Heart rate response to adenosine in patients with diabetes mellitus and normal myocardial perfusion imaging.
Adenosine infusion, as is used in stress single photon-emission computed tomographic (SPECT) imaging, produces an increase in heart rate (HR) and a decrease in blood pressure (BP). The increase in HR is most likely due to direct sympathetic stimulation rather than a reflex to the decrease in BP. In this study, it was hypothesized that the HR response to adenosine is different in patients with versus without diabetes mellitus (DM) in the setting of normal SPECT imaging results. We studied 60 patients with DM (53% women, mean age 62 +/- 10 years) and 60 controls (50% women, mean age 61 +/- 12 years) (p = NS). All patients underwent adenosine SPECT imaging (140 mug/kg/min for 5 minutes) for clinical indications and had normal perfusion and systolic left ventricular function. HR and BP were measured at baseline and during adenosine infusion. HR ratio was defined as peak HR divided by baseline HR and the change as peak HR minus baseline HR. The change in HR (17 +/- 12 vs 22 +/- 14 beats/min, p = 0.034) and the ratio (1.24 +/- 0.20 vs 1.33 +/- 0.25, p = 0.048) were significantly lower in patients with DM compared with those without DM. The baseline and change in mean BP were not significantly different between the 2 groups. In a stepwise regression analysis model, DM was identified as a predictor of the change in HR (p = 0.022). In conclusion, HR response to adenosine infusion is diminished in patients with DM with normal SPECT imaging results. This is likely due to cardiovascular autonomic neuropathy and may carry important prognostic information.


Bed bugs are associated with anemia.
Bed bugs are hematophagous insects that can be problematic in some urban emergency departments. The objective was to determine if red blood cell (RBC) and coagulation indices of bed bug-infested emergency department (ED) patients differed from those of noninfested control patients. A chart review from a single health system was performed for ED patients between February 1, 2011, and February 1, 2017. Bed bug-infested patients were matched to noninfested control patients on the basis of age, sex, and the presenting ED. Variables were analyzed with the t-test and Pearson χ2 test and were modeled with multivariable logistic regression. The study had 332 bed bug-infested patients and 4952 controls. Infested patients had lower hemoglobin (11.7 g/dL vs 12.8 g/dL), hematocrit (35.0% vs 37.9%), RBC counts (4.1 × 109/L vs 4.4 × 109/L), mean corpuscular volume (86.0 vs 87.5 fL/cell), and mean corpuscular hemoglobin concentrations (33.2 vs 33.7 g/dL) and higher RBC distribution width-coefficient of variation (RDW-CV) (15.2% vs 14.2%) than noninfested patients (all P ≤ .003). Infested patients were more likely to be anemic (59.5% vs 36.9%) and to have severe anemia (4.4% vs 0.7%) (P < .001 for both). Blood transfusions were more common in those with bed bugs (5.1%) than those without bed bugs (2.3%) (P < .001). Bed bug infestated patients in the ED are associated with anemia.


Investigating Patients' Continuance Intention Toward Conversational Agents in Outpatient Departments: Cross-sectional Field Survey.
Conversational agents (CAs) have been developed in outpatient departments to improve physician-patient communication efficiency. As end users, patients' continuance intention is essential for the sustainable development of CAs. The aim of this study was to facilitate the successful usage of CAs by identifying key factors influencing patients' continuance intention and proposing corresponding managerial implications. This study proposed an extended expectation-confirmation model and empirically tested the model via a cross-sectional field survey. The questionnaire included demographic characteristics, multiple-item scales, and an optional open-ended question on patients' specific expectations for CAs. Partial least squares structural equation modeling was applied to assess the model and hypotheses. The qualitative data were analyzed via thematic analysis. A total of 172 completed questionaries were received, with a 100% (172/172) response rate. The proposed model explained 75.5% of the variance in continuance intention. Both satisfaction (β=.68; P<.001) and perceived usefulness (β=.221; P=.004) were significant predictors of continuance intention. Patients' extent of confirmation significantly and positively affected both perceived usefulness (β=.817; P<.001) and satisfaction (β=.61; P<.001). Contrary to expectations, perceived ease of use had no significant impact on perceived usefulness (β=.048; P=.37), satisfaction (β=-.004; P=.63), and continuance intention (β=.026; P=.91). The following three themes were extracted from the 74 answers to the open-ended question: personalized interaction, effective utilization, and clear illustrations. This study identified key factors influencing patients' continuance intention toward CAs. Satisfaction and perceived usefulness were significant predictors of continuance intention (P<.001 and P<.004, respectively) and were significantly affected by patients' extent of confirmation (P<.001 and P<.001, respectively). Developing a better understanding of patients' continuance intention can help administrators figure out how to facilitate the effective implementation of CAs. Efforts should be made toward improving the aspects that patients reasonably expect CAs to have, which include personalized interactions, effective utilization, and clear illustrations.


Processing of vasoactive intestinal peptide and transferrin in human cancerous colonic cells.
Endocytosis of vasoactive intestinal peptide (VIP) and of transferrin (Tf) was comparatively studied in human cancerous colonic HT-29 cells. Cellular depletion in potassium inhibits the internalization of VIP (23%) and to a greater extent (42%) that of Tf. This indicates that clathrin-coated pits are also involved, at least in part, in VIP uptake. The distribution of 125I-Tf- or 125I-VIP-containing vesicles in sucrose gradients revealed low and high density vesicle subpopulations. The low density vesicle subpopulation represented a transient compartment from which incoming vesicles containing N-leucyl-beta naphthylamidase were recycled back to the membrane while those containing beta-hexosaminidase (HA) and ligand were mostly transferred into the high density compartment. Subsequent fusion of the latter with heavy vesicles was demonstrated by the shift of HA and ligand with vesicles that had been prelabeled with horseradish peroxidase (HRP). Simultaneous internalization of Tf-HRP and 125I-VIP showed that both the low and high density vesicle subpopulations comprised of two types of VIP-containing vesicle, as confirmed by the density shift reaction: two-thirds of VIP shifted with the Tf-HRP-containing vesicles to denser fractions and the remaining was found with unshifted vesicles. These findings indicate that the VIP-receptor complex processing in HT-29 cells follows two routes, the major route being common with Tf endocytosis.


Histrionicotoxin and alkylguanidine interactions with the solubilized and membrane-bound muscarinic acetylcholine receptor from porcine atria.
The interaction of alkylguanidines and decahydrohistrionicotoxin with the membrane-bound and solubilized muscarinic acetylcholine receptor (mAcChR) from porcine atria was described. Alkylguanidines with alkyl chain lengths from one to ten carbons displaced L-[3H]quinuclidinyl benzilate (L-[3H]QNB) competitively from a single class of sites for the membrane-bound mAcChR. From a plot of -1n Ki versus alkyl carbon chain number, a value of -(473 +/- 30) cal/mol was estimated as the energetic contribution per methylene group to the total binding energy. The binding of alkylguanidines to the digitonin/cholate solubilized mAcChR was complex in nature resulting in titration curves that did not obey the law of mass action for simple competitive inhibition at higher alkyl carbon numbers and a sigmoidal plot of -1n Ki versus carbon number. Decahydrohistrionicotoxin bound in a competitive manner versus L-[3H]QNB to both the membrane-bound (Ki = (6.9 +/- 1.4) X 10(-6) M) and the solubilized (Ki = (1.5 +/- 0.3) X 10(-5) M) preparations.


Mutation-oriented profiling of autoinhibitory kinase conformations predicts RAF inhibitor efficacies.
Kinase-targeted therapies have the potential to improve the survival of patients with cancer. However, the cancer-specific spectrum of kinase alterations exhibits distinct functional properties and requires mutation-oriented drug treatments. Besides post-translational modifications and diverse intermolecular interactions of kinases, it is the distinct disease mutation which reshapes full-length kinase conformations, affecting their activity. Oncokinase mutation profiles differ between cancer types, as it was shown for BRAF in melanoma and non-small-cell lung cancers. Here, we present the target-oriented application of a kinase conformation (KinCon) reporter platform for live-cell measurements of autoinhibitory kinase activity states. The bioluminescence-based KinCon biosensor allows the tracking of conformation dynamics of full-length kinases in intact cells and real time. We show that the most frequent BRAF cancer mutations affect kinase conformations and thus the engagement and efficacy of V600E-specific BRAF inhibitors (BRAFi). We illustrate that the patient mutation harboring KinCon reporters display differences in the effectiveness of the three clinically approved BRAFi vemurafenib, encorafenib, and dabrafenib and the preclinical paradox breaker PLX8394. We confirmed KinCon-based drug efficacy predictions for BRAF mutations other than V600E in proliferation assays using patient-derived lung cancer cell lines and by analyzing downstream kinase signaling. The systematic implementation of such conformation reporters will allow to accelerate the decision process for the mutation-oriented RAF-kinase cancer therapy. Moreover, we illustrate that the presented kinase reporter concept can be extended to other kinases which harbor patient mutations. Overall, KinCon profiling provides additional mechanistic insights into full-length kinase functions by reporting protein-protein interaction (PPI)-dependent, mutation-specific, and drug-driven changes of kinase activity conformations.


Ammonium uptake by nitrogen fixing bacteria I. Azotobacter vinelandii.
Both the changes in the activities of nitrogenase, glutamine synthetase and glutamate dehydrogenase and in the extracellular and intracellular NH4+ concentrations were investigated during the transition from an NH4+ free medium to one containing NH4+ ions for a continuous culture of Azotobacter vinelandii. If added in amounts causing 80-100% repression of nitrogenase, ammonium acetate, lactate and phosphate are absorbed completely, whereas chloride, sulfate and citrate are only taken up to about 80%. After about 1-2 hrs the NH4+ remaining in the medium is absorbed too, indicating the induction or activation of a new NH4+ transport system. One of the new permeases allows the uptake of citrate in the presence of sucrose. Addition of inorganic NH4+ level leads to a reversible rise in the glutamine synthetase activity which is not prevented by chloramphenicol, and to a reversible decrease in nitrogenase activity. During these measurements glutamate dehydrogenase activity remains close to zero. The intracellular NH4+ level of about 0.6 mM does not change when extracellular NH4+ is taken up and repression of nitrogenase starts.


