Esomeprazole formulary exclusion: impact on total health care services use and costs.
Esomeprazole was excluded from the United Healthcare formulary for all commercial health plan members January 1, 2007. A retrospective analysis of the Ingenix LabRx database (September 1, 2005, through June 30, 2007) evaluated the effect of this exclusion on health care utilization and costs in a real-world setting. Total medical care services, including pharmacy claims, were examined for 6 months before and after the esomeprazole exclusion. Patients aged ≥ 18 years were included if they had continuous health plan enrollment (September 1, 2005, through June 30, 2007), ≥ 1 esomeprazole prescription during the index period (March 1 through August 31, 2006), and ≥ 2 esomeprazole prescriptions (with no switch to another proton pump inhibitor [PPI]) during the baseline period (sliding 6-month window from September 1 through August 31, 2006). During the 6-month post-exclusion period (January 1 through June 30, 2007), 19.5% of patients remained on esomeprazole, 43% switched to another PPI, and 37.5% had no prescription PPI claims. Compared with the previous 6 months, post-exclusion was associated with increased health care utilization, including a 4.2% increase in number of inpatient visits, and a 2.7% increase in other services (eg, laboratory testing, ambulatory procedures). Esomeprazole prescriptions decreased by 76.5%, whereas overall pharmacy claims for all drug classes (including gastrointestinal drugs) increased by 5.2%. Six-month prescription drug costs decreased by $177/patient (95% confidence interval [CI], $160-$194/patient), whereas costs for total medical services increased by $450/patient (95% CI, $259-$640/patient), resulting in a net increase of $273/patient (95% CI, $137-$408/patient). Total and gastrointestinal-related medical services costs were significantly higher for those switching to another PPI versus those continuing esomeprazole. Inpatient utilization contributed most (44.5%) to increased costs of nongastrointestinal comorbidities. This study provides real-world evidence that formulary exclusions can lead to unintended increases in overall health care utilization and costs that exceed anticipated pharmacy budget savings.


The chemical roots of the matching polynomial.
The interpretation of topological resonance energy (TRE), the mathematical measure of energetic chemical aromaticity at the Hückel level of theory, is revisited by providing a concise analysis of the matching polynomial of a chemical graph. Whereas the matching (or acyclic) polynomial is not a properly characteristic polynomial in general, it is the arithmetic mean of the characteristic polynomials of the corresponding Hückel and Möbius chemical graphs. For unicyclic graphs, the roots of the matching polynomial (serving to calculate the TRE values) can be graphically approximated from generalized Frost-Musulin-Zimmermann diagrams, the results becoming exact for annulenic monocycles. The matching polynomial is also shown to be a weighted sum of characteristic polynomials of subgraphs: the whole graph itself and the exocyclic graphs obtained by suppression of individual circuits. The performance of these ring twisting and ring masking processes is compared to that of the previously proposed ring opening process. Further prospects for the interpretation and approximation of TRE are discussed.


Optimizing Symptoms and Management of Febrile Neutropenia among Cancer Patients: Current Status and Future Directions.
Febrile neutropenia (FN) is a common and serious complication among cancer patients undergoing myelosuppressive chemotherapy. FN should be treated as a medical emergency because it can lead to life-threatening complications if appropriate treatment is not initiated immediately. This study provides a critical review on the current management of FN and identifies possible directions to optimize FN management.


Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose.
Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. This study had two main objectives: (1) examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and (2) examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Longitudinal study of a cohort ( N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m2) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Maternal BMI explained 16.56% (95% confidence interval [CI] = [13.7, 20.04], p < .001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women ( p < .001). Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation.


Corn oil or corn grain supplementation to steers grazing endophyte-free tall fescue. II. Effects on subcutaneous fatty acid content and lipogenic gene expression.
Twenty-eight Angus steers (289 kg) were finished on a high-concentrate diet (85% concentrate: 15% roughage; CONC), or endophyte-free tall fescue pastures with corn grain supplement (0.52% of BW; PC), corn oil plus soybean hull supplement (0.10% of BW corn oil plus 0.45% of BW soybean hulls; PO), or no supplement (pasture only; PA). Subcutaneous adipose tissues were processed for total cellular RNA extraction and fatty acid composition by GLC. Relative expression of genes involved in lipogenesis [fatty acid synthase (FASN), acetyl-CoA carboxylase, lipoprotein lipase, stearoyl-CoA desaturase (SCD)] and activators of transcription [(peroxisome proliferator-activated receptor-gamma), C/EBPalpha, sterol regulatory binding protein-1, signal transducer and activator of transcription-5, and Spot-14] was determined by real-time quantitative PCR. Housekeeping gene (glyceraldehyde 3-phosphate dehydrogenase and beta-actin) expression was used in analysis to normalize expression data. Total fatty acid content was greatest (P < 0.001) for CONC and least (P < 0.001) for PA. Supplementation of grazing cattle increased (P < 0.001) total fatty acid content compared with PA, but concentrations were less (P < 0.001) than for CONC. Myristic and palmitic acid contents were greater (P < 0.001) for CONC than for PO and PC, which were greater (P < 0.001) than for PA. Stearic acid content was greater (P < 0.01) for PO than for CONC, PC, and PA. Finishing on CONC increased (P < 0.001) total MUFA content by 68% compared with PA. Corn grain supplementation increased (P < 0.001) MUFA content compared with PA; in contrast, MUFA content did not differ (P > 0.05) between PO and PA. Corn oil supplementation increased (P < 0.001) trans-11 vaccenic acid content in subcutaneous fat by 1.2-, 1.7- and 5.6-fold relative to PA, PC, and CONC, respectively. Concentrations of the cis-9, trans-11 CLA isomer were 54, 58, and 208% greater (P < 0.01) for PO than for PA, PC, and CONC, respectively. Corn grain supplementation to grazing steers did not alter (P > 0.05) the cis-9, trans-11 CLA isomer compared with PA. Oil supplementation increased (P < 0.001) linoleic acid (C18:2) content by 56, 98 and 262% compared with CONC, PC, and PA, respectively. Relative mRNA expression of SCD was upregulated (P < 0.001) by 46-, 18- and 7-fold, respectively, for CONC, PC, and PO compared with PA. Relative FASN mRNA expression was also upregulated (P = 0.004) by 9- and 5-fold, respectively, for CONC and PC compared with PA. Grain feeding, either on CONC or supplemented on pasture, upregulated FASN and SCD mRNA to increase MUFA and de novo fatty acids in subcutaneous adipose tissue. Upregulation of SCD with grain feeding and reduced tissue CLA concentrations suggest that the decreased CLA concentrations were the result of limited substrate (trans-11 vaccenic acid) availability.


Bose-Einstein condensation in quantum glasses.
The role of geometrical frustration in strongly interacting bosonic systems is studied with a combined numerical and analytical approach. We demonstrate the existence of a novel quantum phase featuring both Bose-Einstein condensation and spin-glass behavior. The differences between such a phase and the otherwise insulating "Bose glasses" are elucidated.


[Chinese HER2 positive early breast cancer trastuzumab adjuvant therapy: preliminary outcomes].
To evaluate the efficacy and safety of 1-year adjuvant trastuzumab (herceptin) versus 1-year non-trastuzumab observation in Chinese patients with HER2-positive early breast cancer during a median follow-up of 1 year. The HERA trial was an international, multicenter, randomized, open-label, phase III trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard adjuvant chemotherapy, radiotherapy or both in patients with HER2-positive node-positive or high-risk node-negative early breast cancer. The primary endpoint was disease-free survival. Secondary end points included recurrence-free survival, distant disease-free survival, overall survival and cardiac safety. The first planned interim analysis comparing the efficacy and safety of treatment with trastuzumab for 1 year versus observation were completed in April 2005. Only the outcomes of recruited Chinese patients were reported. A total of 122 Chinese patients from 8 participating centers were included for planned interim analysis. And they were divided into trastuzumab (n = 68) and observation (n = 54) groups. Three and eight disease-free survival events were observed in the trastuzumab and observation groups respectively. Two-year disease-free survival rates were 92.9% and 81.4% respectively (P = 0.0489); 2-year recurrence-free survival and distant disease-free survivals were 98.1% vs 81.4% (P = 0.0064) and 98.1% vs 83.3% (P = 0.0117) respectively. Trastuzumab was generally well-tolerated with a decent safety profile. Severe cardiotoxicity was not observed. One-year treatment with adjuvant trastuzumab improves disease-free survival, recurrence-free survival and distant disease-free survival in Chinese patients with HER2-positive early breast cancer.


Non-bacterial thrombotic endocarditis in a patient with COVID.
Non-bacterial thrombotic endocarditis is mainly associated with malignancies and rheumatological diseases. We report the case of mildly symptomatic COVID-19 infection with non-bacterial aortic valve vegetation complicated by transient ischemic attack (TIA) and pulmonary embolism during his hospitalisation. This case emphasised rare life-threatening complications from a hypercoagulable state related to COVID-19 infection. To the best of our knowledge, this is the third case report of non-bacterial endocarditis in a patient with COVID-19 patients as a potential rare complication of COVID-19.


Cementing techniques for the tibial component in primary total knee replacement.
The optimum cementing technique for the tibial component in cemented primary total knee replacement (TKR) remains controversial. The technique of cementing, the volume of cement and the penetration are largely dependent on the operator, and hence large variations can occur. Clinical, experimental and computational studies have been performed, with conflicting results. Early implant migration is an indication of loosening. Aseptic loosening is the most common cause of failure in primary TKR and is the product of several factors. Sufficient penetration of cement has been shown to increase implant stability. This review discusses the relevant literature regarding all aspects of the cementing of the tibial component at primary TKR.


