Protease inhibitor-induced carbamazepine toxicity.
Neurologic manifestations of HIV infection are quite diverse and can develop into seizures. Because new drug therapies have been developed, it is important to know the interactions between antiretroviral and antiepileptic agents. A 36-year-old patient with HIV developed a set of progressive left hemiparesis and secondarily generalized partial seizures related to progressive multifocal leukoencephalopathy. Phenytoin and carbamazepine were necessary to control the seizures. Instead of diverse antiretroviral therapies, the viral load was increased. Protease inhibitors (ritonavir and saquinavir) were added to the treatment and the patient developed progressive ataxia related to carbamazepine toxicity. Carbamazepine was discontinued and the patient remained asymptomatic. The patient was diagnosed with carbamazepine toxicity related to the introduction of ritonavir. Ritonavir is a potent inhibitor of hepatic cytochrome P450, mainly the CYP3A4 isoform. Carbamazepine is metabolized by this subsystem. Ritonavir acted as a CYP3A4 inhibitor, diminishing carbamazepine metabolism and provoking an increase in serum levels and clinical toxicity. We present a case of interaction between ritonavir and carbamazepine. Interaction between antiepileptic and antiretroviral agents is an emergent problem caused by the increasing association of the two therapies. We recommend strict monitoring of serum antiepileptic drug (AED) levels to avoid toxicity and inadequate seizure control.


Progression of Preclinical Heart Failure: A Description of Stage A and B Heart Failure in a Community Population.
The aims of this study are to evaluate the rate of progression of preclinical (Stage A and B) heart failure, identify associated characteristics, and evaluate long-term outcomes. Retrospective review of the Olmsted County Heart Function Study. Individuals categorized as Stage A or B heart failure at initial visit that returned for a second visit 4 years later were included. Logistic regression analyses evaluated group differences with adjustment for age and sex. At visit 1, 413 (32%) individuals were classified as Stage A and 413 (32%) as Stage B. By visit 2, 146 (35%) individuals from Stage A progressed with the vast majority (n=142) progressing to Stage B. In comparison, a total of 23 (6%) individuals progressed from Stage B. A greater rate of progression was seen for Stage A compared with Stage B (8.7 per 100 person-years [95% CI, 7.4-10.2] versus 1.4 per 100 person-years [95% CI, 0.9-2.1]; P<0.001). NT-proBNP correlated with progression for Stage B (P=0.01), but not for Stage A (P=0.39). A multivariate model found female sex (odds ratio, 1.65 [95% CI, 1.05-2.58]; P=0.03), increased E/e' (odds ratio, 1.13 [95% CI, 1.02-1.26], P=0.02), and beta blocker use (odds ratio, 2.19 [95% CI, 1.25-3.82], P=0.006) were associated with progression for Stage A. There was a signal that cardiovascular mortality was higher in individuals who progressed, although not statistically significant (P=0.06 for Stage A and P=0.05 for Stage B). There is significant progression of preclinical heart failure in a community population, with progression rates higher for Stage A. NT-proBNP correlated with progression for Stage B, but not for Stage A. No statistically significant differences in long-term outcomes were seen. Study results have clinical implications important to help guide future heart failure screening and prevention strategies.


VH gene family utilization in colonies derived from B and pre-B cells detected by the RNA colony blot assay.
The immunoglobulin heavy chain variable region (VH) genes of the mouse have been categorized into families based upon sequence homology. Utilizing the RNA colony blot assay we have determined the expression of eight of these families in B cell colonies derived from either surface immunoglobulin positive (sIg+) adult spleen B cells or sIg- fetal liver pre-B cells. We demonstrate, based upon the analysis of greater than 6000 individual colonies, that VH gene usage is a characteristic of the mouse strain studied. C57BL/6 mice most frequently (45%) utilize family VHJ558, the largest VH family, whereas BALB/c mice most frequently (22%) utilize family VH7183, the most JH proximal family in BALB/c mice. Moreover, colonies derived from sIg- fetal liver derived precursors show similar patterns, suggesting that selection based on exogenous antigen is not an important parameter in determining VH gene family usage.


Epstein-Barr virus and Burkitt lymphoma.
Burkitt lymphoma (BL) is an aggressive B-cell malignancy with endemic, sporadic and immunodeficiency-associated variants. It has been known for many years that the fundamental transforming event in BL is the translocation of the MYC gene, and the events that bring about this translocation and those that allow cells to survive with the constitutive expression of MYC have been the subject of intense investigation. Epstein-Barr virus (EBV) infection, malaria, immunodeficiency and spontaneous, somatic mutation can all contribute to the origin and maintenance of this cancer and their mechanisms are the subject of this review.