The analysis of lymphocyte surface receptors recognized by wheat germ agglutinin for negative regulation of immune responses in cancer patients.
The population of peripheral blood lymphocytes expressing surface receptors for a lectin, wheat germ agglutinin (WGA), which has been shown to recognize the same receptors as the soluble immune suppressor factor (SISF) elaborated from suppressor cells on the lymphocyte surface, was analyzed by using fluorescein isothiocyanate-conjugated WGA on flow cytometry in cancer patients. It was found that the populations of WGA+ lymphocytes in cancer patients were significantly higher than those in either normal volunteers or patients with benign disease and increased with progress of the tumor. The populations decreased after treatment in patients who underwent curative resection of the tumor and in responders of immunochemotherapy but not in those who received non-curative surgery or in non-responders. It was suggested that the increase of receptors for SISF on the lymphocyte surface might play an important role in the negative regulation of immune responses in cancer patients and that WGA might be a useful parameter for immunosuppression.


Endoscopy-guided transesophageal echocardiography for large esophageal varices: Use of the "Double Barrel" technique.
Rhythm control strategies in patients with esophageal varices and atrial arrhythmias pose a unique challenge. The left atrium should be imaged for a thrombus prior to attempting cardioversion or ablation, but the presence of varices is a relative contraindication for transesophageal echocardiography. We present a safe, novel technique of evaluating for left atrial thrombus with simultaneous transesophageal echocardiography and esophagogastroduodenoscopy using slim probes in a patient with large, high-risk esophageal varices, and symptomatic atrial flutter with rapid ventricular rates despite medical therapy.


High concentration of free trimethyllysine in red blood cells.
A high concentration of a basic unidentified amino compound was found in the blood of rats. It was isolated and identified as N epsilon,N epsilon,N epsilon-trimethyllysine by paper chromatography, thin-layer chromatography, high-performance liquid chromatography and amino acid analyzer. It was localized exclusively in red blood cells in the blood of rats. Free trimethyllysine was also determined in the liver, kidney, spleen, brain, muscle, heart and testis of rat. The concentration of free trimethyllysine in red blood cells was more than 10-times as high as that in the other tissues. This compound in red blood cells was found in different species of animals. The relationship between this free trimethyllysine and carnitine was discussed.


Flow cytometric sorting of sperm: influence on fertilization and embryo/fetal development in the rabbit.
Viable, intact rabbit sperm, prepared, processed, and flow cytometrically sorted, were used in this study to determine the influence of flow sorting on fertilization and embryo development. In experiment I, flow-sorted or control (unstained and unsorted) sperm were surgically inseminated into the uterine horn of hormonally primed does (10 to 12 does per time point). At 42 hr postsurgical insemination, flushed embryos were assessed for development. Fetal development was determined at day 7, day 14, and day 21 post-surgical insemination. Embryos resulting from does surgically inseminated with control sperm at 42 hr post-insemination were observed to be at the early morula stage of development (> 16 cell), whereas embryos from does inseminated with flow sorted sperm were at the 8- to 16-cell stage. No difference was observed between treatments at day 7, 14, or 21, however, there was a significant decrease in fetus number per doe inseminated with flow-sorted sperm over time. In experiment II, mature oocytes were flushed from the oviducts of superovulated does and coincubated in vitro (IVF) with flow-sorted or control rabbit sperm. Oocytes observed at 6 hr post-coincubation exhibited swollen sperm heads in the cytoplasm, demonstrating that fertilization had occurred (2 PN + T). There was a higher percentage of fertilized oocytes by 8 hr post-coincubation for both control (31%) and flow-sorted sperm (31%) when used for IVF. By 10 and 12 hr post-coincubation, little difference was observed in the number of fertilized oocytes between sperm treatments (52% and 66% for control vs. 57 and 54% for flow-sorted, respectively). These studies demonstrate that flow-sorted sperm are capable of fertilizing mature oocytes under in vitro conditions. In addition they show that flow sorting may not negatively influence fertilization events, but likely interferes during early embryonic and fetal development.


Multiple linear regression.
This chapter describes multiple linear regression, a statistical approach used to describe the simultaneous associations of several variables with one continuous outcome. Important steps in using this approach include estimation and inference, variable selection in model building, and assessing model fit. The special cases of regression with interactions among the variables, polynomial regression, regressions with categorical (grouping) variables, and separate slopes models are also covered. Examples in microbiology are used throughout.


Overexpression of the 14-3-3gamma protein in embryonic mice results in neuronal migration delay in the developing cerebral cortex.
The 14-3-3 protein family is a group of multifunctional proteins that are highly expressed in the brain; however, their functions in brain development are largely unknown. Williams Syndrome is a neurodevelopmental disorder caused by a deletion in the 7q11.23 chromosome locus, including the gene encoding 14-3-3gamma, resulting in developmental delay, intellectual disabilities and epilepsy. We have previously shown that knocking down the 14-3-3gamma protein in utero in mice results in delays in neuronal migration of pyramidal neurons in the cortex. Importantly, there is a reciprocal duplication syndrome to Williams Syndrome where the 7q11.23 locus is duplicated, resulting in epilepsy and intellectual disabilities. Thus, the deletion or the duplication of the 7q11.23 chromosome locus results in epilepsy. Taken together with the fact that defects in neuronal migration are one of main causes for epilepsy, we analyzed if the overexpression of 14-3-3gamma causes neuronal migration defects. In this work, we found that the overexpression of 14-3-3gamma in utero in the developing mouse cortex results in delays in pyramidal neuron migration, similar to what was previously observed when 14-3-3gamma was knocked down. These results, in conjunction with our previous research, indicate that a balance of 14-3-3gamma expression is required during cortical development to prevent delays in neuronal migration. This work provides clear evidence as to the involvement of 14-3-3gamma in neurodevelopmental disorders and how a disruption in 14-3-3gamma expression may contribute to the neurodevelopmental disorders that manifest when the 7q11.23 locus is altered.


Negative inotropic effects of endothelin-1 in mouse cardiomyocytes: evidence of a role for Na+-Ca2+ exchange.
Endothelin-1 (ET-1) is a peptide hormone produced within the myocardium which may modulate myocardial contractility in a paracrine-autocrine fashion. In the majority of species, ET-1 has a direct positive inotropic effect on the myocardium that involves both increased myofilament Ca(2+) sensitivity and increased Ca(2+) transients. Ca(2+) entry through reverse-mode Na(+)-Ca(2+) exchange, involving both indirect effects via elevation of intracellular [Na(+)] and direct activation of the Na(+)-Ca(2+) exchanger, have been suggested to contribute to the increase in Ca(2+) transients. Conversely, mouse cardiomyocytes show an exclusively negative inotropic response to ET-1. Here, Nishimaru and colleagues present novel evidence that the negative inotropic effect of ET-1 in mouse cardiomyocytes involves both a reduction in myofilament Ca(2+) sensitivity and increased Ca(2+) extrusion, via Na(+)-Ca(2+) exchange. Data obtained using the selective Na(+)-Ca(2+) exchange blocker, SEA0400, suggest that a re-assessment of the role of the exchanger in Ca(2+)-handling by mouse cardiomyocytes may be necessary.


Retrograde esophageal dilation in children without the string.
A new technique for retrograde esophageal dilation is presented, which does away with the indwelling string. The method utilizes a Teflon-coated arterial guide wire, which is passed through the gastrostomy and, under fluoroscopy, is directed up the esophagus and out the mouth. The wire is followed by the string and dilators. This method avoids both embarrassment caused by the string and occurence of the usual complications.


Chronic wound healing: A specific antibiofilm protein-asymmetric release system.
Chronic infection is a major cause of delayed wound-healing. It is recognized to be associated with infectious bacterial communities called biofilms. Currently used conventional antibiotics alone often reveal themselves ineffective, since they do not specifically target the wound biofilm. Here, we report a new conceptual tool aimed at overcoming this drawback: an antibiofilm drug delivery system targeting the bacterial biofilm as a whole, by inhibiting its formation and/or disrupting it once it is formed. The system consists of a micro/nanostructured poly(butylene-succinate-co-adipate) (PBSA)-based asymmetric membrane (AM) with controlled porosity. By the incorporation of hydrophilic porogen agents, polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG), we were able to obtain AMs with high levels of porosity, exhibiting interconnections between pores. The PBSA-PEG membrane presented a dense upper layer with pores small enough to block bacteria penetration. Upon using such porogen agents, under dry and wet conditions, membrane's integrity and mechanical properties were maintained. Using bovine serum albumin (BSA) as a model protein, we demonstrated that protein loading and release from PBSA membranes were affected by the membrane structure (porosity) and the presence of residual porogen. Furthermore, the release curve profile consisted of a fast initial slope followed by a second slow phase approaching a plateau within 24 h. This can be highly beneficial for the promotion of wound healing. Cross-sectional confocal laser scanning microscopy (CLSM) images revealed a heterogeneous distribution of fluorescein isothiocyanate (FITC) labeled BSA throughout the entire membrane. PBSA membranes were loaded with dispersin B (DB), a specific antibiofilm matrix enzyme. Studies using a Staphylococcus epidermidis model, indicate significant efficiency in both inhibiting or dispersing preformed biofilm (up to 80 % eradication). The asymmetric PBSA membrane prepared with the PVP porogen (PBSA-PVP) displayed highest antibiofilm activity. Moreover, in vitro cytotoxicity assays using HaCaT and reconstructed human epidermis (RHE) models revealed that unloaded and DB-loaded PBSA-PVP membranes had excellent biocompatibility suitable for wound dressing applications.


SuperDendrix algorithm integrates genetic dependencies and genomic alterations across pathways and cancer types.
Recent genome-wide CRISPR-Cas9 loss-of-function screens have identified genetic dependencies across many cancer cell lines. Associations between these dependencies and genomic alterations in the same cell lines reveal phenomena such as oncogene addiction and synthetic lethality. However, comprehensive identification of such associations is complicated by complex interactions between genes across genetically heterogeneous cancer types. We introduce and apply the algorithm SuperDendrix to CRISPR-Cas9 loss-of-function screens from 769 cancer cell lines, to identify differential dependencies across cell lines and to find associations between differential dependencies and combinations of genomic alterations and cell-type-specific markers. These associations respect the position and type of interactions within pathways: for example, we observe increased dependencies on downstream activators of pathways, such as NFE2L2, and decreased dependencies on upstream activators of pathways, such as CDK6. SuperDendrix also reveals dozens of dependencies on lineage-specific transcription factors, identifies cancer-type-specific correlations between dependencies, and enables annotation of individual mutated residues.


