT).
Electrical properties (EPs) are expected as biomarkers for early cancer detection. Magnetic resonance electrical properties tomography (MREPT) is a technique to non-invasively estimate the EPs of tissues from MRI measurements. While noise sensitivity and artifact problems of MREPT are being solved progressively through recent efforts, the loss of tissue contrast emerges as an obstacle to the clinical applications of MREPT. To solve the problem, we propose a reconstruction error compensation neural network scheme (REC-NN) for a typical analytic MREPT method, Stab-EPT. Two NN structures: one with only ResNet blocks, and the other hybridizing ResNet blocks with an encoder-decoder structure. Results of experiments with digital brain phantoms show that, compared with Stab-EPT, and conventional NN based reconstruction, REC-NN improves both reconstruction accuracy and tissue contrast. It is found that, the encoder-decoder structure could improve the compensation accuracy of EPs in homogeneous region but showed worse reconstruction than only ResNet structure for tumorous tissues unseen in the training samples. Future research is required to address overcompensation problems, optimization of NN structure and application to clinical data.


PACKMAN - A portable instrument to investigate space weather.
PACKMAN (PArticle Counter k-index Magnetic ANomaly) is an autonomous, light and robust space weather instrument for operation within the subsurface, surface and atmosphere (as payload in stratospheric balloons) of the Earth. It has been designed using Commercial Off-The-Shelf (COTS) components to reduce the cost of each unit and to allow to have multiple units monitoring simultaneously at different sites and also incorporate an open-access citizen science approach. The hardware-core of each PACKMAN units, weights around 600 g and consumes about 500 mA of current at 12 V. PACKMAN has been deployed at multiple latitudes and altitudes ranging from stratospheric heights (corroborating its TRL8 maturity) to subsurface depths of around 1 km. The data from PACKMAN have been compared with the state-of-the-art ground-based observatories, and satellites and scientific observations have been documented. A 3-D network of PACKMAN units operating continuously around the globe, from the subsurface to the stratosphere, would help to improve the understanding of the space weather phenomena, and its implications on the climate and infrastructures. PACKMAN is also an excellent tool for education and outreach. This article outlines the building instructions of two types of PACKMAN units: PACKMAN-S for ground-based measurements and PACKMAN-B for stratospheric measurements aboard high-altitude balloons.


Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial.
Upfront surgery followed by postoperative treatment is a commonly adopted treatment for resectable pancreatic ductal adenocarcinoma (rPDAC). However, the risk of positive surgical margins, the poor recovery that often impairs postoperative treatments, and the risk of recurrence might limit the outcome of this strategy. This study evaluated the safety and the activity of liposomal irinotecan 50 mg/m2 + 5-fluorouracil 2400 mg/m2 + leucovorin 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX) in the perioperative treatment of patients with rPDAC. Eligible patients had a rPDAC with < 180° interface with major veins' wall. Patients received 3 cycles before and 3 cycles after resection with NALIRIFOX, days 1 and 15 of a 28-day cycle. The primary endpoint was the proportion of patients undergoing an R0 resection. 107 patients began preoperative treatment. Nine patients discontinued the treatment because of related or unrelated adverse events. Disease-control rate was 92.9%. 87 patients underwent surgical exploration, 11 had intraoperative evidence of metastatic disease, and 1 died for surgical complications. R0 resection rate was 65.3%. 49 patients completed the three postoperative cycles. The most common grade ≥ 3 adverse events were diarrhea and neutropenia. Median overall survival (OS) of ITT patients was 32.3 months (95% CI 27.8-44.3). Median disease-free and OS from surgery of resected patients were 19.3 (95% CI 12.6-34.1) and 40.3 months (95% CI 29-NA), respectively. Perioperative NALIRIFOX was manageable and active, and deserves further investigation in randomized trials comparing it with standard upfront surgery followed by adjuvant therapy.


Characterization of an ssDNA ligase and its application in aptamer circularization.
Aptamers are widely used in various biomedical areas as novel molecular recognition elements, however, short single-stranded DNA (ssDNA) or RNA oligonucleotides are easily degraded by nucleases in biological fluids. This problem can be solved by circularizing aptamers with circular ligases. Herein, a moderately thermostable ssDNA ligase was expressed and purified. The purified ligase showed good circularization activity for different length substrates and much higher circularization efficiency than T4 RNA ligase 1. Biochemical characterization revealed that the enzyme showed optimal circularization activity at pH 7.5 and 50 ᵒC. Mn2+ and Mg2+ increased enzyme circularization activity, with Mn2+ having higher activity than Mg2+. The optimal concentrations of Mn2+ and ligase were 1.25-2.5 mM and 0.02 nM, respectively. The kinetic parameters Km, Vmax and Kcat of ssDNA ligase were 1.16 μM, 10.71 μM/min, and 10.7 min-1, respectively. The ssDNA ligase efficiency was nucleotide-dependent, and 5'-G and 3'-T were the most ligase-favored terminal nucleotides. In addition, the affinity and stability of the circular aptamer were determined. The affinity constant (KD) was 4.9 μM, and the stability increased compared to its linear form. Molecular docking results showed that the circular aptamer bound to the target via two hydrogen bonds. This study provides a simple and efficient aptamer circularization modification method for improving aptamer stability and expanding its applications.


TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.
Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor-β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.


Respiratory syncytial virus infections in Central Australia.
Little is known about the epidemiology of respiratory syncytial virus (RSV) infection in arid desert regions and in the Aboriginal population. We describe the seasonality and epidemiology of RSV infection in Central Australia, an arid area with a large Aboriginal population. Five-year retrospective study from 2000 through 2004 of children less than 2 years old admitted to Alice Springs Hospital with documented RSV infection. RSV infection was documented in 173 children <2 years old admitted over a 5-year period, 165 community-acquired and 8 nosocomial. The annual incidence rate of community-acquired RSV infection in hospitalised Central Australian children <2 years old was 20.4 per 1000. The rate in Aboriginal children of 29.6 per 1000 children was significantly greater than in non-Aboriginal children of 10.9 per 1000 (P < 0.0001). Associated risk factors were common; 52% of infected children had at least one other comorbidity. Younger children had more severe illness and longer duration of hospital stay. RSV-related illness peaked in winter but infections occurred throughout the year, and the winter predominance was less marked than in temperate climates. In the arid, desert region of Central Australia, RSV infection occurs throughout the year, but is more frequent in winter and more common in Aboriginal children. These data are important for understanding RSV epidemiology in desert regions, and for planning active or passive RSV immunoprophylaxis in these and other similar populations.