Yeast cytochrome c peroxidase: mutagenesis and expression in Escherichia coli show tryptophan-51 is not the radical site in compound I.
Using oligonucleotide-directed site-specific mutagenesis, we have constructed a system for the mutation and expression of yeast cytochrome c peroxidase (CCP, EC 220.127.116.11) in Escherichia coli and applied it to test the hypothesis that Trp-51 is the locus of the free radical observed in compound I of CCP [Poulos, T. L., & Kraut, J. (1980) J. Biol. Chem. 255, 8199-8205]. The system was created by substituting a CCP gene modified by site-directed mutagenesis, CCP(MI), for the fol gene in a vector previously used for mutagenesis and overexpression of dihydrofolate reductase. E. coli transformed with the resulting plasmid produced the CCP(MI) enzyme in large quantities, more than 15 mg/L of cell culture, of which 10% is holo- and 90% is apo-CCP(MI). The apoenzyme was easily converted to holoenzyme by the addition of bovine hemin. Purified CCP(MI) has the same catalytic activity and spectra as bakers' yeast CCP. A mutation has been made in CCP(MI), Trp-51 to Phe. The Phe-51 mutant protein CCP(MI,F51) is fully active, and the electron paramagnetic resonance (EPR) spectrum, at 89 K, of its oxidized intermediate, compound I, displays a strong sharp resonance at g = 2.004, which is very similar to the signal observed for compound I of both bakers' yeast CCP and CCP(MI). However, UV-visible and EPR spectroscopy revealed that the half-life of CCP(MI,F51) compound I at 23 degrees C is only 1.4% of that observed for the compound I forms of CCP(MI) or bakers' yeast CCP. Thus, Trp-51 is not necessary for the formation of the free radical observed in compound I but appears to exert a significant influence on its stability.


Allylsamarium Bromide-Mediated Cascade Cyclization of Homoallylic Esters. Synthesis of 2-(2-Hydroxyalkyl)cyclopropanols and 2-(2-Hydroxyethyl)bicyclo[2.1.1]hexan-1-ols.
In continuation of our previous study on the intramolecular reductive coupling of simple homoallylic esters promoted by allylSmBr/HMPA/H2O, which afforded a facile synthesis of 2-(2-hydroxyalkyl)cyclopropanols, here we report the reductive cascade cyclization of but-3-enyl but-3-enoates mediated by allylSmBr/HMPA/CuCl2·2H2O, in which the two C═C bonds were successively coupled to allow the construction of the structurally interesting bridged bicyclic tertiary alcohols. Thus, the 2-(2-hydroxyethyl)bicyclo[2.1.1]hexan-1-ols were prepared in moderate to good yields with excellent diastereoselectivity.


Synthesis and binding properties of deltorphin I analogues containing (R) and (S)-alpha-hydroxymethylnaphtylalanine.
New analogues of deltorphin I (DT I), in which the phenylalanine residue in position 3 is substituted with amphiphilic alpha,alpha-disubstituted amino acid enantiomers, (R) and (S)-alpha-hydroxymethylnaphtylalanine, were synthesized and tested for mu and delta opioid receptor affinity and selectivity. Although both analogues have lower affinity to delta receptors than DT I, they both expressed specificity to delta receptors.


A new nude mouse model for postmenopausal breast cancer using MCF-7 cells transfected with the human aromatase gene.
MCF-7 cells transfected with human placental aromatase gene (MCF-7Ca cells) or cells transfected with plasmid vector only (MCF-7Cc cells) were inoculated into nude mice with Matrigel. Tumors formed from both MCF-7Ca and MCF-7Cc cells grew faster in intact mice than in ovariectomized mice, suggesting that the tumors maintained their responsiveness to estrogen stimulation and that their growth was supported by ovarian estrogen. Injections of androstenedione (0.1 mg/mouse/day) to provide the substrate for aromatization to ovariectomized mice bearing MCF-7Ca tumors accelerated their growth but did not affect growth of MCF-7Cc tumors. This result indicates that local production of estrogen by intratumoral aromatase was sufficient to stimulate tumor growth. When ovariectomized mice with MCF-7Ca tumors supplemented with androstenedione were treated with aromatase inhibitors 4-hydroxyandrostenedione (1 mg/mouse/day, s.c.) or CGS 16949A (0.5 mg/mouse/day, s.c.), or with the antiestrogen tamoxifen (10 micrograms/mouse/day, s.c.), tumor growth was significantly inhibited. Tumor aromatase activity measured at the end of treatment was also inhibited by 4-hydroxyandrostenedione when the mice were sacrificed 4 h after the last injection. The tumors of this mouse model are dependent for their growth on estrogens from an endogenous nonovarian source. Thus, it simulates the situation in the postmenopausal breast cancer patient and could be used to evaluate the effect of aromatase inhibitors and antiestrogens.


Induction of murine hemopoietic growth factors by toxic shock syndrome toxin-1.
Toxic shock syndrome toxin-1 (TSST-1), an extra-cellular 22 kDa single chain protein produced by most Staphylococcus aureus strains isolated from patients with toxic shock syndrome (TSS), induces modifications of blood cell values similar to those observed during TSS. We therefore analyzed the effects of TSST-1 on the proliferation and differentiation of murine granulocyte-macrophage progenitor cells (CFU-culture) and the eventual role of endotoxin in this response. TSST-1 had no direct effect on the proliferation of CFU-culture and was unable to influence the CSF-induced proliferation and differentiation of these progenitors. In contrast, TSST-1 was a potent inducer in spleen cell cultures of a factor with an ability to induce both colony formation by bone marrow cells and proliferation of an IL-3-dependent cell line. Nanogram amounts of TSST-1 were able to induce the release of CSF activity in spleen cell cultures from both normal and LPS-hyporesponsive mice. Cells from C3H/HeJ mice were as responsive as cells from C3H/He Pas mice. Furthermore, in spleen cell cultures from normal mice, TSST-1 and LPS did not act synergistically to induce CSF activity. Nanogram amounts of TSST-1 were also able to induce CSF activity in vivo but failed to induce IL-3 activity in the serum and organ-conditioned media from TSST-1-treated mice.


Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML.
Disruption of Mdm2-p53 interaction activates p53 signaling, disrupts the balance of antiapoptotic and proapoptotic Bcl-2 family proteins and induces apoptosis in acute myeloid leukemia (AML). Overexpression of Bcl-2 may inhibit this effect. Thus, functional inactivation of antiapoptotic Bcl-2 proteins may enhance apoptogenic effects of Mdm2 inhibition. We here investigate the potential therapeutic utility of combined targeting of Mdm2 by Nutlin-3a and Bcl-2 by ABT-737, recently developed inhibitors of protein-protein interactions. Nutlin-3a and ABT-737 induced Bax conformational change and mitochondrial apoptosis in AML cells in a strikingly synergistic fashion. Nutlin-3a induced p53-mediated apoptosis predominantly in S and G2/M cells, while cells in G1 were protected through induction of p21. In contrast, ABT-737 induced apoptosis predominantly in G1, the cell cycle phase with the lowest Bcl-2 protein levels and Bcl-2/Bax ratios. In addition, Bcl-2 phosphorylation on Ser70 was absent in G1 but detectable in G2/M, thus lower Bcl-2 levels and absence of Bcl-2 phosphorylation appeared to facilitate ABT-737-induced apoptosis of G1 cells. The complementary effects of Nutlin-3a and ABT-737 in different cell cycle phases could, in part, account for their synergistic activity. Our data suggest that combined targeting of Mdm2 and Bcl-2 proteins could offer considerable therapeutic promise in AML.


Protection of the myocardium during ischemic arrest: possible toxicity of carnitine in cardioplegic solutions.
Carnitine has been suggested as an agent for the protection of the myocardium during regional ischemia and it might therefore be able to reduce tissue injury during surgically induced global ischemia. Using an isolated working rat heart model we have assessed the way in which various concentrations of carnitine infuence the efficacy of the St. Thomas' Hospital Cardioplegic Solution. Carnitine was found to exert a dose-dependent detrimental effect upon the ischemic myocardium, with high concentrations abolishing all the protective properties of the cardioplegic solution. Furthermore, this compound appeared to promote the occurrence of reperfusion dysrhythmias.


HbA1c and Glycated Albumin Levels Are High in Gastrectomized Subjects with Iron-Deficiency Anemia.
We report that glycated albumin (GA) is higher relative to HbA1c in non-diabetic, gastrectomized subjects without anemia, and thus is a sign of oxyhyperglycemia. It is known that gastrectomized subjects are prone to iron-deficiency anemia (IDA), and that the HbA1c levels of subjects with IDA are falsely high. In the present study, the HbA1c and GA levels of gastrectomized subjects with IDA were compared with gastrectomized subjects without anemia. Seven non-diabetic gastrectomized subjects with IDA were enrolled in the present study. Twenty-eight non-diabetic gastrectomized subjects without anemia matched with the subjects with IDA in terms of age, gender, and body mass index were used as the controls. Although there were no significant differences in fasting plasma glucose and OGTT 2-hour plasma glucose (2-h PG) between the two groups, the HbA1c and GA levels in gastrectomized subjects with IDA were significantly higher than the controls. For all of the gastrectomized subjects (n=35), ferritin exhibited a significant negative correlation with HbA1c and GA, and a significant positive correlation with 2-h PG. In addition, the HbA1c and GA levels exhibited a significant negative correlation with the mean corpuscular hemoglobin and hemoglobin. The HbA1c and GA levels in gastrectomized subjects with IDA were significantly higher than those in controls. The high GA levels are attributed to a tendency in which patients with total gastrectomy, who are prone to IDA, are susceptible to postprandial hyperglycemia and reactive hypoglycemia, which in turn leads to large fluctuations in plasma glucose.


Ethical Dimensions and Filial Caregiving.
The elderly are growing rapidly today as life expectancy increases. As this longevity has increased, so has the need for filial caregivers. While much has been written about caregiving stress, little has been written regarding the ethical dimensions of filial responsibility and daughter and son caregivers' perceptions of responsibility and moral demands. This paper will address the concept of family caregiving and contextual family characteristics. Family characteristics will expand awareness of the interrelationship value between the nature of the prior filial relationship, image of caregiving, and ethical views that underscore acceptance of the filial obligation. An explanation of both the interview process and selected measurements that speak to ethical perspective, sense of caregiving image, and expectations of filial caregiving will also be addressed. Therefore, the purpose of this paper is to elucidate how adult children may be helped in an anticipatory and proactive manner as more and more adult children take on parent care for longer durations of time.


Identification of Anti-Influenza A Compounds Inhibiting the Viral Non-Structural Protein 1 (NS1) Using a Type I Interferon-Driven Screening Strategy.
There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164, were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-β expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets.