Curcumin suppresses growth of head and neck squamous cell carcinoma.
The purpose of this study was to determine whether curcumin would trigger cell death in the head and neck squamous cell carcinoma (HNSCC) cell lines CCL 23, CAL 27, and UM-SCC1 in a dose-dependent fashion. HNSCC cells were treated with curcumin and assayed for in vitro growth suppression using 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide and fluorescence-activated cell sorting analyses. Expression of p16, cyclin D1, phospho-Ikappabeta, and nuclear factor-kappabeta (NF-kappabeta) were measured by Western blotting, gel shift, and immunofluorescence. Addition of curcumin resulted in a dose-dependent growth inhibition of all three cell lines. Curcumin treatment resulted in reduced nuclear expression of NF-kappabeta. This effect on NF-kappabeta was further reflected in the decreased expression of phospho-Ikappabeta-alpha. Whereas the expression of cyclin D1, an NF-kappabeta-activated protein, was also reduced, there was no difference in the expression of p16 at the initial times after curcumin treatment. In vivo growth studies were done using nude mice xenograft tumors. Curcumin was applied as a noninvasive topical paste to the tumors and inhibition of tumor growth was observed in xenografts from the CAL27 cell line. Curcumin treatment resulted in suppression of HNSCC growth both in vitro and in vivo. Our data support further investigation into the potential use for curcumin as an adjuvant or chemopreventive agent in head and neck cancer.


The radiology corner: two cases showing the radiographic appearance of Meckel's stones.
The authors describe two cases of Meckel's diverticulum containing radiopaque stones that were diagnosed peroperatively by plain abdominal films and barium small bowel studies. One case of this rare condition was very unusual in that it had extremely symmetric, laminar calcifications on many projections.


[Cloning and sequence analysis of Trichomonas vaginalis ferredoxin gene].
To construct a recombinant plasmid containing ferredoxin gene of Trichomonas vaginalis. Total DNA was extracted from Trichomonas vaginalis with Chelex-100 method and used as templates for PCR. Primers were designed based on the published sequence of the ferredoxin gene and used to amplify the Trichomonas vaginalis gene using PCR method. The ferredoxin gene obtained by PCR technique was directionally cloned into plasmid pMD-18T simple vector. The constructed recombinant plasmid was transferred into E. coli JM109. The transformants were screened and identified by PCR and restriction analysis. The DNA sequence of the gene was determined by Sanger's method. The size of amplified ferredoxin gene was 306bp. The correct recombinant plasmid was isolated and confirmed by PCR and restriction analysis. The DNA sequence of cloned gene was the same as the published sequence. The ferredoxin gene was successfully amplified and cloned into plasmid pMD-18T simple vector. The cloned ferredoxin gene could be used to produce recombinant protein and for study of its function.


Effects of septal lesions on shock thresholds in weanling male and female rats.
Twenty-four-day old weanling male and female rats were either lesioned in the septal area, gonadectomized, lesioned and gonadectomized, or untreated. Tests for reactivity to electric shock were conducted at 26 and at 40 days of age. Neither males nor females showed any effect of the lesions are measured by flinch and jump thresholds to electric shock immediately following surgery; both male and female lesioned groups showed a significant lowering of thresholds when tested at 40 days of age. The effects of septal lesions on response to electric shock were dissociated from the effects on hyperemotionality measured over the same period of time after the lesions, and appeared to have their effect independent of the sex or hormonal condition of the animals.


Division of the left renal vein. Guidelines and consequences.
Ligation and division of the left renal vein is a reasonable safe procedure in selected patients when exposure of the perirenal aorta is crucial. This manipulation is possible because of extensive venous collateralization from the left kidney in man. Measurement of the venous stump pressure before ligation is recommended to assess the degree of collateralization, and the upper limit within which the vein may be divided safely is probably in the neighborhood of 60 cm of water. Reanastomosis of the vein is not necessary for preservation of renal function, although transient left renal dysfunction may occur. Examination of the urine and careful monitoring of renal function should be routine in the postoperative period. Intravenous urography and left spermatic venography later in the postoperative course can indicate the ultimate degree of function of the left kidney and the pathways of venous collateralization. Preservation of normal function and venous architecture at the renal hilum should be the rule.


Dural mesenchymal chondrosarcoma of the lumbar spine. Case report.
A case of a lumbar mesenchymal chondrosarcoma is reported. Radical removal of the lesion, irradiation, and chemotherapy led to a long and favorable outcome in this patient.


The time interval between oocyte retrieval and frozen embryo transfer does not impact reproductive outcomes.
Does the time interval between oocyte retrieval and frozen embryo transfer (FET) affect pregnancy outcomes after a freeze-all strategy? Retrospective study including a total of 5995 patients who underwent their first FET following a freeze-all cycle between 1 January 2017 and 31 December 2020. Patients were divided into immediate (the interval between oocyte retrieval and the day of first FET ≤40 days), delayed (>40 days but ≤180 days) and overdue groups (>180 days). Pregnancy and neonatal outcomes were analysed, and multivariable regression analysis was used to study the effect of FET timing on the live birth rate (LBR) in the entire cohort and the different subgroups. The LBR was significantly lower in the overdue group than in the delayed group (34.9% versus 42.8%, P = 0.002); however, after adjusting for confounding factors, the difference was not statistically significant. The immediate group had a comparable LBR (36.9%) to the other two groups in both the crude and adjusted analyses. Multivariable regression analysis showed no impact of FET timing on LBR in the whole cohort or in the subgroups according to ovarian stimulation protocol, trigger type, insemination method, reason for freezing all, FET protocol or transferred embryo stage. The time interval between oocyte retrieval and FET does not impact reproductive outcomes. Unnecessary delays in FET should be avoided to shorten the time to live birth.


Craniofrontonasal dysplasia: phenotypic expression in females and males and genetic considerations.
The phenotype and pattern of inheritance of craniofrontonasal dysplasia were analyzed in 66 affected persons from 18 families, including one four-generation kindred personally studied. Females were more severely affected than males. Affected females had hypertelorism, broad nasal root, frontal bossing, craniosynostosis, syndactyly of toes and fingers, and vertical grooving of nails. Males had increased bony interorbital distances and distances between the inner canthi of the eyes, broad nasal root, broad halluces, and vertical grooving of nails but no craniosynostosis. Affected men transmitted the condition to all of their daughters but to no sons, while affected women transmitted the disorder to about half their daughters and half their sons. This pattern is compatible with X-linked dominant inheritance, but the far milder manifestation of the syndrome in males cannot be explained by simple mendelian genetics.


A controlled investigation of optimal internal medicine ward team structure at a teaching hospital.
The optimal structure of an internal medicine ward team at a teaching hospital is unknown. We hypothesized that increasing the ratio of attendings to housestaff would result in an enhanced perceived educational experience for residents. Harbor-UCLA Medical Center (HUMC) is a tertiary care, public hospital in Los Angeles County. Standard ward teams at HUMC, with a housestaff∶attending ratio of 5:1, were split by adding one attending and then dividing the teams into two experimental teams containing ratios of 3:1 and 2:1. Web-based Likert satisfaction surveys were completed by housestaff and attending physicians on the experimental and control teams at the end of their rotations, and objective healthcare outcomes (e.g., length of stay, hospital readmission, mortality) were compared. Nine hundred and ninety patients were admitted to the standard control teams and 184 were admitted to the experimental teams (81 to the one-intern team and 103 to the two-intern team). Patients admitted to the experimental and control teams had similar age and disease severity. Residents and attending physicians consistently indicated that the quality of the educational experience, time spent teaching, time devoted to patient care, and quality of life were superior on the experimental teams. Objective healthcare outcomes did not differ between experimental and control teams. Altering internal medicine ward team structure to reduce the ratio of housestaff to attending physicians improved the perceived educational experience without altering objective healthcare outcomes.


A difference in abomasal pH between Canadian wapiti affected with chronic illthrift and unaffected deer.
The pH of abomasal fluid from five purebred Canadian wapiti which were diagnosed with chronic illthrift ("fading") was found to be elevated compared to ten clinically normal red and hybrid (wapiti x red) deer. The average abomasal pH of the affected elk was 6.3, compared to 2.5 for the unaffected red and hybrid deer.


EZH2 blockade by RNA interference inhibits growth of ovarian cancer by facilitating re-expression of p21(waf1/cip1) and by inhibiting mutant p53.
The enhancer of zeste homolog 2 (EZH2) methyltransferase is a transcriptional repressor. EZH2 is abnormally elevated in epithelial ovarian cancer (EOC). We demonstrated that EZH2 knockdown inhibited cell growth, activated apoptosis, and enhanced chemosensitivity. Further, silencing of EZH2 resulted in re-expression of p21(waf1/cip1) and down-regulation of mutant p53. Finally, EZH2 knockdown contributed to attenuated EOC growth in SCID mice.


Pediatric thyroid cancer: Recent developments.
Thyroid cancer is rare in children but its incidence is increasing. Recent data have clarified important similarities and differences between thyroid cancers originating in childhood and in adulthood. The genetic drivers of pediatric thyroid cancers are similar to those in adult tumors but comprise more gene fusions and fewer point mutations. Clinically, despite frequent metastatic spread, pediatric thyroid cancer has an excellent prognosis and mortality is rare. Therefore, treatment approaches must weigh carefully the morbidity of thyroid cancer treatments against their benefits. Current key questions include which children require total thyroidectomy rather than more limited-and safer-lobectomy, and in which children does the benefit of radioactive iodine therapy outweigh its risk of inducing a secondary malignancy. Finally, molecular therapies targeting genetic drivers of thyroid cancer now provide effective treatment for children with progressive, radioiodine-refractory disease, as well as opportunities to explore novel neoadjuvant uses that facilitate therapeutic surgery or radioactive iodine.


Effect of environmental carcinogens and other chemicals on murine alpha/beta interferon production.
Mouse embryo fibroblast cultures were pretreated with a variety of chemicals found in the environment. After chemical treatment, polyriboinosinic-polyribocytidylic acid was added to the cultures to induce alpha/beta interferon. Pretreatment of the cell cultures with the chemical carcinogens chloroform and beta-propiolactone severely inhibited the production of alpha/beta interferon, while pretreatment of the cell cultures with their poorly or noncarcinogenic analogs 1,1,1-trichloroethane and gamma-butyrolactone had no effect on interferon induction. Pretreatment of the cell cultures with the possible carcinogen diethylstilbestrol had no effect on alpha/beta interferon induction. Pretreatment of the cells with the poor or noncarcinogens pyrene and ascorbic acid did not effect interferon induction; in fact, treatment with ascorbic acid may have enhanced interferon production. These results augment previous findings that most potent carcinogens can inhibit the induction of alpha/beta interferon.


Multicenter comparison of cefotetan and cefoxitin in the treatment of acute obstetric and gynecologic infections.
Two hundred eighty-seven women were treated in a multicenter, randomized, comparative study to compare the safety and efficacy of cefotetan every 12 hours with that of cefoxitin every 6 or 8 hours in the treatment of acute obstetric and gynecologic pelvic infections. The most frequent primary diagnoses in both groups were endometritis and pelvic inflammatory disease; 24 of these patients were also bacteremic. The mean duration of treatment was 5.2 and 5.4 days for the cefotetan and cefoxitin groups, respectively, and the total doses administered were 18.1 and 32.1 gm, respectively. The rate of clinical failure for the cefotetan group was 8.5% and 12.2% for the cefoxitin group. Laboratory and clinical adverse reactions were infrequent and none was serious; both antimicrobials were well tolerated. These results suggest the administration of cefotetan provided adequate clinical and bacteriologic effectiveness in the treatment of hospital- and community-acquired, polymicrobial obstetric and gynecologic pelvic infections.


Dietary protein restriction deciphers new relationships between lifespan, fecundity and activity levels in fruit flies Drosophila melanogaster.
Drosophila melanogaster has been used in Diet Restriction (DR) studies for a few decades now, due to easy diet implementation and its short lifespan. Since the concentration of protein determines the trade-offs between lifespan and fecundity, it is important to understand the level of protein and the extent of its influence on lifespan, fecundity and activity of fruit flies. In this study, we intend to assess the effect of a series of protein restricted diets from age 1 day of the adult fly on these traits to understand the possible variations in trade-off across tested diets. We found that lifespan under different protein concentrations remains unaltered, even though protein restricted diets exerted an age-specific influence on fecundity. Interestingly, there was no difference in lifetime activity of the flies in most of the tested protein restricted (PR) diets, even though a sex-dependent influence of protein concentrations was observed. Additionally, we report that not all concentrations of PR diet increase activity, thereby suggesting that the correlation between lifespan and the lifetime activity can be challenged under protein-restricted condition. Therefore, the PR does not need to exert its effect on lifespan and fecundity only but can also influence activity levels of the flies, thereby emphasizing the role of nutrient allotment between lifespan, fecundity and activity.


Multiple myeloma with pleural involvement: a case report.
Malignant pleural effusions are rare in multiple myeloma (MM). We report a case of MM with left myelomatous pleural effusion, which reflects aggressive disease.


Family perspectives on the transition from active treatment to survivorship for children with cancer.
Completing therapy for childhood cancer is an exciting milestone. However, this adjustment can be extremely stressful for patients and their families as they transition from cancer patient to survivor. A better understanding of the patient and family experience and their needs during this transition is crucial for developing guidelines and leveraging support for future patients and families. Participants were recruited from across the United States using a maximum variation sampling strategy. Families were eligible if they had a child diagnosed with cancer before age 15 and had completed treatment at least 1 year prior to their interview. Participants completed a 90-180-minute semi-structured interview either in person or virtually. Interviews focused on the experiences of getting a diagnosis, experiences with treatment, information seeking, impact of cancer on the family, social support, and transitions to survivorship. Inductive thematic analysis revealed a wide variety of themes. This paper examines the transition from active cancer therapy into survivorship. Identified primary themes included (i) feelings about transitioning off therapy; (ii) coping with lingering effects; and (iii) experiences of transitioning off therapy and survivorship care. Subthemes highlighted the need for more support for both patients and families during this transition. Patients and families desire more support during the transition off therapy. Suggestions included access to additional resources, earlier transition to receiving survivorship care, and more holistic survivorship care. Further research is needed to determine best models and feasibility of delivering this desired support to all patients and families.


Phenotypic and Genotypic Characterization of Virulence Factors and Susceptibility to Antibiotics in Salmonella Infantis Strains Isolated from Chicken Meat: First Findings in Chile.
Salmonella Infantis is a zoonotic pathogen that causes gastroenteritis in humans and animals, with poultry being its main reservoir. In Chile, there are no data to characterize S. Infantis strains in poultry production. In this study, 87 S. Infantis strains were isolated from chicken meat for sale in supermarkets in Santiago, Chile, and characterized according to their virulence genes, biofilm formation abilities, antibiotic susceptibility, and resistance genes. Through polymerase chain reaction or PCR, the strains were analyzed to detect the presence of 11 virulence genes, 12 antibiotic resistance genes, and integrase genes. Moreover, disc diffusion susceptibility to 18 antimicrobials and the ability to form biofilm in vitro were evaluated. Results demonstrated six different virulence gene profiles. Ninety-four percent of the strains were multi-resistant to antibiotics with weak biofilm formation abilities, 63.2% of the strains were broad spectrum β- lactam resistant, and the bla CTX-M-65 gene was amplified in 13 strains. Only 3.4% of the strains were fluoroquinolone resistant, and the qnrB gene was amplified in two strains. Colistin resistance was exhibited in 28.7% of the strains, but mrc genes were not amplified in any strain under study. The isolated S. Infantis strains are pathogenic and antibiotic multi-resistant, and thus, this Salmonella serotype should be under surveillance in the poultry food production chain with the aim of protecting public health.


A randomized controlled trial comparing alpha blocker (tamsulosin) and anticholinergic (solifenacin) in treatment of ureteral stent-related symptoms.
To compare the effectiveness of tamsulosin and solifenacin in relieving ureteral stents related symptoms. A randomized controlled trial was conducted between January 2013 and July 2014. Inclusion criteria were patients aged 20-50 years who underwent temporary unilateral ureteral stent for drainage of calcular upper tract obstruction or after ureteroscopic lithotripsy. Patients with history of lower urinary tract symptoms before stent placement, stents that were fixed after open or laparoscopic procedures, and those who developed complications related to the primary procedure were not included. Eligible patients were randomly assigned to 1 of 3 groups using computer-generated random tables. Patients in group 1 received placebo, patients in group 2 received tamsulosin 0.4 mg once daily, and those in group 3 received solifenacin 5 mg once daily. Ureteral Stent Symptom Questionnaire (USSQ) was answered by all patients 1-2 weeks after stent placement. The primary outcome was the comparison of total score of USSQ between all groups. The study included 131 patients. All baseline characteristics (age, sex, side, indication, length, and duration of stent) were comparable for all groups. Total USSQ score was 61 in solifenacin group, 76 in tamsulosin group, and 83 in control group (P < 0.001). The total USSQ scores and all domains, except sexual index, were significantly better in solifenacin than in tamsulosin group (P < 0.05). The use of tamsulosin alone or solifenacin alone in patients with ureteral stents can improve the quality of life by decreasing ureteral stent-related symptoms. Solifenacin was better than tamsulosin. CLINICALTRIAL. NCT01880619.


Murine leukemia virus (T-8)-transformed cells: identification of a precursor polyprotein containing gag gene-coded proteins (p15 and p12) and a nonstructural component.
Mink cells nonproductively transformed by the T-8 strain of mink cell focus-inducing virus express two type C viral amino terminal gag gene-coded structural proteins, p15 and p12, in the form of a 90,000 to 110,000 molecular weight polyprotein that lacks detectable immunological reactivity with other known type C virus-coded translational products. The observation concurs with the previous demonstration of similar high-molecular-weight precursor polyproteins in cell lines nonproductively transformed by either of two other mammalian sarcoma viruses also limited in virus-coded structural protein expression to p15 and p12.


Characterization of the fluorescent bimane derivative of E. coli initiator transfer RNA (tRNAfMet).
The invariant modified base 4-thiouridine of the E. Coli initiator tRNA was chemically modified using a sulfhydryl specific fluorogenic probe, monobromobimane. The modified tRNAfMet is virtually indistinguishable biochemically from the native form in the aminoacylation and formylation reactions, and in its binding behavior to the ribosomal P site. Fluorescence quenching by I- increases 40% when the modified tRNA is charged with formylmethionine, even at this relatively well-shielded position in the tRNA elbow. Most important, the fluorescence polarization increases by a factor of 2, to almost the irrotational value, when fMet-tRNAfMet binds to the ribosomal P site, providing a useful tool for studying fMet-tRNAfMet-ribosome interaction equilibria and kinetics.


Insomnia in women: an overlooked epidemic?
Insomnia is a common and significant healthcare problem, and affects a large percentage of women seen by general practitioners, obstetrician-gynecologists and mental health professionals. Specific risk factors for insomnia may be gender-related, including higher prevalence rates of depression and anxiety among women, environmental and social factors, as well as reproductive-related factors (e.g., peri-menstrual difficulties and menopause-related symptoms). Sleep problems interfere significantly with daytime functioning and overall well-being, and may lead to serious clinical consequences. Treatment options include benzodiazepines, non-benzodiazepines, nonprescription sleep aids, and non-pharmacologic interventions such as sleep hygiene measures. This article reviews the existing literature on the prevalence, clinical characteristics of insomnia in women, and highlights some of the treatment options available. Healthcare providers should be aware of the variety of pharmacologic and non-pharmacologic options for treatment of insomnia and, in particular, be able to weigh their efficacy against the risks of side effects and next-day sedation.


Transient yellow discoloration of the nails for differential diagnosis with yellow nail syndrome.
A differential diagnosis must be made between transient yellow discoloration of the nails and yellow nail syndrome. We highlight some practical aspects of yellow nail discoloration.