Conduction studies along the accessory nerve and follow-up of patients with trapezius palsy.
The accessory nerve was stimulated at the posterior triangle of the neck and responses were evoked simultaneously from the upper, middle and lower part of the trapezius muscle. Sixteen patients were investigated, 10 with trapezius palsy following surgical procedures at the posterior cervical triangle, three with a history suggestive of neuralgic amyotrophy and three of unknown origin. On the unaffected side the latency increases 0.16 ms per 10 mm increase in conduction distance corresponding to a conduction velocity of 63 m/s. Evidence is presented that the upper, middle and lower part of the trapezius muscle receive innervation from the accessory nerve. Follow-up of patients showed spontaneous nerve regeneration after complete axonal degeneration. These findings suggest that surgical intervention should be delayed to allow for spontaneous reinnervation. Clinical recovery was incomplete in cases of iatrogenic origin.


Dual oxidase 1 is dispensable during Mycobacterium tuberculosis infection in mice.
Mycobacterium tuberculosis (Mtb) is the primary cause of human tuberculosis (TB) and is currently the second most common cause of death due to a singleinfectious agent. The first line of defense against airborne pathogens, including Mtb, is the respiratory epithelium. One of the innate defenses used by respiratory epithelial cells to prevent microbial infection is an oxidative antimicrobial system consisting of the proteins, lactoperoxidase (LPO) and Dual oxidase 1 (Duox1), the thiocyanate anion (SCN-) and hydrogen peroxide (H2O2), which together lead to the generation of antimicrobial hypothiocyanite (OSCN-) in the airway lumen. OSCN- kills bacteria and viruses in vitro, but the role of this Duox1-based system in bacterial infections in vivo remains largely unknown. The goal of this study was to assess whether Duox1 contributes to the immune response against the unique respiratory pathogen, Mtb. Duox1-deficient (Duox1 KO) and wild-type (WT) mice were infected with Mtb aerosols and bacterial titers, lung pathology, cytokines and immune cell recruitment were assessed. Mtb titers in the lung, spleen and liver were not different 30 days after infection between WT and Duox1 KO mice. Duox1 did not affect lung histology assessed at days 0, 30, and 90 post-Mtb infection. Mtb-infected Duox1 KO animals exhibited enhanced production of certain cytokines and chemokines in the airway; however, this response was not associated with significantly higher numbers of macrophages or neutrophils in the lung. B cell numbers were lower, while apoptosis was higher in the pulmonary lesions of Mtb-infected Duox1 KO mice compared to infected WT animals. Taken together, these data demonstrate that while Duox1 might influence leukocyte recruitment to inflammatory cell aggregates, Duox1 is dispensable for the overall clinical course of Mtb lung infection in a mouse model.


Knockdown of a putative argininosuccinate lyase gene reduces arginine content and impairs nymphal development in Nilaparvata lugens.
Nilaparvata lugens is a typical phloem feeder. Rice phloem is high in simple sugars and very low in essential amino acids. Nilaparvata lugens harbors an ascomycete Entomomyces delphacidicola that hypothetically biosynthesizes several amino acids to meet the nutrition requirement of the planthopper. Among these amino acids, here, we focused on arginine biosynthesis. A complete cDNA of an E. delphacidicola gene, arginine-succinate lyase, EdArg4, the last step in arginine biosynthesis, was obtained. RNAi-mediated suppression of EdArg4 reduced arginine content in the hemolymph, and decreased the expression of several arginine biosynthesis genes. Silencing of EdArg4 delayed nymphal development and led to nymphal lethality. About 20% of the EdArg4 RNAi surviving adults were deformed. The most obvious defect was wider and larger abdomen. The EdArg4 RNAi-treated planthoppers had thickened wings and enlarged antennae, legs, and anal tubes and a few adults did not normally emerge. Arginine deficiency in the EdArg4 RNAi planthoppers repressed nitric oxide signaling, determined at the transcriptional level. We infer that E. delphacidicola biosynthesizes essential arginine to compensate for nutrition deficiency in N. lugens.


Nuclear Factor-κB is a Prime Candidate for the Diagnosis and Control of Inflammatory Cardiovascular Disease.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is responsible for the regulation of genes involved in inflammation and immune responses. NF-κB may play an important role in cardiovascular diseases (CVDs), atherosclerosis and diabetes. Several therapeutic agents used for the treatment of CVDs and diabetes, such as pimobendan and sodium-glucose cotransporter 2 inhibitors, exert anti-inflammatory effects by inhibiting NF-κB activation; anti-inflammatory therapy may have beneficial effects in CVDs and diabetes. Several pharmacological agents and natural compounds may inhibit NF-κB, and these agents alone or in combination may be used to treat various inflammatory diseases. Immunoglobulin-free light chains could be surrogate biomarkers of NF-κB activation and may be useful for evaluating the efficacy of these agents. This review discusses recent advances in our understanding of how the NF-κB signalling pathway controls inflammation, metabolism and immunity, and how improved knowledge of these pathways may lead to better diagnostics and therapeutics for various human diseases.


[Gel with provitamin B5 applied during tests with the Goldmann triple-mirror].
The objective of the study was, to determine whether the new medicine developed in the Faculty of Pharmacy of the Medical University of Gdańsk in the form of gel containing 5% of provitamin B5, was a good agent for applying into the contact surface of the Goldmann triple-mirror, while examining the retina. 42 people were subject in the observation. 84 eyes, which had not been operated yet, were tested. One eye was examined by using the gel with provitamin B5/proper name D--panthenol/, the other eye by applying 3% methylcellulose. Congestion of conjunctiva, oedema and defects of cornea epithelium, and substance transparency as well as surface adherence were indicated. One obtained the statistical significance proving the lesser congestion effect, while applying D--panthenol. Better adherence of the preparation to the cornea surface and to the triple-mirror was noticed, which considerably improved the procedure of the very examination. D--panthenol protected and regenerated cornea epithelium. The gel containing provitamin B5 is a safe and convenient agent for application during the examination with a triple-mirror.


Developing an exercise intervention to improve bone mineral density in traumatic amputees: protocol for a Delphi study.
Lower limb amputation results in reduced bone mineral density (BMD) on the amputated side. Exercise interventions have proven effective in improving BMD. However, such interventions have not been attempted in an amputee population. Exercises designed for people with intact limbs may not be suitable for amputees, due to joint loss and the mechanical interface between the exercise equipment and the femoral neck being mediated through a socket. Therefore, prior to intervention implementation, it would be prudent to leverage biomechanical knowledge and clinical expertise, alongside scientific evidence in related fields, to assist in intervention development. The objective of this study is to elicit expert opinion and gain consensus to define specific exercise prescription parameters to minimise/recover BMD loss in amputees. The Delphi technique will be used to obtain consensus among international experts; this will be conducted remotely as an e-Delphi process. 10-15 experts from ≥2 continents and ≥5 countries will be identified through published research or clinical expertise. Round 1 will consist of participants being asked to rate their level of agreement with statements related to exercise prescription to improve amputee BMD using a 5-point Likert Scale. Agreement will be deemed as ≥3 on the Likert Scale. Open feedback will be allowed in round 1 and any statement which less than 50% of the experts agree with will be excluded. Round 2 will repeat the remaining statements with the addition of any input from round 1 feedback. Round 3 will allow participants to reflect on their round 2 responses considering statistical representation of group opinion and whether they wish to alter any of their responses accordingly. Statements reaching agreement rates of 70% or above among the experts will be deemed to reach a consensus and will be implemented in a future exercise interventional trial. Ethical approval was received from Imperial College Research Ethics Committee (reference: 6463766). Delphi participants will be asked to provide digital informed consent. The findings will be disseminated through peer-reviewed publications.


A High Precision Machine Learning-Enabled System for Predicting Idiopathic Ventricular Arrhythmia Origins.
Radiofrequency catheter ablation (CA) is an efficient antiarrhythmic treatment with a class I indication for idiopathic ventricular arrhythmia (IVA), only when drugs are ineffective or have unacceptable side effects. The accurate prediction of the origins of IVA can significantly increase the operation success rate, reduce operation duration and decrease the risk of complications. The present work proposes an artificial intelligence-enabled ECG analysis algorithm to estimate possible origins of idiopathic ventricular arrhythmia at a clinical-grade level accuracy. A total of 18,612 ECG recordings extracted from 545 patients who underwent successful CA to treat IVA were proportionally sampled into training, validation and testing cohorts. We designed four classification schemes responding to different hierarchical levels of the possible IVA origins. For every classification scheme, we compared 98 distinct machine learning models with optimized hyperparameter values obtained through extensive grid search and reported an optimal algorithm with the highest accuracy scores attained on the testing cohorts. For classification scheme 4, our pioneering study designs and implements a machine learning-based ECG algorithm to predict 21 possible sites of IVA origin with an accuracy of 98.24% on a testing cohort. The accuracy and F1-score for the left three schemes surpassed 99%. In this work, we developed an algorithm that precisely predicts the correct origins of IVA (out of 21 possible sites) and outperforms the accuracy of all prior studies and human experts.


Ocular adnexal Langerhans cell histiocytosis clinical features and management.
To review the clinical features, investigations, management, and outcomes of Langerhans cell histiocytosis (LCH) with ocular adnexal involvement. Retrospective, non-comparative, chart review of 30 patients with LCH involving the ocular adnexa treated at 6 major Australian hospitals. Clinical features, imaging findings, treatment, local and distant recurrence and outcome were evaluated. Twenty-four patients (80%) were male with a mean age of presentation of 9.5 years. Females presented at an earlier age (mean age 4.1 years) with more severe involvement. Eighty percent of the cases presented with periorbital swelling. Computed tomography usually showed destructive osteolytic lesions centred on the frontal bone. Twenty-four patients (80%) had unifocal, unisystem disease. From this group, none of 13 treated with excision alone had recurrence whereas 2 of 6 treated with excision followed by chemotherapy recurred. Unifocal, unisystem LCH often presents to the ophthalmologist and can usually be diagnosed on clinical and imaging grounds. Computed tomography and magnetic resonance imaging are complementary imaging studies. Biopsy is essential to confirm diagnosis. Unifocal, unisystem disease can be treated with local excision and curettage. Incomplete excision, recurrent disease or multifocal disease may require systemic chemotherapy.