Sustainability and efficiency analysis w.r.t adoption of climate-smart agriculture (CSA) in Pakistan: a group-wise comparison of adopters and conventional farmers.
Climate change, conventional agricultural management practices, and increasing water scarcity pose a major threat to agricultural production and biodiversity as well as environmental sustainability. Climate-smart agriculture (CSA) is recognized as an efficient, sustainable, and feasible agricultural system that plays a vital role in addressing the potential impacts of climate change in Pakistan. First-hand information was collected from 450 farm households in 24 villages from Okara, Sahiwal, and Khanewal irrigation divisions, having various wheat-based cropping systems of Pakistan. This includes rice-wheat (RW), maize-wheat (MW), and cotton-wheat (CW) cropping systems in the Lower Bari Doab Canal (LBDC) irrigation system. This study estimated and compared the sustainability and efficiency analysis of CSA and conventional agricultural practices. This study also estimated the impact of water-smart practices of the CSA, technical training, and groundwater quality on agricultural production by using production function and bootstrap truncated regression. The findings of this study revealed that adopters of CSA of the wheat-based cropping systems have higher economic benefits and improved resource use efficiencies compared to the conventional farmers. The findings of the study also revealed the increased efficiency of CSA adopters over other two systems in CW cropping system. The water-smart practices of CSA, access to credit, technical training, use of groundwater of varying quality, and other inputs also showed variations in the agricultural production and resource use efficiency. It has been concluded that farmers can earn more profit, save inputs (such as water), and increase their production by adopting water-smart practices of CSA. Hence, the government and other relevant institutions should devise and implement policies that adequately addressed the importance and enhance the use of water-smart practices of CSA in Punjab and beyond.


Artificial intelligence inspired design of non-isothermal aging for γ-γ' two-phase, Ni-Al alloys.
In this paper, a state-of-the-art Artificial Intelligence (AI) technique is used for a precipitation hardening of Ni-based alloy to predict more flexible non-isothermal aging (NIA) and to examine the possible routes for the enhancement in strength that may be practically achieved. Additionally, AI is used to integrate with Materials Integration by Network Technology, which is a computational workflow utilized to model the microstructure evolution and evaluate the 0.2% proof stress for isothermal aging and NIA. As a result, it is possible to find enhanced 0.2% proof stress for NIA for a fixed time of 10 min compared to the isothermal aging benchmark. The entire search space for aging scheduling was ~ 3 billion. Out of 1620 NIA schedules, we succeeded in designing the 110 NIA schedules that outperformed the isothermal aging benchmark. Interestingly, it is found that early-stage high-temperature aging for a shorter time increases the γ' precipitate size up to the critical size and later aging at lower temperature increases the γ' fraction with no anomalous change in γ' size. Therefore, employing this essence from AI, we designed an optimum aging route in which we attained an outperformed 0.2% proof stress to AI-designed NIA routes.


Amniotic Membrane Transplantation for the Treatment of Infectious Ulcerative Keratitis Before Elective Penetrating Keratoplasty.
Emergency keratoplasties for inflamed eyes are considered to have a worse prognosis because of immunologic graft rejection. Amniotic membranes have antiinflammatory and antiangiogenic abilities. Therefore, amniotic membrane transplantation (AMT) was performed to stabilize the situation of eyes with severe infectious keratitis before elective penetrating keratoplasty (PK). Retrospective, nonrandomized observational case series. Seven to 41 days (median, 20 days) after the onset of intensive antiinfectious medication, an AMT (6 multigrafts and 6 sandwich) was performed in 12 patients [8 men and 4 women; age 46-80 years (median, 66 years)] with herpetic (n = 5), bacterial keratitis (n = 3), or combinations (n = 4). Three to 12 months (median, 5 months) after cessation of the inflammatory status of the eye, a central elective PK (diameter, 7-8 mm) became feasible in 10 eyes. Follow-up ranged from 4 to 38 months (median, 20 months) after PK. The primary success rate of AMT was 11/12 (92%). Five recurrences (41%) were treated successfully 4 times by repeat AMT (sandwich) and 1 time by emergency PK. In 2 of the 12 eyes, an irreversible endothelial immunologic graft reaction appeared 18 and 21 months after PK. One eye suffered from reversible recurrence of herpetic keratitis on the corneal graft. At the end of the follow-up, 10 of 12 grafts (83%) were clear. A rapid decrease in the inflammatory reaction and a fast reepithelialization because of AMT after intensive antiinfectious medication in case of severe ulcerative keratitis may help to avoid an emergency keratoplasty and improves the prognosis of the elective keratoplasty.


Three-Dimensional Volume Imaging in Gynecology.
3D ultrasound imaging of the female pelvis is one of the most important recent advances in diagnostic imaging. Volume acquisitions can provide a large number of images of the pelvic organs simultaneously and in any plane or orientation desired. The coronal plane of the uterus is only visible when reconstructed from a volume and is key to imaging the uterus for indications such as uterine anomalies, IUD positioning, locations of fibroids and polyps, or early pregnancies. 3D ultrasonography has huge potential for evaluating infertile patients, performing difficult procedures under guidance, and studying patients with abnormal uterine bleeding, hydrosalpinges, and cancer.


The FLY-project: study protocol for mixed methods research to explore the complex social dynamics of sustainable food-related lifestyles in youth in practical education.
The present-day food system is a key driver of climate change and biodiversity loss, making it imperative for populations to shift towards more sustainable diets. The involvement of youth in this transition is vital because they are in a formative period where their identities, values, and norms, including their food behaviours, are being shaped. Special attention should be paid to youth in practical education because they are often overlooked in existing studies, yet evidence suggests they may lack the necessary resources to support dietary changes, resulting in lower levels of pro-environmental food-related behaviours. The aim of the FLY (Food-related Lifestyles in Youth) project is to study how sustainable food-related lifestyles and underlying factors develop in early adolescence, particularly in Dutch youth in practical education, how these spread in social networks, and to develop community-level intervention strategies to support youths' transition to sustainable food-related behaviours. The FLY-project adopts a mixed-method approach. First, two literature reviews are conducted. A systematic review assesses how capabilities, opportunities and motivation are associated with sustainable food behaviours in youth, and how these elements interrelate in determining sustainable food-related lifestyles. A scoping review studies community-level interventions that target sustainable and healthy food-related behaviours. Second, focus groups are conducted to explore the barriers and facilitating factors concerning capabilities, opportunities, and motivations that Dutch youth in practical-level education experience to transition to more sustainable food-related lifestyles. Third, a cohort survey study is conducted to track the dynamic interplay between capabilities, opportunities, motivation, and changes in specific sustainable food behaviours over time, and to assess the diffusion of sustainable food-related lifestyles via social (media) networks. Fourth, an experimental research programme tests promising intervention approaches, some of which are co-created with youth, targeting relevant underlying factors. This paper describes the rationale, conceptual framework, design and methods of the FLY-project. The FLY-project contributes to an understanding of underlying factors of sustainable food-related behaviours in adolescence and results in a multi-component intervention toolkit, with a particular focus on youth in practical education programmes.


Myeloid Sarcoma Presenting With Multiple Skin and Subcutaneous Mass Without Leukemic Manifestations After Renal Transplantation.
Myeloid sarcoma is well described and known in clinical practice, however, it is a rare condition after receiving renal transplantation. Immunosuppressive therapy is thought to be the main cause in these cases. A 45-year-old woman accepted a right kidney transplantation because of her chronic renal insufficiency and uremia in May 2011. She had to receive a left kidney transplantation again in February 2012 because she had renal failure again after receiving the right kidney transplantation. She received immune inhibitors treatment. After the latter operation, her renal function was normal. The third operation was done to remove the right transplanted kidney in July 2012. The diagnosis of the kidney was myeloid sarcoma. The blood and bone marrow biopsy had no evidence of leukemia. She then received chemotherapy. There was a small skin nodule on the left arm of approximately 0.5 cm in August 2012; after that its diameter enlarged progressively to about 5 cm and more nodules and masses gradually appeared on her face, arms, trunk, lower limbs, and feet over the course of 1 year. The skin biopsy specimen obtained from her left arm showed myeloid sarcoma too. She was admitted to the Orthopedics Department for severe pain and swelling in the left foot in September 2014 and underwent an operation for resecting the mass in the left foot. Pain was apparently alleviated and the incision healed well. The patient is still alive with no evidence of leukemia after a 30-month follow-up.


Electronic clinical decision support systems attitudes and barriers to use in the oncology setting.
There is little evidence regarding attitudes to clinical decision support systems (CDSS) in oncology. We examined the current usage, awareness, and concerns of Irish medical oncologists and oncology pharmacists in this area. A questionnaire was sent to 27 medical oncologists and 34 oncology pharmacists, identified through professional interest groups. Respondents ranked concerns regarding their use of a CDSS on a scale from 1 to 4, with 4 being most important. Overall, 67% (41/61) responded, 48% (13/27) of oncologists and 82% (28/34) of pharmacists surveyed. Concerns included "difficulty defining complex clinical situations with a set of rules" (mean ± SD) (3.2 ± 0.9), "ensuring evidence base is up to date and relevant" (3.2 ± 0.9) and "lack of clinically relevant suggestions" (2.9 ± 0.9). Ninety-three percent reported using a CDSS but 54% were unaware of this. While there are benefits to using a CDSS, concerns must be addressed through user education. This may be a starting point for a user-centred design approach to the development of future local systems through a consultative process.


Clinicopathological Characteristics and Surgical Outcomes of Primary Cystic Duct Carcinoma: A Multi-institutional Study.
The role of surgery in the management of primary cystic duct carcinoma (CDC) remains unclear especially in advanced disease. This study aimed to evaluate long-term outcomes in patients undergoing surgery for primary CDC. From a multi-institutional database, we identified 41 patients who underwent surgery for primary CDC, defined as a part of gallbladder carcinoma with the tumor centre located in the cystic duct. Of the 41 patients, 31 (75.6%) underwent preoperative biliary drainage for jaundice. Twenty-eight (68.3%) patients underwent extensive resection including major hepatectomy (n = 21), pancreaticoduodenectomy (n = 4), or both procedures (n = 3). Thirty-four (82.9%) patients had ≥ pT3 tumor, while 31 (75.6%) patients had involvement of contiguous organs/structures. Nodal and distant metastasis was found in 26 (63.4%) and 7 (17.1%) patients, respectively. Most patients (90.2%) had perineural invasion. Median overall survival was 23.7 months in all 41 patients. Factors independently associated with both overall and disease-specific survival were pN (P = 0.003 and P = 0.007, respectively) and pM (P = 0.003 and P = 0.013, respectively) classification. Median survival was 75.3, 17.7, and 5.2 months for patients with pN0M0 (n = 14), pN1/2pM0 or pN0pM1 (n = 21), and pN1/2pM1 (n = 6) disease, respectively (P < 0.001). Primary CDC is characterized by locally advanced disease with aggressive histopathological characteristics at surgery, leading to extensive resection during treatment. Surgery provides potential benefits for patients with pN0pM0 disease, whereas pN1/2 and/or pM1 status appear to have strong adverse effects on survival.


Regulatory mechanisms of atrial fibrotic remodeling in atrial fibrillation.
Electrical, contractile and structural remodeling have been characterized in atrial fibrillation (AF), and the latter is considered to be the major contributor to AF persistence. Recent data show that interstitial fibrosis can predispose to atrial conduction impairment and AF induction. The interplay between cardiac matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs), is thought to be critical in atrial extracellular matrix (ECM) metabolism. At the molecular level, angiotensin II, transforming growth factor-beta1, inflammation and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodeling in AF. Therefore, we review recent advances in the understanding of the atrial fibrotic process, the major downstream components in this remodeling process, and the expression and regulation of MMPs and TIMPs. We also describe the activation of bioactive molecules in both clinical studies and animal models to modulate MMPs and TIMPs and their effects on atrial fibrosis in AF.


Treatment summaries in radiation oncology and their role in improving patients' quality of care: past, present, and future.
Through treatment summaries, radiation oncologists can build upon past efforts and improve the future quality of care for all patients receiving treatment with radiation. This article looks at what treatment summaries should contain and how they might be improved.


[Systemic side-effects of topical preparations in children (author's transl)].
Any topical treatment may lead to systemic side-effects through epidermal penetration. In children the ratio surface treated/weight is usually high, implying greater risk. Factors which determine percutaneous absorption in childhood are reviewed as well as the main drugs which are toxic when applied to the skin.


[Follow-up in superficial and metastatic bladder cancer].
Concerning follow-up in bladder cancer, it must be distinguished between superficial, muscle-invasive, and metastatic tumors. In superficial bladder cancer, urethrocystoscopy is still standard for follow-up. Frequency depends on the risk classification. Even muscle-invasive carcinomas, which underwent a R0 resection, will metastasize in about 30% of cases. These tumors as well as primarily metastasized cancer cannot be cured. Therefore, in these cases, one should not speak about follow-up but therapeutic control. Nonetheless, even in these cases the S3 guideline recommends regular follow-up examinations because new therapeutic options can clearly improve patient survival. Possible complications of urinary diversions need consideration during follow-up.


A novel multifunctional bilayer scaffold based on chitosan nanofiber/alginate-gelatin methacrylate hydrogel for full-thickness wound healing.
Due to their lack of multifunctionality, the majority of traditional wound dressings do not support all the clinical requirements. Bilayer wound dressings with multifunctional properties can be attractive for effective skin regeneration. In the present study, we designed a multifunctional bilayer scaffold containing Chitosan-Polycaprolactone (PC) nanofiber and tannic acid (TA) reinforced methacrylate gelatin (GM)/alginate (Al) hydrogel (GM/Al/TA). PC nanofibers were coated with GM/Al/TA hydrogel to obtain a bilayer nanocomposite scaffold (Bi-TA). The GM/Al/TA hydrogel layer of Bi-TA showed antibacterial, free radical scavenging, and biocompatibility properties. Also, PC nanofiber acted as a barrier for preventing bacterial invasion and moisture loss of the hydrogel layer. The wound healing performance of the Bi-TA scaffold was investigated via a full-thickness wound model. In addition, the histopathological and immunohistochemical (IHC) stainings of transforming growth factor-β1(TGF-β1) and tumor necrosis factor-α (TNF-α) were assessed. The results indicated an enhanced wound closure rate, effective collagen deposition, quick re-epithelialization, more skin appendages, and replacement of defect area with normal skin tissue by Bi-TA scaffold compared to other groups. Additionally, the regulation of TGF-β1 and TNF-α was observed by Bi-TA dressing. Overall, the Bi-TA with appropriate structural and multifunctional properties can be an excellent candidate for developing effective dressings for wound healing applications.


Epidemic suicide among Micronesian adolescents.
Suicide rates since 1960 in Micronesia (the U.S. Trust Territory of the Pacific Islands) have undergone an epidemic-like increase. This phenomenon is focused narrowly within the 15--24-year male age-group. Extremely high rates and culturally patterned motives and methods are now characteristic of this group. Survey research throughout Micronesia suggests that the epidemic increase in adolescent male suicide is a cohort effect among the first post-war generation. Traditional adolescent socialization in pre-war Micronesia largely involved village-level subsistence activities organized around communal lineage-houses. This extra-familial level of socialization served as a cultural solution to the residential and psychological distance post-pubertal males maintained from their domestic families. With the post-war social change in Micronesia, the communal village-level of organization has largely disintegrated, causing adolescent socialization functions to be absorbed by the nuclear family. The resulting situations of intergenerational domestic discord appear the primary social triggers for adolescent suicide. At the same time, suicides have acquired subcultural significance among male youth, giving rise to fad-like and imitative acts. A 3-year research project is now being undertaken to conduct an ethnographic study of factors contributing to adolescent stress and suicide in one Micronesian community.


Immobilized metal-affinity chromatography protein-recovery screening is predictive of crystallographic structure success.
The recombinant expression of soluble proteins in Escherichia coli continues to be a major bottleneck in structural genomics. The establishment of reliable protocols for the performance of small-scale expression and solubility testing is an essential component of structural genomic pipelines. The SSGCID Protein Production Group at the University of Washington (UW-PPG) has developed a high-throughput screening (HTS) protocol for the measurement of protein recovery from immobilized metal-affinity chromatography (IMAC) which predicts successful purification of hexahistidine-tagged proteins. The protocol is based on manual transfer of samples using multichannel pipettors and 96-well plates and does not depend on the use of robotic platforms. This protocol has been applied to evaluate the expression and solubility of more than 4000 proteins expressed in E. coli. The UW-PPG also screens large-scale preparations for recovery from IMAC prior to purification. Analysis of these results show that our low-cost non-automated approach is a reliable method for the HTS demands typical of large structural genomic projects. This paper provides a detailed description of these protocols and statistical analysis of the SSGCID screening results. The results demonstrate that screening for proteins that yield high recovery after IMAC, both after small-scale and large-scale expression, improves the selection of proteins that can be successfully purified and will yield a crystal structure.


Plasma lipoprotein(a) concentration as an independent predictor of hemodynamic progression of aortic valve stenosis.
Calcific aortic valve disease (CAVD) is a common cardiovascular disorder of high social significance. This study aimed to identify independent predictors of hemodynamic progression of CAVD. The relationship between some risk factors, including the rs10455872 polymorphism in the intron 25 of the lipoprotein(a) [Lp(a)] coding region and the plasma Lp(a) concentration, and CAVD severity were prospectively examined in 114 patients. Age (p = 0.023), smoking (p = 0.038), lack of obesity (p = 0.005), triglyceride levels (p = 0.039), and plasma Lp(a) (p < 0.0001) levels were found to be significant determinants of stenosis progression. The rs10455872 polymorphism; however, was not found to be a significant factor for neither the stenosis severity (p = 0.773) nor for plasma Lp(a) levels (p = 0.617). We established a highly significant Lp(a) cut-off concentration (21.2 mg/dL) distinguishing the aortic valve calcification without stenosis from the significant stenosis. Plasma Lp(a) concentration was the only independent predictor of disease progression (p < 0.0001). Moreover, patients with plasma levels of Lp(a) ≥ 21.2 mg/dL were 55 times more likely to develop aortic valve stenosis. We conclude that Lp(a) concentration may prove valuable for more reliable identification of patients at risk of accelerated CAVD development. Future studies are desirable to determine whether plasma Lp(a) levels could be used as a potential biomarker for aortic stenosis progression.


Dataset for dose and time-dependent transcriptional response to ionizing radiation exposure.
Exposure to ionizing radiation associated with highly energetic and charged heavy particles is an inherent risk astronauts face in long duration space missions. We have previously considered the transcriptional effects that three levels of radiation (0.3 Gy, 1.5 Gy, and 3.0 Gy) have at an immediate time point (1 hr) post-exposure [1]. Our analysis of these results suggest effects on transcript levels that could be modulated at lower radiation doses [2]. In addition, a time dependent effect is likely to be present. Therefore, in order to develop a lab-on-a-chip approach for detection of radiation exposure in terms of both radiation level and time since exposure, we developed a time- and dose-course study to determine appropriate sensitive and specific transcript biomarkers that are detectable in blood samples. The data described herein was developed from a study measuring exposure to 0.15 Gy, 0.30 Gy, and 1.5 Gy of radiation at 1 hr, 2 hr, and 6 hr post-exposure using Affymetrix® GeneChip® PrimeView™ microarrays. This report includes raw gene expression data files from the resulting microarray experiments representing typical radiation exposure levels an astronaut may experience as part of a long duration space mission. The data described here is available in NCBI's Gene Expression Omnibus (GEO), accession GSE63952.