Superior mesenteric artery syndrome (Wilkie Syndrome) with unusual clinical onset: Description of a rare case.
Wilkie's Syndrome is a very rare disease caused by reduction of aorto-mesenteric space with consequent duodenum compression. It can combine with left renal vein stenosis which, when symptomatic, is known as "Nutcracker Syndrome". We describe a clinical onset case with epigastric pain without vomiting in a normal weight patient. 28-year-old woman who came to our observation for intense epigastric pain after a weight loss of 14 kg in 4 months. Multidetector Computed Tomography and Ultrasound revealed gastric and duodenal overdistension with hydro-air levels, severe duodenum stenosis, and left renal vein compression. Wilkie's Syndrome is common in anorexic individuals suffering from recurrent postprandial vomiting, onset with severe epigastric pain, without vomiting, is quite unusual. High-calorie diet must be first therapeutic approach, in case of failure treatment of first choice should be endovascular stenting and, only in selected cases, surgical treatment should be used because it is very invasive and burdened with numerous complications. Failure to diagnose this disease can expose patients to serious health risks.


The negative Poisson's ratio in graphene-based carbon foams.
Using molecular dynamics simulations, we find an in-plane negative Poisson's ratio intrinsically existing in the graphene-based three-dimensional (3D) carbon foams (CFs) when they are compressed uniaxially. Our study shows that the negative Poisson's ratio in the present CFs is attributed to their unique molecular structures and triggered by the buckling of the CF structures. This mechanism makes the negative Poisson's ratio of CFs strongly depend on their cell length, which offers us an efficient means to tune the negative Poisson's ratio in nanomaterials. Moreover, as the buckling modes of CFs are topographically different when they are compressed in different directions, their negative Poisson's ratio is found to be strongly anisotropic, which is in contrast to the isotropic positive Poisson's ratio observed in CFs prior to buckling. The discovery of the intrinsic negative Poisson's ratio in 3D CFs will significantly expand the family of auxetic nanomaterials. Meanwhile, the mechanism of nano-auxetics proposed here may open up a door to manufacture new auxetic materials on the nanoscale.


Assessment of the perceived need for a psychiatric service to a magistrates' court.
One approach to diversion from custody of mentally disordered offenders is to provide a psychiatric liaison service to local magistrates' courts. We aimed to establish whether such a scheme was needed locally. Questionnaires for the bench, defence solicitors and bail information officers, enquiring as to the perceived need for a psychiatric assessment, social service care and specialist bail provision, were distributed for all those appearing in a magistrates' court who had been held overnight in police custody. Responses were received for 223 individuals. An immediate psychiatric report was considered necessary for 4.9% of cases. In 2.2% of cases it was thought that remand in custody could have been avoided if such an opinion had been available. In 8% of cases it was thought that remand in custody could have been avoided if specialist bail provision were available. We conclude that availability of a specialist bail provision would lead to a greater number of diversions from custody than providing a psychiatric service to this magistrates' court.


Teaching catheterization to children.
Children can learn to perform self-catheterization as early as their preschool years with the aid of newly developed teaching techniques. Clean self-catheterization is widely accepted and allows the child to remain dry, without infection, and independent in the management of the lower urinary tract.


The presence of molecular markers of in vivo lipid peroxidation in osteoarthritic cartilage: a pathogenic role in osteoarthritis.
To investigate the role of oxidative functions in human osteoarthritic (OA) chondrocytes and to investigate the presence of in vivo molecular markers of lipoxidation in OA cartilage. An in vitro model of cartilage collagen degradation was used. Lipid peroxidation activity and overall oxidative function in OA chondrocytes were monitored by cis-parinaric acid and dichlorofluorescein assays, respectively. In vivo molecular markers of lipoxidation in normal and OA cartilage were studied using immunohistochemistry to detect the presence of malondialdehyde and hydroxynonenal adducts. Human OA chondrocytes showed a robust amount of 3H-proline-labeled collagen degradation upon stimulation with lipopolysaccharide and calcium ionophore A21387, as compared with that in untreated OA chondrocytes. Primary OA chondrocytes showed both spontaneous and inducible levels of lipid peroxidation activity. However, lipid peroxidation activity was already maximally elevated in more than 50% of the OA chondrocyte samples. Overall, spontaneous and inducible oxidative activities were observed in all OA samples. Immunohistochemical analysis of control OA tissue sections that were not treated with monoclonal antibody showed little immunoreactivity. OA cartilage sections treated with monoclonal antibodies showed specific immunoreactivity on the cartilage surface, at sites of OA lesions, at the pericellular matrix, and at intra- and intercellular matrices. Normal cartilage sections showed faint surface reactivity. Our observations suggest that human OA chondrocytes demonstrate spontaneous and inducible cell-associated lipoxidative and nonlipoxidative activity. Lipoxidative activity appears to be enhanced in OA chondrocytes. The presence of molecular markers of in vivo lipid peroxidation was demonstrated in OA cartilage, suggesting its role in the pathogenesis of the disease.


Embryonal Rhabdomyosarcoma of the Cervix: A Rare Disease at an Uncommon Age.
Embryonal rhabdomyosarcoma (RMS) is a rare type of sarcoma, primarily seen in the pediatric and adolescent population. Three subtypes of embryonal RMS are described, with the botryoid type being the most common. The incidence of this disease in adult females is 0.4% to 1% with the affected age group being patients in the third to fourth decade of life. It is exceedingly rare in patients above 40 years of age. We describe the case of a 48-year-old female, gravida 9 para 5, who presented with abnormal vaginal bleeding and an exophytic mass on examination. Given her lack of requirement of maintaining parity, she underwent radical surgery. The tumor was 8 cm in the largest dimension with a high histologic grade and some cartilaginous differentiation. Immunohistochemical stains were positive for vimentin, CD99, myogenin, and MyoD1 consistent with a diagnosis of embryonal rhabdomyosarcoma, botryoid subtype. Based on high survival rates when treated with aggressive adjuvant chemotherapy, a decision was made to treat the patient with the ARST0331 regimen. We discuss the diagnostic pathologic features of the disease, the epidemiology, and the most common presentation along with prognostic factors, treatment strategies, and outcomes.


Design study of a compact ultra-wide-angle high-spatial-resolution high-spectral-resolution snapshot imaging spectrometer.
An ultra-wide-angle high-spatial-resolution high-spectral-resolution snapshot imaging spectrometer (UWA-2HSR-SIS) is presented, which comprises a microlens array (MLA), multiple fiber bundles, a micro-cylindrical-lens array (MCLA), a cylindrical lens, a static grating interferometer (SGI), and an area-array detector. The MLA is arranged in a circular arc of 120° or more. The MCLA is arranged in a straight line. The SGI includes a fixed reflection grating in Littrow configuration, a beam splitter, and a fixed plane mirror. Each fiber bundle containing multiple optical fibers is coupled to a separate microlens of the MLA, subdividing the field angle of each microlens into multiple smaller field angles. The light passing through each subdivided smaller field angle of each microlens of the MLA is received by a separate part of the detector. The UWA-2HSR-SIS is a new concept that not only obtains both high spatial resolution and high spectral resolution based on a single sensor for the first time, but also has an ultra-wide field angle in the horizontal plane, can obtain spectral information covering the full spectral range of interest in real time, and is very stable against various disturbances. The UWA-2HSR-SIS has great potential for remote sensing electro-optical reconnaissance sensors in the visible and near-infrared region.


Articulating antibiotic impregnated spacers in prosthetic joint infections: Where do we stand?
Peri-prosthetic joint infection remains one of the most difficult and challenging complications following hip and knee arthroplasty for both patients and surgeons. Two-stage revision arthroplasty for infection remains the most popular option for the majority of patients and arguably the only option for some. The use antibiotic spacers and in particular articulating spacers has improved the quality of life for patients between stages. The spacers provides local delivery of high concentration antibiotics and provides many benefits to the soft tissues including maintaining soft tissue tension and range of movement. This benefit to the soft tissues also translates into reducing the difficulty and time spent doing the exposure during the second stage procedure. It is generally accepted that peri-prosthetic joint infection should be dealt with my specialist centers who deal with high volumes of patients with this diagnosis in a multidisciplinary approach.


Ensemble Empirical Mode Decomposition With Principal Component Analysis: A Novel Approach for Extracting Respiratory Rate and Heart Rate From Photoplethysmographic Signal.
The photoplethysmographic (PPG) signal measures the local variations of blood volume in tissues, reflecting the peripheral pulse modulated by cardiac activity, respiration, and other physiological effects. Therefore, PPG can be used to extract the vital cardiorespiratory signals like heart rate (HR), and respiratory rate (RR) and this will reduce the number of sensors connected to the patient's body for recording these vital signs. In this paper, we propose an algorithm based on ensemble empirical mode decomposition with principal component analysis (EEMD-PCA) as a novel approach to estimate HR and RR simultaneously from PPG signal. To examine the performance of the proposed algorithm, we used 310 (from 35 subjects) and 632 (from 42 subjects) epochs of simultaneously recorded electrocardiogram, PPG, and respiratory signal extracted from MIMIC (Physionet ATM data bank) and Capnobase database, respectively. Results of EEMD-PCA-based extraction of HR and RR from PPG signal showed that the median RMS error (1st and 3rd quartiles) obtained in MIMIC data set for RR was 0.89 (0, 1.78) breaths/min, for HR was 0.57 (0.30, 0.71) beats/min and in Capnobase data set it was 2.77 (0.50, 5.9) breaths/min and 0.69 (0.54, 1.10) beats/min for RR and HR, respectively. These results illustrated that the proposed EEMD-PCA approach is more accurate in estimating HR and RR than other existing methods. Efficient and reliable extraction of HR and RR from the pulse oximeter's PPG signal will help patients for monitoring HR and RR with low cost and less discomfort.


Two-dimensional grating coupler on an X-cut lithium niobate thin-film.
A two-dimensional grating coupler for coupling light between a standard single-mode fiber and ridge waveguides on an X-cut lithium niobate thin-film is designed and demonstrated. Using circular holes for grating cells, simulated coupling losses reach -3.88 dB at 1550 nm and -5.78 dB at 1563 nm with 1-dB bandwidths of 49 nm and 45 nm for P-polarized and S-polarized light inputs, respectively. Experimentally, peak coupling losses of -5.13 dB at 1561 nm and -7.6 dB at 1568 nm are obtained for P-polarized and S-polarized light inputs, respectively, and corresponding 1 dB bandwidths are about 30 nm. An approach to improve the coupling performance of the grating coupler is also proposed using two crossing ellipses as grating cells as well as a bottom metal reflector. The coupling loss and the polarization dependent loss are decreased to around -3.4 dB and 0.44 dB, respectively.


A wearable, highly stable, strain and bending sensor based on high aspect ratio graphite nanobelts.
A simple and scalable method was developed for the fabrication of wearable strain and bending sensors, based on high aspect ratio (length/thickness ∼10(3)) graphite nanobelt thin films deposited by a modified Langmuir-Blodgett technique onto flexible polymer substrates. The sensing mechanism is based on the changes in contact resistance between individual nanobelts upon substrate deformation. Very high sensor response stability for more than 5000 strain-release cycles and a device power consumption as low as 1 nW were achieved. The device maximum stretchability is limited by the metal electrodes and the polymer substrate; the maximum strain that could be applied to the polymer used in this work was 40%. Bending tests carried out for various radii of curvature demonstrated distinct sensor responses for positive and negative curvatures. The graphite nanobelt thin flexible films were successfully tested for acoustic vibration and heartbeat sensing.


Antiandrogenic therapy for the treatment of early stage prostatic cancer.
The goal of this study was to achieve clinical application of antiandrogens for the treatment of carcinoma of the prostate. Based on the results obtained from animal experiments and from a pilot clinical trial on prostatic cancer patients using various antiandrogenic compounds, chlormadinone acetate (CMA) was selected for a clinical trial in patients with carcinoma of the prostate. With nine universities and their affiliated hospitals participating, the therapeutic effect of CMA for carcinoma of the prostate was investigated nationwide. Highly satisfactory antitumor effects with CMA were observed in stage A and B patients of the primary treatment group. For stage C patients in the primary treatment group, good antitumor effects were obtained with CMA treatment. For stage D patients, however, results were poor. No serious side effects were observed in spite of the long period (as long as 6.3 years) and relatively large doses (100 mg daily) of CMA. Therefore, it was concluded that CMA can be recommended as a first choice drug for patients with carcinoma of the prostate.


Endovascular Stent-Graft Repair of Spontaneous Isolated Dissection of the Superior Mesenteric Artery.
The aim of this study was to determine the short-term clinical outcomes, safety, and efficacy of covered stents implantation for patients with spontaneous isolated dissection of the superior mesenteric artery (SMA). Between October 2013 and December 2016, 12 patients (mean age, 50.0 ± 6.2 years; range 38-62 years) with spontaneous isolated dissection of SMA received endovascular treatment with the placement of covered stents at our institution. Patients' clinical characteristics were analyzed including sex, age, medical history, risk factors, symptoms, and diagnostic imaging modality. The technical and clinical successes of covered stents placement were retrospectively analyzed. Standard follow-up protocol included abdominal computed tomography angiography and clinical examinations at 1, 3, 6, and 12 months and annually thereafter to confirm patients' general condition. All dissections were located at the anterior wall and around the convex curvature of SMA. The mean length of the SMA dissection was 37.8 ± 31.5 mm (range 6.9-105.0 cm). Immediate technical success was defined as normal blood flow in the SMA and no contrast medium in the false lumen achieved in all patients. The mean duration of follow-up was 26.9 ± 7.2 months (range 16-36 months). Abdominal CT angiography demonstrated that no patients experienced endoleak or stent stenosis during follow-up. For symptomatic spontaneous isolated dissection of SMA in patients without aneurysms rupture and bowel necrosis, endovascular treatment with covered stents may be a safe and effective treatment option with a good short-term outcome.


Reconciling Incongruencies: A Straussian Grounded Theory Approach to Defining Oncology Nurses' Professional Quality of Life.
This grounded theory study explored the processes and actions enacted by oncology nurses to enhance professional quality of life and the related meaning, facilitators, and barriers. Oncology nurses described a process by which they continually Reconcile Incongruencies. This process involves 4 categories: Accepting the Context of Oncology Nursing, Bettering the World, Pursuing a Calling, and Being Valued. External facilitators and barriers, self-driven actions to maintain, and consequences of professional quality of life were also revealed. The findings from this study offer an operational definition, a foundation for instrument development, and the consequences of oncology nurses' professional quality of life.


The Association between Non-Alcoholic Fatty Liver Disease and Cardiovascular Risk in Children.
The rising prevalence of childhood obesity in the past decades has made Non-Alcoholic Fatty Liver Disease (NAFLD) the most common cause of pediatric chronic liver disease worldwide. Currently, a growing body of evidence links NAFLD with cardiovascular disease (CVD) even at an early age. Data on the pediatric population have shown that NAFLD could represent an independent risk factor not only for cardiovascular events but also for early subclinical abnormalities in myocardial structure and function. Briefly, we review the current knowledge regarding the relationship between pediatric NAFLD and cardiovascular risk in an attempt to clarify our understanding of NAFLD as a possible cardiovascular risk factor in childhood.


Structural evidence for stabilization of inhibitor binding by a protein cavity in the dehaloperoxidase-hemoglobin from Amphitrite ornata.
A functional role for a protein cavity that stabilizes inhibitor binding has been established based on a comparison of Xe-derivatized and inhibitor-bound X-ray crystal structures in dehaloperoxidase-hemoglobin (DHP A) of Amphitrite ornata. The internal binding affinity of four different inhibitors, 4-fluorophenol, 4-chlorophenol, 4-bromophenol, and 4-iodophenol in the distal pocket has been shown previously to increase proportional to the radius of the para-halogen atom. Inhibition of oxidation of the native substrate, 2,4,6-tribromophenol, has been shown to follow the trend in inhibitor binding strength, because of a two-site competitive inhibition mechanism that involves displacement of the substrate by the inhibitor in a gated mechanism involving the distal histidine of DHP A. In this study, it is shown that the origin of the stronger binding by a larger para-halogen substituent coincides structurally with a Xe-binding cavity (Xe1) characterized structurally by X-ray crystallography. The Xe1 site is surrounded by amino acid resides L100, F21, F24, F35, F60, and V59 in the distal pocket, located 4.8 Å from the heme iron, in a position that is coincident with the para-bromine atom of the inhibitor 4-bromophenol. 4-bromophenol is prevalent in benthic ecosystems where A. ornata resides. A second, less well-defined, binding site in DHP A, labeled as Xe2, is located near the surface of the protein in the vicinity of amino acid residues L62, R69, D79, T82, and L83, which may be related to substrate docking on the surface of DHP A.


Pre-engagement cohabitation and gender asymmetry in marital commitment.
The authors longitudinally examined couples' (N = 197) dedication (interpersonal commitment) levels on the basis of their premarital cohabitation history. Findings suggested that men who cohabited with their spouse before engagement were less dedicated than men who cohabited only after engagement or not at all before marriage. Furthermore, these husbands were less dedicated to their wives than their wives were to them. Hierarchical linear modeling showed that such asymmetries were apparent before marriage and through the early years of marriage. Relationship adjustment and religiousness were related to dedication but did not account for the findings. The authors suggest that couples considering cohabitation before engagement could benefit from discussions about commitment and expectations about marriage.


Carcinogenic and health risk assessment of respiratory exposure to acrylonitrile, 1,3-butadiene and styrene in the petrochemical industry using the US Environmental Protection Agency method.
Objectives. This study aimed to assess carcinogenic and health risks of respiratory exposure to acrylonitrile, 1,3-butadiene and styrene (ABS) in the petrochemical industry. Methods. This cross-sectional study was conducted in a petrochemical plant producing ABS copolymers. Respiratory exposure to each of acrylonitrile, 1,3-butadiene and styrene was measured using methods No. 1604, No. 1024 and No. 1501 of the National Institute of Occupational Safety and Health (NIOSH), respectively. The US Environmental Protection Agency (USEPA) method was used to assess carcinogenic and health risks. Results. The average occupational exposure to ABS was 560.82 µg m-3 for 1,3-butadiene, 122.8 µg m-3 for acrylonitrile and 1.92 µg m-3 for styrene. The average lifetime cancer risk in the present study was 2.71 × 10-3 for 1,3-butadiene, 2.1 × 10-3 for acrylonitrile and 6.6 × 10-3 for styrene. Also, the mean non-cancer risk (hazard quotient) among all participants for each of 1,3-butadiene, acrylonitrile and styrene was 4.04 ± 6.93, 10.82 ± 14.76 and 0.19 ± 0.11, respectively. Conclusion. The values of carcinogenic and health risks in the majority of the subjects were within the unacceptable risk levels due to exposure to ABS vapors. Hence, corrective actions are required to protect the workers from non-cancer and cancer risks.


Changes in thrombin generation and D-dimer concentrations in women injecting enoxaparin during pregnancy and the puerperium.
It is well accepted that the gravid state is hypercoagulable and a significant cause of both maternal morbidity and mortality in the Western world. Although thrombin generation is reported to be increased in pregnant women, uncertainty exists on the pattern of thrombin generation change during this time. The aim of this study is to describe thrombin generation changes and D-dimer concentrations in women injecting enoxaparin during pregnancy the postnatal period. One hundred and twenty-three women injecting enoxaparin had their thrombin generation, as measured by Calibrated Automated Thombinography (CAT), repeatedly assayed during pregnancy, once in each trimester, at delivery and 8 weeks post-partum. Furthermore, to understand the impact enoxaparin has on D-dimer concentrations during pregnancy, D-dimer concentrations were measured monthly in the recruited women. Thrombin generation was found to increase in the first trimester (mean endogenous thrombin potential (ETP): 1391 nmol/L.min), further increasing during the second trimester (mean ETP: 1757 nmol/L.min), after which it plateaued through to delivery, where it peaked (mean ETP: 1857 nmol/L.min) and then fell back at 8 weeks post-partum (ETP: 1293 nmol/L.min). In contrast D-dimer concentrations increased exponentially during the antenatal period, despite the enoxaparin prescription. Our results provide further evidence on alterations of thrombin generation during pregnancy and the postnatal period.