Antithrombotic Medication and Major Complications After Mechanical Aortic Valve Replacement.
Patients with mechanical aortic valve replacement (AVR) require lifelong vitamin K antagonist (VKA) therapy for stroke and systemic embolism prevention. However, VKA treatment predisposes patients to various types of bleeding. In the present study, we sought to assess the success of antithrombotic therapy and the occurrence and timing of strokes and bleeding events after mechanical AVR. A total of 308 patients who underwent isolated mechanical AVR were included in the study, and follow-up data were completed for 306 patients (99.4%). The median follow-up time was 7.3 (interquartile range 4.2 to 10.9) years. The risk for major bleeding was 5-fold compared with major stroke (6.2% vs 1.3% and 20.9% vs 4.0%, respectively; events rates 3.1 vs 0.5 per 100 patient-years, respectively) at 30-day and long-term follow-up, indicating good efficacy but inadequate safety of stroke prevention. At the time of the early postoperative major bleeding, the international normalized ratio was under the therapeutic range in 73.7% of the patients. However, most patients were on triple antithrombotic treatment consisting of subcutaneous enoxaparin, VKA, and a tail effect of discontinued aspirin. During the long-term follow-up, the most common site of bleeding was gastrointestinal (41.7%), followed by genitourinary bleeding (23.3%) and intracranial hemorrhage (18.3%). Furthermore, mortality was relatively high, with a 10-year survival estimate of 78.3%. In conclusion, although ischemic stroke is a well-identified adverse event after mechanical AVR, it seems that major bleeding is a frequent clinically relevant complication during perioperative and long-term follow-up. This finding underscores the recognition and management of modifiable bleeding risk factors.


Interpersonal Stress and Late Adolescent Depressive Symptoms: Moderation by Perceptual Sensitivity to Facial Expression of Anger.
The interpersonal theories of depression highlight the role of interpersonal stress and individual's sensitivity to social rejection in the development of depression. However, previous research has tested their respective effects, whereas whether or not these two factors interact to affect depression, especially in ways of differential susceptibility or diathesis-stress, remains unknown. By adopting a morphed facial expressions recognition paradigm, the current study investigated the potential moderating role of perceptual sensitivity to facial expressions, especially that to angry expression which signaled social rejection, in the association between interpersonal stress and adolescent depressive symptoms. A total of 186 Chinese late adolescents (Mage = 21.16 ± 1.81 years; 73.7% females) participated in this study. The results demonstrated that perceptual sensitivity for angry faces, but not sad or happy faces, functioned as a plasticity factor significantly moderating the effect of interpersonal stress on depressive symptoms, which was consistent with hypothesis of differential susceptibility rather than diathesis-stress. No interactions were observed regarding non-interpersonal dimensions. These results were robust and survived a series of sensitivity analyses, including k-fold cross-validation test. The current findings highlight the crucial role of perceptual sensitivity to angry expression in explaining individual differences behind the links between interpersonal stress and adolescent depressive symptoms.


Critical temperature threshold measurement for cold urticaria: a randomized controlled trial of H(1) -antihistamine dose escalation.
Cold urticaria is a rare but severe and potentially lethal condition. It is primarily treated symptomatically with H(1) -antihistamines. However, patients have a variable response to these drugs and, to date, it has not been possible to predict readily the response to therapy of individual patients. To assess the severity of the cold urticaria in naive patients and the response to therapy of patients treated with increasing doses of an H(1) -antihistamine by measurement of critical temperature thresholds (CTT) for producing weals on the forearm. This was a two-centre, hospital-based, double-blind, randomized, parallel-group study of patients with a confirmed diagnosis of cold urticaria of at least 6 months' duration. Patient groups received either a constant dose of desloratadine 5 mg daily for 6 weeks (n = 13), or escalating doses of desloratadine: 5 mg daily for the first 2 weeks, 10 mg daily for the second 2 weeks and 20 mg daily for the final 2 weeks (n = 15). Only one adverse event that appeared to be drug related was reported: mild fatigue after treatment with desloratadine 10 mg that lasted for about 3 weeks and resolved at the end of the study. The desloratadine 5 mg daily dose produced a submaximal reduction of mean CTT which remained relatively constant over 6 weeks. Dose escalation increased efficacy, the reduction in mean CTT at four-times the standard daily dose being significantly greater (P = 0·03) than with the standard dose. Individually, no patient became symptom free (CTT < 4 °C) on 5 mg, while two became symptom free on 10 mg and a further three on 20 mg desloratadine daily. Measurement of CTT allows for individualized risk management and therapy in patients with cold urticaria.


Superior even skin tone and anti-ageing benefit of a combination of 4-hexylresorcinol and niacinamide.
To demonstrate the synergistic effect of 4-hexylresorcinol (4-HR) with niacinamide in boosting anti-melanogenic efficacy in vitro and establish the in vivo efficacy and safety of the combination in a human trial. Primary human epidermal melanocytes and 3D pigmented skin equivalents were treated with 4-HR, niacinamide, and their combinations for their effect on pigmentation. This was followed by a randomized, double-blind, split-face clinical study in Chinese subjects, and effects on skin tone, hyperpigmentation, fine lines and wrinkles, hydration, and skin firmness were measured for a 12-week study period. In vitro tyrosinase enzyme activity studies showed that 4-HR is one of the most potent tyrosinase inhibitors. The combination of 4-HR and niacinamide showed a synergistic reduction in melanin production in cultured melanocytes and lightened the 3D skin equivalent model. In vitro as well as in the human trial, the combination of 4-HR and niacinamide showed significantly improved efficacy over niacinamide alone on hyperpigmentation spots as measured by L*, the visual appearance of fine lines and wrinkles in crow's feet and perioral area and skin firmness, with no product-related adverse events. A formulation containing a combination of 4-HR and niacinamide delivered superior skin tone and anti-ageing benefits significantly better than niacinamide alone with no adverse events. This study demonstrates that a product designed to affect multiple pathways of melanogenesis, inflammation, and ageing may provide an additional treatment option, beyond hydroquinone and retinoids, for hyperpigmentation and ageing.


Alteration in P-glycoprotein at the blood-brain barrier in the early period of MCAO in rats.
The aim of this work was to investigate the alteration in P-glycoprotein (P-gp) at the blood-brain barrier (BBB) after middle cerebral artery occlusion (MCAO) in rats. Permanent MCAO was verified via 2,3,5-triphenyltetrazolium staining and hematoxylin-eosin staining. The expression of P-gp, matrix metalloproteinase-2 (MMP-2), MMP-9, claudin-5, tumour necrosis factor-α (TNF-α) and nitric oxide synthase (NOS) at the BBB was evaluated using western blot or immunostaining analysis. The content of fluorescein sodium (NaF), rhodamine-123 and nimodipine in ischaemic brain tissues was determined using high-performance liquid chromatography. Elevated expression of P-gp at the BBB and decreased concentration of P-gp substrates in the ischaemic brain tissues were observed within 4 h after MCAO. However, at 6 h after MCAO, the concentration of P-gp substrates in the ischaemic hemisphere began to rise even though the expression of P-gp was still increased. Moreover, the expression of claudin-5 was decreased; contrarily, the expression of MMP-2, MMP-9, TNF-α as well as NOS gradually increased within 6 h after MCAO. P-gp plays a crucial role in limiting the entrance of agents into the brain after MCAO and the specific regulation of P-gp expression/activity may provide an important approach for the improvement of pharmacotherapy in ischaemic stroke.


A Curious Case of Croup: Laryngotracheitis Caused by COVID-19.
We describe a case of croup in a 14-month-old boy caused by severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019. The patient presented with classic signs and symptoms consistent with croup. Workup was remarkable for a positive point-of-care test for severe acute respiratory syndrome coronavirus 2. This case represents recognition of a new clinical entity caused by coronavirus disease 2019.


Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways.
Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during nematode infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode, Steinernema carpocapsae, we describe here the first in vivo study demonstrating that FARs modulate animal immunity, causing an increase in susceptibility to bacterial co-infection. Moreover, we show that FARs dampen key components of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Our data also reveal that FARs deplete lipid signaling precursors in vivo as well as bind to these fatty acids in vitro, suggesting that FARs elicit their immunomodulatory effects by altering the availability of lipid signaling molecules necessary for an efficient immune response. Collectively, these data support a complex role for FARs in immunosuppression in animals and provide detailed mechanistic insight into parasitism in phylum Nematoda.


Daytime napping and its effects on alertness and short-term memory performance in shiftworkers.
Daytime napping and its effects on 145 female shiftworkers were studied by comparing the individual characteristics, alertness, and short-term memory performance of subjects who took or did not take naps. Of the subjects 56% (n = 82) took a nap before a night shift and 21% (n = 30) after a morning shift. After a morning shift, napping was more frequent among evening types and subjects living alone (not married). Before a night shift, daytime napping was not connected to individual characteristics, but the total sleep time of nappers during the preceding night was shorter than that of non-nappers. At 10.00 and at 04.00-08.00, at the end of the night shift, nappers were significantly more alert than subjects who had not taken naps. The length and timing of the daytime nap did not correlate to either alertness or performance during the following night. In a questionnaire, nappers before a night shift had less sleep disturbances than non-nappers.


The fine structure of blood follicles in the earthworm genera Amynthas and Lumbricus (Annelida: Oligochaeta).
Blood follicles of the earthworm Amynthas are hemoglobin-containing, sac-like dilatations of blood vessels which connect to the general circulation. Grape-like clusters of follicles are found posterior to the pharynx, among tufts of micronephridia, and single follicles are located among cells of the pharyngeal gland. In Lumbricus, follicles take the form of simple swellings and irregular-shaped diverticula of nephridial capillaries. The fundamental structure of the wall of follicles and of vessels in both genera is the same and consists of two layers: an extracellular vascular lamina and an outer (coelomic) covering of smooth muscle-like myoperithelial cells. Hemocytes may be free and circulating or they may facultatively attach to the vascular lamina as littoral cells, constituting an incomplete endothelium-like surface. Hemocytes that appear to be in the process of attaching or detaching are rounded, while adherent cells are flattened and elongate. Free and littoral hemocytes actively endocytose packets of circulating extracellular hemoglobin. Hemocytes within follicles possess radiating cell processes which also endocytose hemoglobin. Although these cells were presumed to secrete hemoglobin, staining with 3,3'-diaminobenzidine confirms the presence of hemoglobin only within pinosomes and not within protein-synthesizing or packaging organelles. The presence of hemosiderin-like bodies suggests that follicular hemocytes catabolize hemoglobin. Blood follicles apparently provide a means of significantly increasing cell-surface area for hemoglobin processing, without substantially increasing the volume and pumping load of the circulatory system.