Anthropogenic marine litter composition in coastal areas may be a predictor of potentially invasive rafting fauna.
Anthropogenic plastic pollution is a global problem. In the marine environment, one of its less studied effects is the transport of attached biota, which might lead to introductions of non-native species in new areas or aid in habitat expansions of invasive species. The goal of the present work was to assess if the material composition of beached anthropogenic litter is indicative of the rafting fauna in a coastal area and could thus be used as a simple and cost-efficient tool for risk assessment in the future. Beached anthropogenic litter and attached biota along the 200 km coastline of Asturias, central Bay of Biscay, Spain, were analysed. The macrobiotic community attached to fouled litter items was identified using genetic barcoding combined with visual taxonomic analysis, and compared between hard plastics, foams, other plastics and non-plastic items. On the other hand, the material composition of beached litter was analysed in a standardized area on each beach. From these two datasets, the expected frequency of several rafting taxa was calculated for the coastal area and compared to the actually observed frequencies. The results showed that plastics were the most abundant type of beached litter. Litter accumulation was likely driven by coastal sources (industry, ports) and river/sewage inputs and transported by near-shore currents. Rafting vectors were almost exclusively made up of plastics and could mainly be attributed to fishing activity and leisure/ household. We identified a variety of rafting biota, including species of goose barnacles, acorn barnacles, bivalves, gastropods, polychaetes and bryozoan, and hydrozoan colonies attached to stranded litter. Several of these species were non-native and invasive, such as the giant Pacific oyster (Crassostrea gigas) and the Australian barnacle (Austrominius modestus). The composition of attached fauna varied strongly between litter items of different materials. Plastics, except for foam, had a much more diverse attached community than non-plastic materials. The predicted frequency of several taxa attached to beached litter significantly correlated with the actually observed frequencies. Therefore we suggest that the composition of stranded litter on a beach or an area could allow for predictions about the corresponding attached biotic community, including invasive species.


Carcinoma within a fibroadenoma: a case report.
Carcinoma within a fibroadenoma is an extremely rare occurrence with a reported incidence of 0.1% and is most often diagnosed incidentally on post-operative examination of excision biopsy specimens. One such case is reported here for its rarity and also for stressing upon the need for compulsory excision of all breast masses clinically diagnosed as fibroadenoma and for highlighting the importance of histopathological evaluation of all breast masses irrespective of their clinical diagnosis as benign.


Kinetics and thermodynamics of the unfolding and refolding of the three-stranded alpha-helical coiled coil, Lpp-56.
Temperature-induced reversible unfolding and refolding of the three-stranded alpha-helical coiled coil, Lpp-56, were studied by kinetic and thermodynamic methods, using CD spectroscopy, dynamic light scattering, and scanning calorimetry. It was found that both unfolding and refolding reactions of this protein in neutral solution in the presence of 100 mM NaCl are characterized by unusually slow kinetics, which permits detailed investigation of the mechanism of these reactions. Kinetic analyses show that the unfolding of this coiled coil represents a single-stage first-order reaction, while the refolding represents a single-stage third-order reaction. The activation enthalpy and entropy for unfolding do not depend noticeably on temperature and are both significantly greater than those for the folding reaction, which show a significant dependence on temperature. The activation heat capacity change for the unfolding reaction is close to zero, while it is quite significant for the folding reaction. The correlation between the activation and structural parameters obtained for the Lpp-56 coiled coil suggests that interhelical van der Waals interactions are disrupted in the transition state, which is nevertheless still compact, and water has not yet penetrated into the interface; the transition from the transient state to the unfolded state results in hydration of exposed apolar groups of the interface and the disruption of helices. The low propensity for the Lpp-56 strands to fold and associate is caused by the high number of charged groups at neutral pH. On one hand, these charges give rise to considerable repulsive forces destabilizing the helical conformation of the strands. On the other hand, they align the folded helices in parallel and in register so that the apolar sides face each other, and the oppositely charged groups may form salt links, which are important for the formation of the trimeric coiled coil. A decrease in pH, which eliminates the salt links, dramatically decreases the stability of Lpp-56; its structure becomes less rigid and unfolds much faster.


Dose-incidence modeling: consequences of linking quantal measures of response to depletion of critical tissue targets.
In developing mechanistic PK-PD models, incidence of toxic responses in a population has to be described in relation to measures of biologically effective dose (BED). We have developed a simple dose-incidence model that links incidence with BED for compounds that cause toxicity by depleting critical cellular target molecules. The BED in this model was the proportion of target molecule adducted by the dose of toxic compound. Our modeling approach first estimated the proportion depleted for each dose and then calculated the tolerance distribution for toxicity in relation to either administered dose or log of administered dose. We first examined cases where the mean of the tolerance distribution for toxicity occurred when a significant proportion of target had been adducted (i.e., more than half). When a normal distribution was assumed to exist for the relationship of incidence and BED, the tolerance distribution based on administered dose for these cases becomes asymmetrical and logarithmic transformations of the administered dose axis lead to a more symmetrical distribution. These linked PK-PD models for tissue reactivity, consistent with conclusions from other work for receptor binding models (Lutz et al., 2005), indicate that log normal distributions with administered dose may arise from normal distributions for BED and nonlinear kinetics between BED and administered dose. These conclusions are important for developing biologically based dose response (BBDR) models that link incidences of toxicity or other biological responses to measures of BED.


[Bactericidal effect of ozonated camellia oil on Staphylococcus aureus in vitro].
To explore a new method for detecting the bactericidal effect of oiling agent in vitro, and to determine the disinfectant effecacy of ozonated camellia oil on Staphylococcus aureus. Methods: Suspension of Staphylococcus aureus was prepared and innoculated on the LB plate by plate scribing method. After culture overnight, 21 bacterial monoclones with the same diameter were selected and divided into 3 groups: A negative control group, a baseoil (camellia oil) group and an ozonated camellia oil group. We used a ring to isolate the single clone and added oil inside the ring, cultured the whole plate over night, picked out each single clone (with gel) to 5 mL LB medium and cultured it for 12 h. The final concentration of the LB medium was detected by plate count method and turbidimetry. Results: According to the plate count method and turbidimetry, the bacterial concentration in the ozonated camellia oil group was lower than that in the negative control group and base oil group (P<0.001). Conclusion: Bacterial monoclone culture method shows that ozonated camellia oil can significantly kill Staphylococcus aureus, and this method is an effective method for evaluating the bactericidal function of the oiling agent in vitro.


Who Shall Not Be Treated: Public Attitudes on Setting Health Care Priorities by Person-Based Criteria in 28 Nations.
The principle of distributing health care according to medical need is being challenged by increasing costs. As a result, many countries have initiated a debate on the introduction of explicit priority regulations based on medical, economic and person-based criteria, or have already established such regulations. Previous research on individual attitudes towards setting health care priorities based on medical and economic criteria has revealed consistent results, whereas studies on the use of person-based criteria have generated controversial findings. This paper examines citizens' attitudes towards three person-based priority criteria, patients' smoking habits, age and being the parent of a young child. Using data from the ISSP Health Module (2011) in 28 countries, logistic regression analysis demonstrates that self-interest as well as socio-demographic predictors significantly influence respondents' attitudes towards the use of person-based criteria for health care prioritization. This study contributes to resolving the controversial findings on person-based criteria by using a larger country sample and by controlling for country-level differences with fixed effects models.


Prediction of help-seeking with the MMPI: the problem of base rates.
The usefulness of combined elevation of the Depression and Psychasthenia scales of the MMPI as a predictor of psychological help-seeking was investigated for two classes at a small liberal arts college for men. Counseling service use rates during the 4 years of college for all students who scored at or above T = 60 on both MMPI scales (N = 83) were compared with rates for all other students (N = 269). Students in the high Depression-Psychasthenia group were significantly more likely to seek counseling during their freshman years than were other students (p less than .05). Among counselees the high MMPI group also made significantly more visits to the service (p less than .05). Application of a Bayesian rule disclosed that the MMPI measure would have improved decision accuracy only with respect to the prediction that a student would come in for counseling at some time during college. In this population, the MMPI measure is both a valid and a useful predictor.


Serial mixed-mode cation- and anion-exchange solid-phase extraction for separation of basic, neutral and acidic pharmaceuticals in wastewater and analysis by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.
A novel solid-phase extraction (SPE) method is presented whereby 15 basic, neutral and acidic pharmaceuticals in wastewater were simultaneously extracted and subsequently separated into different fractions. This was achieved using mixed-mode cation- and anion-exchange SPE (Oasis MCX and MAX) in series. Analysis was performed by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC/QTOF-MS). A fast separation was achieved, with all compounds eluting within 6min, narrow chromatographic peaks, with a peak base width of 6s on average, and a high mass accuracy of quantified wastewater sample ions, with average mass errors in absolute value of 0.7mDa or 2.7ppm. The recovery of the SPE method in the analysis of sewage treatment plant (STP) influent and effluent wastewater was on average 80% and the ion suppression 30%. For less demanding samples Oasis MCX used alone may be an alternative method, although for STP influent waters containing high loads of organic compounds the clean-up achieved using only Oasis MCX was insufficient, leading to unreliable quantitation. Furthermore, serial SPE separation according to molecular charge added an additional degree of analyte confirmation. For quantitation, an approach combining external standard calibration curves, isotopically labelled surrogate standards and single-point standard addition was used. The applicability of the method was demonstrated in the analysis of influent and effluent wastewater from an STP, using small sample volumes (25-50mL). The effluent wastewater had been subjected to three different treatments; activated sludge, activated sludge followed by ozonation, and a membrane bioreactor (MBR). Ozone treatment proved superior in removal of the analysed pharmaceuticals, while the MBR provided higher removal efficiencies than the activated sludge process.


A new strategy for identification of N-glycosylated proteins and unambiguous assignment of their glycosylation sites using HILIC enrichment and partial deglycosylation.
Characterization of glycoproteins using mass spectrometry ranges from determination of carbohydrate-protein linkages to the full characterization of all glycan structures attached to each glycosylation site. In a novel approach to identify N-glycosylation sites in complex biological samples, we performed an enrichment of glycosylated peptides through hydrophilic interaction liquid chromatography (HILIC) followed by partial deglycosylation using a combination of endo-beta-N-acetylglucosaminidases (EC 188.8.131.52). After hydrolysis with these enzymes, a single N-acetylglucosamine (GlcNAc) residue remains linked to the asparagine residue. The removal of the major part of the glycan simplifies the MS/MS fragment ion spectra of glycopeptides, while the remaining GlcNAc residue enables unambiguous assignment of the glycosylation site together with the amino acid sequence. We first tested our approach on a mixture of known glycoproteins, and subsequently the method was applied to samples of human plasma obtained by lectin chromatography followed by 1D gel-electrophoresis for determination of 62 glycosylation sites in 37 glycoproteins.