Importance of the liver ultrasound scores in pubertal obese children with nonalcoholic fatty liver disease.
The purpose of our study was to determine the relationship between liver ultrasound scores and insulin sensitivity in a population of obese children with nonalcoholic fatty liver disease (NAFLD) and the relationships between other metabolic features and ultrasound scores. One hundred sixty-nine obese adolescents, 96 girls, and 73 boys (mean age: 12.7 ± 1.3 years, mean body mass index: 26.3 ± 4.6) were enrolled the study. The obese subjects were divided into 2 groups based on their pubertal status. Ultrasonography findings were scored in this study included hepatorenal echo contrast, liver brightness, deep attenuation, and vascular blurring. Scores ranged from 0 to 6 points, and NAFLD was defined if ultrasound score was ≥ 1. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) from fasting samples. Prevalence of NAFLD in pubertal children (61.9%) had significantly higher than pre-pubertal children (40.8%) (P=.008). Transaminases ratio was significantly correlated in both prepubertal (r=0.231; P=.03) and pubertal (r=0.628, P=0.017) groups. HOMA-IR values were elevated in both groups; however, liver ultrasound score was positively correlated with HOMA-IR (r=0.735, P=.014) in pubertal children. NAFLD prevalence among obese children is quite high, especially pubertal adolescents than prepubertal children. We demonstrated an association between insulin resistance and NAFLD ultrasound scoring in pubertal obese children. We suggested that ultrasound examination of the liver be included in the routine check-up of the pubertal obese children with insulin resistance to allow the detection of NAFLD at an early stage.


Comparison of Metabolic Response to Colonic Fermentation in Lean Youth vs Youth With Obesity.
Pediatric obesity is a growing health care burden. Understanding how the metabolic phenotype of youth with obesity may modify the effect of intestinal fermentation on human metabolism is key to designing early intervention. To assess whether adiposity and insulin resistance in youth may be associated with colonic fermentation of dietary fibers and its production of acetate, gut-derived hormone secretion, and adipose tissue lipolysis. Cross-sectional study of youths aged 15 to 22 years with body mass index in the 25th to 75th percentile or higher than the 85th percentile for age and sex throughout the New Haven County community in Connecticut. Recruitment, studies, and data collection occurred from June 2018 to September 2021. Youths were assigned to a lean, obese insulin sensitive (OIS), or obese insulin resistant (OIR) group. Data were analyzed from April 2022 to September 2022. Participants consumed 20 g of lactulose during a continuous 10-hour sodium d3-acetate intravenous infusion to measure the rate of appearance of acetate in plasma. Plasma was obtained hourly to measure acetate turnover, peptide tyrosine tyrosine (PYY), ghrelin, active glucagon-like peptide 1 (GLP-1), and free fatty acids (FFA). A total of 44 youths participated in the study (median [IQR] age, 17.5 [16.0-19.3] years; 25 [56.8%] were female; 23 [52.3%] were White). Consequent to lactulose ingestion, there was a reduction of plasma FFA, an improvement of adipose tissue insulin sensitivity index, an increase in colonic acetate synthesis, and an anorexigenic response characterized by an increased plasma concentration of PYY and active GLP-1 and a reduction of ghrelin in the subgroups. Compared with the lean and OIS groups, the OIR group showed a less marked median (IQR) rate of acetate appearance (OIR: 2.00 [-0.86 to 2.69] μmol × kg-1 × min-1; lean: 5.69 [3.04 to 9.77] μmol × kg-1 × min-1; lean vs OIR P = .004; OIS: 2.63 [1.22 to 4.52] μmol × kg-1 × min-1; OIS vs OIR P = .09), a blunted median (IQR) improvement of adipose insulin sensitivity index (OIR: 0.043 [ 0.006 to 0.155]; lean: 0.277 [0.220 to 0.446]; lean vs OIR P = .002; OIS: 0.340 [0.048 to 0.491]; OIS vs OIR P = .08), and a reduced median (IQR) PYY response (OIR: 25.4 [14.8 to 36.4] pg/mL; lean: 51.3 [31.6 to 83.3] pg/mL; lean vs OIR P = .002; OIS: 54.3 [39.3 to 77.2] pg/mL; OIS vs OIR P = .011). In this cross-sectional study, lean, OIS, and OIR youth demonstrated different associations between colonic fermentation of indigestible dietary carbohydrates and the metabolic response, with OIR youth showing minimal metabolic modifications as compared with the other 2 groups. ClinicalTrials.gov Identifier: NCT03454828.


Structure of nitrilotriacetate monooxygenase component B from Mycobacterium thermoresistibile.
Mycobacterium tuberculosis belongs to a large family of soil bacteria which can degrade a remarkably broad range of organic compounds and utilize them as carbon, nitrogen and energy sources. It has been proposed that a variety of mycobacteria can subsist on alternative carbon sources during latency within an infected human host, with the help of enzymes such as nitrilotriacetate monooxygenase (NTA-Mo). NTA-Mo is a member of a class of enzymes which consist of two components: A and B. While component A has monooxygenase activity and is responsible for the oxidation of the substrate, component B consumes cofactor to generate reduced flavin mononucleotide, which is required for component A activity. NTA-MoB from M. thermoresistibile, a rare but infectious close relative of M. tuberculosis which can thrive at elevated temperatures, has been expressed, purified and crystallized. The 1.6 Å resolution crystal structure of component B of NTA-Mo presented here is one of the first crystal structures determined from the organism M. thermoresistibile. The NTA-MoB crystal structure reveals a homodimer with the characteristic split-barrel motif typical of flavin reductases. Surprisingly, NTA-MoB from M. thermoresistibile contains a C-terminal tail that is highly conserved among mycobacterial orthologs and resides in the active site of the other protomer. Based on the structure, the C-terminal tail may modulate NTA-MoB activity in mycobacteria by blocking the binding of flavins and NADH.


Prevalence of Unmet Rehabilitation Needs Among Canadians Living With Long-term Conditions or Disabilities During the First Wave of the COVID-19 Pandemic.
We aimed to describe the prevalence of unmet rehabilitation needs among a sample of Canadians living with long-term conditions or disabilities during the first wave of the COVID-19 pandemic. Cross-sectional survey. Individuals residing in Canada during the first wave of the COVID-19 pandemic. Eligible participants were Canadians living with long-term conditions or disabilities, 15 years or older living in 1 of the 10 provinces or 3 territories (n=13,487). Not applicable. We defined unmet rehabilitation needs as those who reported needing rehabilitation (ie, physiotherapy/massage therapy/chiropractic, speech, or occupational therapy, counseling services, support groups) but did not receive it because of the COVID-19 pandemic. We calculated the national, age, gender, and province/territory-specific prevalence and 95% confidence interval of unmet rehabilitation needs. During the first wave of the pandemic, the prevalence of unmet rehabilitation needs among Canadians with long-term conditions or disabilities was 49.3% (95% confidence interval [CI]; 48.3, 50.3]). The age-specific prevalence was higher among individuals 15-49 years old (55.6%; 95% CI [54.2, 57.1]) than those 50 years and older (46.0%; 95% CI [44.5, 47.4]). Females (53.7%; 95% CI [52.6, 54.9]) had higher unmet needs than males (44.1%; 95% CI [42.3, 45.9]). Unmet rehabilitation needs varied across provinces and territories. In this sample, almost 50% of Canadians living with long-term conditions or disabilities had unmet rehabilitation needs during the first wave of the COVID-19 pandemic. This suggests that a significant gap between the needs for and delivery of rehabilitation care existed during the early phase of the pandemic.


In situ generation of the silica shell layer--key factor to the simple high yield synthesis of silver nanowires.
a-Silica encapsulated silver nanowires (diameter of 25 +/- 5 nm, average length of 10 mum) have been synthesized by reacting (Me3Si)4Si with AgNO3 in nearly quantitative yield. Formation of the a-silica shell layer (1-3 nm) in situ appears to be one of the most important factors in this simple process.


The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications.
Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood-brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.


Nanometer analysis of cell spreading on matrix-coated surfaces reveals two distinct cell states and STEPs.
When mouse embryonic fibroblasts in suspension contact a matrix-coated surface, they rapidly adhere and spread. Using total internal reflection fluorescence microscopy of dye-loaded fibroblasts to quantify cell-substrate contact, we found that increasing the surface matrix density resulted in faster spreading initiation whereas lamellipodial dynamics during spreading were unaltered. After spreading initiation, most cells spread in an anisotropic manner through stochastic, transient extension periods (STEPs) with approximately 30 STEPs over 10 min to reach an area of 1300 micro m(2) +/- 300 micro m(2). A second mode of spreading, increased in serum-deprived cells, lacked STEPs and spread in a rapid, isotropic manner for 1-4 min. This isotropic mode was characterized by a high rate of area increase, 340 micro m(2)/min with 78% of the cell edge extending. Anisotropic cells spread slower via STEPs, 126 micro m(2)/min with 34% of the edge extending. During the initial 2-4 min of fast, isotropic spreading, centripetal flow of actin was low (0.8 micro m/min) whereas in anisotropic cells it was high from early times (4.7 micro m/min). After initial isotropic spreading, rearward actin movement increased and isotropic cells displayed STEPs similar to anisotropic cells. Thus, the two cell states display dramatically different spreading whereas long-term motility is based on STEPs.


Early outcomes of patients undergoing total hip arthroplasty for trauma during COVID-19.
This study aimed to identify patients receiving total hip arthroplasty (THA) for trauma during the peak of the COVID-19 pandemic in the UK and quantify the risks of contracting SARS-CoV-2 virus, the proportion of patients requiring treatment in an intensive care unit (ICU), and rate of complications including mortality. All patients receiving a primary THA for trauma in four regional hospitals were identified for analysis during the period 1 March to 1 June 2020, which covered the current peak of the COVID-19 pandemic in the UK. Overall, one of 48 patients (2%) contracted COVID-19 during their admission. Although they required a protracted stay in hospital, they did not require ICU treatment. Two patients did require ICU support for medical problems but not relating to COVID-19. Complications were no greater than expected given the short follow-up. There were no mortalities. There is a paucity of evidence to guide restarting elective joint arthroplasties following the COVID-19 pandemic. Although THAs for trauma are by no means a perfect surrogate, the results of this study show a low incidence of contracting COVID-19 virus during admission and no significant sequalae during this period.Cite this article: Bone Joint Open 2020;1-7:438-442.


Monensin inhibits mast cell mediated airway contractions in human and guinea pig asthma models.
Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.