Factors influencing the change in cerebral hemodynamics in pediatric patients during and after corrective cardiac surgery of congenital heart diseases by means of full-flow cardiopulmonary bypass.
The pathophysiology of hypoxic-ischemic brain injury in relation to extracorporeal circulation is multifactorial and can be interpreted, in part, as possible alteration in cerebral perfusion and inadequate oxygen delivery to the brain cells. The aim of this study was to evaluate influencing factors on the change in cerebral blood flow velocity (CBFV) patterns determined by transcranial Doppler sonography (TCD) in infants who undergo corrective cardiac surgery by means of full-flow cardiopulmonary bypass (CPB). Included in the study were 67 neonates, infants, and children with a median age of 4 months (0.1-70 months), median weight of 4.8 kg (2.5-18.8 kg), and with cyanotic and noncyanotic congenital heart disease (CHD), who underwent surgical correction of CHD by means of CPB [flow rate 144 +/- 47 ml/kg body weight (BW)] and the alpha-stat strategy. The patients were divided into three groups with respect to the minimum rectal temperature during perfusion: deep hypothermic CPB (<18 degrees C) n=18, moderate hypothermic CPB (22-35 degrees C) n=29, normothermic CPB (36 degrees C) n=20. Continuous determination of mean flow velocity (Vmean) in the middle cerebral artery (MCA) by TCD provided qualitative on-line information on cerebral perfusion. The pulsatility index (PI) was calculated in accordance with the formula: Maximum flow velocity - end - diastolic flow velocity/ Mean flow velocity and was used as a parameter for the qualitative assessment of cerebrovascular resistance after the end of CPB. The Vmean was significantly increased 15 min after cross-clamping in the normothermic group (p=0.03) and decreased in the moderate hypothermic group (p=0.02) and deep hypothermic group (p=0.009). The postoperative Vmean values correlated significantly with age (r=0.79, p<0.0001), weight (r=0.75, p<0.0001), bypass time (r=-0.51, p=0.0006), and minimum rectal temperature (r=0.60, p=0.0001). Mean arterial pressure and hemoglobin concentration, but not pCO2, seem to significantly influence the change in Vmean after the termination of CPB (r=0.5, p=0.001; r=-0.55, p=0.002, respectively). In comparison with the values at the start of CPB, the Vmean was significantly decreased after the end of CPB in the hypothermic and moderate hypothermic groups and still significantly elevated in the normothermic group. The age-independent PI was increased after termination of bypass in all groups (p<0.05) and still slightly elevated after the end of operation in the hypothermic group (p=0.05). The changes in CBFV patterns before, during, and after the termination of CPB were dependent on age, weight, perfusion pressure, and degree of hypothermia during CPB.


Plasma TNFRSF11B as a New Predictive Inflammatory Marker of Sepsis-ARDS with Endothelial Dysfunction.
Inflammation plays an important role in the development of sepsis-acute respiratory distress syndrome (ARDS). Olink inflammation-related biomarker panels were used to analyze the levels of 92 inflammation-related proteins in plasma with sepsis-ARDS (n = 25) and healthy subjects (n = 25). There were significant differences in 64 inflammatory factors, including TNFRSF11B in sepsis-ARDS, which was significantly higher than that in controls. Functional analysis showed that TNFRSF11B was closely focused on signal transduction, immune response, and inflammatory response. The TNFRSF11B level in sepsis-ARDS plasma, LPS-induced mice, and LPS-stimulated HUVECs significantly increased. The highest plasma concentration of TNFRSF11B in patients with sepsis-ARDS was 10-20 ng/mL, and 10 ng/mL was selected to stimulate HUVECs. Western blot results demonstrated that the levels of syndecan-1, claudin-5, VE-cadherin, occludin, aquaporin-1, and caveolin-1 in TNFRSF11B-stimulated HUVECs decreased, whereas that of connexin-43 increased in TNFRSF11B-stimulated HUVECs. To the best of the authors' knowledge, this study was the first to reveal elevated TNFRSF11B in sepsis-ARDS associated with vascular endothelial dysfunction. In summary, TNFRSF11B may be a new potential predictive and diagnostic biomarker for vascular endothelium damage in sepsis-ARDS.


For Whom the Bell Tolls? A Toll-Like Receptor 9 Agonist's Journey from Vaccine Adjuvant to Promising Agent in Anti-PD-1-Resistant Melanoma.
Developing effective therapies in anti-PD-1-resistant melanoma is a key unmet need. The combination of pembrolizumab with the intralesional TLR9 agonist vidutolimod showed promise in this patient population with correlative analysis suggesting that patients with a "cold" tumor immune microenvironment may be the best patients to study further. See related article by Ribas et al., p. 2998.


Research progress of p38 as a new therapeutic target against morphine tolerance and the current status of therapy of morphine tolerance.
With the development of the medical industry, new painkillers continue to appear in people's field of vision, but so far no painkiller can replace morphine. While morphine has a strong analgesic effect, it is also easy to produce pain sensitivity and tolerance. Due to the great inter-individual differences in patient responses, there are few clear instructions on how to optimise morphine administration regimens, which complicates clinicians' treatment strategies and limits the effectiveness of morphine in long-term pain therapy. P38MAPK is a key member of the MAPK family. Across recent years, it has been discovered that p38MAPK rises dramatically in a wide range of morphine tolerance animal models. Morphine tolerance can be reduced or reversed by inhibiting p38MAPK. However, the role and specific mechanism of p38MAPK are not clear. In this review, we synthesise the relevant findings, highlight the function and potential mechanism of p38MAPK in morphine tolerance, as well as the present status and efficacy of morphine tolerance therapy, and underline the future promise of p38MAPK targeted morphine tolerance treatment.


Direct collapse to supermassive black hole seeds: comparing the AMR and SPH approaches.
We provide detailed comparison between the adaptive mesh refinement (AMR) code enzo-2.4 and the smoothed particle hydrodynamics (SPH)/N-body code gadget-3 in the context of isolated or cosmological direct baryonic collapse within dark matter (DM) haloes to form supermassive black holes. Gas flow is examined by following evolution of basic parameters of accretion flows. Both codes show an overall agreement in the general features of the collapse; however, many subtle differences exist. For isolated models, the codes increase their spatial and mass resolutions at different pace, which leads to substantially earlier collapse in SPH than in AMR cases due to higher gravitational resolution in gadget-3. In cosmological runs, the AMR develops a slightly higher baryonic resolution than SPH during halo growth via cold accretion permeated by mergers. Still, both codes agree in the build-up of DM and baryonic structures. However, with the onset of collapse, this difference in mass and spatial resolution is amplified, so evolution of SPH models begins to lag behind. Such a delay can have effect on formation/destruction rate of H2 due to UV background, and on basic properties of host haloes. Finally, isolated non-cosmological models in spinning haloes, with spin parameter λ ∼ 0.01-0.07, show delayed collapse for greater λ, but pace of this increase is faster for AMR. Within our simulation set-up, gadget-3 requires significantly larger computational resources than enzo-2.4 during collapse, and needs similar resources, during the pre-collapse, cosmological structure formation phase. Yet it benefits from substantially higher gravitational force and hydrodynamic resolutions, except at the end of collapse.


The prion-like protein Doppel (Dpl) interacts with the human receptor for activated C-kinase 1 (RACK1) protein.
Doppel (Dpl) is a homologue of the prion protein (PrPC). In contrast to PrP(C), Dpl is dispensable for prion disease, but appears to have an essential function in male spermatogenesis. Recently, Dpl has been found to be aberrantly expressed in astrocytic and leukaemic tumor specimens, showing a peculiar cytosolic cellular localization. The aim of this study was to clarify some of the putative Dpl interacting proteins. A yeast two hybrid system was employed and the results were verified by co-immunoprecipitation using transfected cells. Several potential Dpl-binding candidates were identified and, among them, the receptor for activated C-kinase (RACK1) protein was further investigated. RACK1 deletion mutants showed that some of its WD containing domains were directly involved in the binding with Dpl. Our data showed that Dpl interacts with RACK1 by means of its structured globular carboxyl-terminal region. This new Dpl interacting partner might suggest functional hypotheses about the role of this protein in an astrocytoma context where Dpl was found ectopically expressed.


Subclinical herpesvirus shedding among HIV-1-infected men on antiretroviral therapy.
We evaluated the subclinical shedding of six different herpesviruses in antiretroviral drug-treated HIV-positive [HIV(+)] MSM, and determined how this is associated with markers of inflammation and immune activation. We obtained blood, semen, throat washing, urine, and stool from 15 antiretroviral-treated HIV-1-infected MSM with CD4 T-cell reconstitution, and 12 age-matched HIV-negative [HIV (-)] MSM from the Multicenter AIDS Cohort Study at four timepoints over 24 weeks to measure DNA levels of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 and 2, human herpesvirus 6 (HHV6), and HHV8. T-cell activation and plasma levels of soluble markers of inflammation and activation were also measured at the corresponding timepoints. HIV(+) participants had a trend for higher total herpesvirus shedding rate. HIV(+) participants also had a significantly higher rate of shedding EBV and CMV compared with the HIV(-) group. Herpesvirus shedding was mostly seen in throat washings. In the HIV(+) group, herpesvirus shedding rate inversely correlated with plasma levels of interferon γ-induced protein 10 and soluble CD163. CMV DNA levels negatively correlated with levels of T-cell activation. There was a trend for a positive correlation between EBV shedding rate and plasma soluble CD14. HHV6 shedding rate negatively correlated with plasma levels of interleukin-6, soluble CD163, and interferon gamma-induced protein 10. Correlations were not observed among HIV(-) individuals. Among treated HIV-infected MSM, there are higher subclinical shedding rates of some herpesviruses that occur in different body compartments and negatively correlate with levels of inflammation and immune activation.


Acetylation of some novel hemicholinium compounds by soluble choline acetyltransferase: structure-activity relationships.
Four bisquaternary nitrogen analogues of 2,2'-[1,1'-biphenyl]-4, 4'- diylbis [2-hydroxy-4,4- dimethylmorpholinium ] bromide (hemicholinium 3, HC-3) have been synthesized. These analogues differ from HC-3 in that they have a number of methylene groups inserted between the two phenyl rings. This study examines the significance of the internitrogen distance in these compounds with regard to their acetylation by soluble choline acetyltransferase (ChAc) in vitro. The hemicholinium compounds were incubated with [14C] acetylcoenzyme A and any acetylated products were isolated by liquid ion exchange. Only HC-3 and the analogue with three methylene groups between the two phenyl rings, that is, 2,2'-(1,3- propanediyldi -1,4-phenylene)bis[2-hydroxy-4, 4- dimethylmorpholinium ] ( 3CHC ), were found to be significantly acetylated. The acetylation rate of both these two compounds was 28% that of choline. It is concluded that an internitrogen distance of 14 A in bisquaternary nitrogen choline analogues provides the optimum distance for acetylation by ChAc in vitro.


Finding a Trans-Affirmative Provider: Challenges Faced by Trans and Gender Diverse Psychologists and Psychology Trainees.
This article explores some of the challenges faced by trans and gender diverse (TGD) individuals who not only are attempting to access trans-affirmative care, but who are also members of the very profession from which they are seeking services. The authors explore challenges related to finding supervision, accessing care for assessment services, and finding a provider for personal counseling. With each example, the authors unpack the challenges and also address the implications for training for all involved. Based on these challenges that TGD psychologists and trainees face in attempting to access care, the authors provide recommendations related to trans-affirmative training for psychologists.


Phase-separated ribosome-nascent chain complexes in genotoxic stress response.
Assemblysomes are EDTA- and RNase-resistant ribonucleoprotein (RNP) complexes of paused ribosomes with protruding nascent polypeptide chains. They have been described in yeast and human cells for the proteasome subunit Rpt1, and the disordered amino-terminal part of the nascent chain was found to be indispensable for the accumulation of the Rpt1-RNP into assemblysomes. Motivated by this, to find other assemblysome-associated RNPs we used bioinformatics to rank subunits of Saccharomyces cerevisiae protein complexes according to their amino-terminal disorder propensity. The results revealed that gene products involved in DNA repair are enriched among the top candidates. The Sgs1 DNA helicase was chosen for experimental validation. We found that indeed nascent chains of Sgs1 form EDTA-resistant RNP condensates, assemblysomes by definition. Moreover, upon exposure to UV, SGS1 mRNA shifted from assemblysomes to polysomes, suggesting that external stimuli are regulators of assemblysome dynamics. We extended our studies to human cell lines. The BLM helicase, ortholog of yeast Sgs1, was identified upon sequencing assemblysome-associated RNAs from the MCF7 human breast cancer cell line, and mRNAs encoding DNA repair proteins were overall enriched. Using the radiation-resistant A549 cell line, we observed by transmission electron microscopy that 1,6-hexanediol, an agent known to disrupt phase-separated condensates, depletes ring ribosome structures compatible with assemblysomes from the cytoplasm of cells and makes the cells more sensitive to X-ray treatment. Taken together, these findings suggest that assemblysomes may be a component of the DNA damage response from yeast to human.


[Iatrogenic hydrothorax in a premature infant and its treatment].
Iatrogenic hydrothorax in a premature infant of 36 weeks' gestation was caused by misplacement of a central venous catheter leading to massive pleural effusion in the left hemithorax. Subsequently respiratory insufficiency developed which could be treated successfully within 24 h by complete removal of the i.v. fluid via the misplaced catheter and simultaneous mechanical ventilation.


Low oxygen: a constraint on the evolution of viviparity in reptiles.
The evolution of reptilian viviparity (live bearing) from oviparity (egg laying) is thought to require transitional stages of increasingly longer periods of embryonic development in utero, that is, longer periods of egg retention by the gravid female. Studies on sceloporine lizards demonstrate that embryonic responses to egg retention that is extended beyond the time of normal oviposition range from developmental arrest to normal development. The present study was designed to test the hypothesis that O(2) availability is the proximate factor that determines the rate and degree of development that reptilian embryos undergo in utero. Eggs of Sceloporus undulatus were incubated under conditions of low (LOX), normal (NOX), and high (HOX) oxygen both early and late in development. The LOX treatment consistently had a negative effect on development in terms of embryonic differentiation and growth, length of incubation, egg mortality, and hatchling size. Moreover, the LOX treatment had a stronger negative effect later in development than earlier in development. The results support the hypothesis that limited oxygen availability in utero acts as a developmental constraint. They further indicate that selection for extended egg retention, per se, will not lead to viviparity unless each incremental increase in the duration of egg retention is coupled with selection for traits (e.g., vascularity of oviduct and chorioallantois, hemoglobin oxygen affinity, etc.) that enhance O(2) availability to embryos. Such selection would be the most efficacious in cold climates where the effects of hypoxia would be the least likely to limit embryonic development.


Reexamination of London, England, mortality in relation to exposure to acidic aerosols during 1963-1972 winters.
Air pollution epidemiology since the 1950s has been able to demonstrate that increases in daily mortality in London, England, were associated with elevated concentrations of index air pollutants, i.e., British Smoke (BS) and sulfur dioxide (SO2). In this work, we reanalyze that portion of the 1958-1972 winter mortality-pollution record for which daily direct acid aerosol measurements were made at a central site in London (St. Bartholomew's Medical College). The purposes of these exploratory analyses are to examine the dataset for indications of a relationship between acid aerosol pollution and human mortality and to compare any noted associations with those for other pollution variables. It is found that the log of acid aerosol concentrations is more strongly associated with raw total mortality in bivariate analyses than is BS or SO2, despite the fact that acid data are available from only one central site (versus seven disperse sites for BS and SO2). The logarithmic nature of the exposure side of the H2SO4-mortality relationship implies a saturation model of pollution effects, possibly due to multiday pollution harvesting influences on a susceptible subpopulation. Moreover, mortality-pollution cross-correlation analyses indicate that mortality effects usually follow pollution in time, supporting a causal relationship between the two. The apparent advantage of H2SO4 over BS in predicting total raw mortality is consistent with the hypothesis that it is the portion of particulate mass of greater health significance and may also allow the development of London mortality results which are more easily transferable to other environments than is the case for existing BS results.


Decellularized Human Kidney Cortex Hydrogels Enhance Kidney Microvascular Endothelial Cell Maturation and Quiescence.
The kidney peritubular microvasculature is highly susceptible to injury from drugs and toxins, often resulting in acute kidney injury and progressive chronic kidney disease. Little is known about the process of injury and regeneration of human kidney microvasculature, resulting from the lack of appropriate kidney microvascular models that can incorporate the proper cells, extracellular matrices (ECMs), and architectures needed to understand the response and contribution of individual vascular components in these processes. In this study, we present methods to recreate the human kidney ECM (kECM) microenvironment by fabricating kECM hydrogels derived from decellularized human kidney cortex. The majority of native matrix proteins, such as collagen-IV, laminin, and heparan sulfate proteoglycan, and their isoforms were preserved in similar proportions as found in normal kidneys. Human kidney peritubular microvascular endothelial cells (HKMECs) became more quiescent when cultured on this kECM gel compared with culture on collagen-I-assessed using phenotypic, genotypic, and functional assays; whereas human umbilical vein endothelial cells became stimulated on kECM gels. We demonstrate for the first time that human kidney cortex can form a hydrogel suitable for use in flow-directed microphysiological systems. Our findings strongly suggest that selecting the proper ECM is a critical consideration in the development of vascularized organs on a chip and carries important implications for tissue engineering of all vascularized organs.


Laparoscopic Single-Port versus Mini-Laparoscopic Hysterectomy: An International Study.
Laparoendoscopic single-site surgery (LESS) and mini-laparoscopic surgery (Mini-LPS) have been performed with comparable results to conventional laparoscopy. However, there are few data on the comparison between them. Our main objective was to compare LESS and Mini-LPS in terms of surgical time, postoperative pain, and hospital stay in patients who underwent hysterectomy for benign pathology. It is a retrospective international multicentric study carried out in 5 centers including 2 Spanish and 3 Italian. Data from patients who underwent hysterectomy for benign pathology between January 1, 2010, and December 31, 2015, were reviewed. We collected the clinical-pathological characteristics of the patients and the perioperative results. The main variables of the study were surgical time, the switch to oral analgesia, and the hospital stay. The two comparison groups in the study included patients undergoing hysterectomy for benign pathology by LESS or by Mini-LPS. The decision to perform the type of procedure was left to the discretion of the surgeon, based primarily on the surgical skills and experience of the center. All data were collected retrospectively by an online encrypted platform. 161 patients were included in the study. 104 (64.6%) patients underwent LESS hysterectomy and 57 (35.4%) Mini-LPS. Median surgical time was significantly longer in the LESS group when compared to the Mini-LPS group (120 vs. 75 min, respectively; p < 0.001). Moreover, longer median hospital stay was observed in the LESS group compared to Mini-LPS (48 vs. 36 h, respectively; p < 0.001). Conversion of the technique to conventional LPS was performed in 4 (2.5%) patients, all of them in the Mini-LPS group (p = 0.015). It is a retrospective study with the biases that this implies. Furthermore, some variables have been incompletely registered in the database, which implies loss of information. This is a nonrandomized study since the decision to intervene with one or another technique was made by the surgeon, which generated 2 nonhomogeneous groups in terms of the number of patients. On the other hand, all the patients who underwent Mini-LPS hysterectomy belonged to the same center, which may have made these results center dependent. Significant shorter surgical time and shorter hospital stay were observed in patients undergoing Mini-LPS hysterectomy compared to LESS technique; however, intraoperative complications related to instrumentation flaws were higher in the mini-LPS group that required conversion to standard laparoscopy in all cases. Both ultra-minimally invasive techniques seem safe to perform hysterectomies for benign pathology and emphasize the importance in surgical training to adapt them to our current practice.