Nutritionally induced relationships between insulin levels during the weaning-to-ovulation interval and reproductive characteristics in multiparous sows: II. Luteal development, progesterone and conceptus development and uniformity.
Insulin-stimulating sow diets before mating improve piglet uniformity. We studied effects of nutritionally induced differences in insulin levels during the weaning-to-ovulation interval (WOI) on luteal development, progesterone secretion and pre-implantation conceptus development and uniformity (d10). To create insulin contrasts, 32 multiparous sows were fed either a dextrose plus lactose containing diet (each 150 g/day) at 4 h intervals (DL treatment) or an isocalorically control diet (containing soybean oil) at 12 h intervals (CTRL treatment) during the WOI. After ovulation, all sows received a standard gestation diet at 12 h intervals. Ovulation rate, plasma progesterone levels, pregnancy rate and embryo survival did not differ between treatments. CTRL sows had a higher total luteal weight (11.2 vs 9.7 g; p = 0.03) than DL sows. Conceptus diameter at d10 of pregnancy tended to be larger in CTRL sows (diameter: 7.1 vs 6.4 mm; p = 0.07). Conceptus uniformity was not influenced by treatment. Insulin area under the curve (AUC) and mean insulin during the WOI were positively related with mean progesterone (β values were 0.78 (ng/ml)/1000 μU and 0.14 (ng/ml)/(μU/ml) for AUC and mean, respectively; p < 0.05) and maximal progesterone (β values were 1.46 (ng/ml)/1000 μU and 0.27 (ng/ml)/(μU/ml) for AUC and mean, respectively; p < 0.05) levels during the first 10 days of pregnancy, but not with conceptus development and uniformity. In conclusion, high insulin levels during the WOI seem to be beneficial for progesterone secretion in sows, probably mediated through beneficial effects of insulin on follicle development.


The impact of serum uric acid on cardiovascular outcomes in the LIFE study.
The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated the superiority of a losartan-based regimen over atenolol-based regimen for reduction of cardiovascular (CV) morbidity and mortality. It has been suggested that the LIFE study results may be related to the effects of losartan on serum uric acid (SUA). SUA has been proposed as an independent risk factor for CV morbidity and death. Cox regression analysis was used to assess relationship of SUA and treatment regimens with the LIFE primary composite outcome (CV death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke). Baseline SUA was significantly associated with increased CV events [hazard ratio (HR) 1.024 (95% CI 1.017-1.032) per 10 micromol/L, P < 0.0001] in the entire study population. The association was significant in women [HR = 1.025 (1.013-1.037), P < 0.0001], but not in men [HR = 1.009 (0.998-1.019), P= 0.108]. After adjustment for Framingham risk score (FRS), SUA was no longer significant in the entire study population [HR = 1.006 (0.998-1.014), P= 0.122] or in men [HR = 1.006 (0.995-1.017), P= 0.291], but was significant in women [HR = 1.013 (1-1.025), P= 0.0457]. The baseline-to-end-of-study increase in SUA (standard deviation, SD) was greater (P < 0.0001) in atenolol-treated subjects (44.4 +/- 72.5 micromol/L) than in losartan-treated subjects (17.0 +/- 69.8 micromol/L). SUA as a time-varying covariate was strongly associated with events (P < 0.0001) in the entire population. The contribution of SUA to the treatment effect of losartan on the primary composite end point was 29% (14%-107%), P= 0.004. The association between time-varying SUA and increased CV risk tended to be stronger in women (P < 0.0001) than in men (P= 0.0658), although the gender-outcome interaction was not significant (P= 0.079). The increase in SUA over 4.8 years in the LIFE study was attenuated by losartan compared with atenolol treatment, appearing to explain 29% of the treatment effect on the primary composite end point. The association between SUA and events was stronger in women than in men with or without adjustment of FRS.


Supercontinuum generation at 1.06 mum in holey fibers with dispersion flattened profiles.
We report the results of a systematic experimental and theoretical study of 1.06 mum pumped supercontinuum generation in a range of holey fibers with different flattened dispersion profiles. Clear differences in terms of the underpinning mechanisms emerge depending on the spacing between the two fiber zero-dispersion wavelengths. By examining the phase matched wavelength range of the corresponding fiber dispersions, one can predict the maximum achievable supercontinuum bandwidth.


The iron-regulated iupABC operon is required for saprophytic growth of the intracellular pathogen Rhodococcus equi at low iron concentrations.
Rhodococcus equi is a facultative intracellular pathogen which proliferates rapidly in both manure-enriched soil and alveolar macrophages. Although both environments are characterized by extremely low concentrations of free iron, very little is known regarding the strategies employed by R. equi to thrive under these conditions. This paper reports the characterization of an R. equi transposome mutant that fails to grow at low iron concentrations. The transposome was shown to be inserted into iupA, the first gene of the iupABC operon encoding an ABC transport system highly similar to siderophore uptake systems. Disruption of the iupA gene also resulted in a failure of R. equi to utilize heme and hemoglobin as a source of iron. Introduction of the iupABC operon in trans restored the wild-type phenotype of the mutant strain. iupABC transcripts were 180-fold more abundant in R. equi grown in iron-depleted medium than in organisms grown in iron-replete medium. Proliferation of the iupABC mutant strain in macrophages was comparable to that of the wild-type strain. Furthermore, the iupABC mutant was not attenuated in mice, showing that the iupABC operon is not required for virulence.


Outcomes of corneal collagen crosslinking using a customized epithelial debridement technique in keratoconic eyes with thin corneas.
The purpose of the study was to evaluate the outcomes and possible complications of CXL performed with customized epithelial debridement technique to keratoconic corneas with the thinnest pachymetry values less than 400 µm. Nineteen eyes of 19 patients were included. The uncorrected (UCVA) and best corrected visual acuity (BCVA), flattest and steepest keratometric (K) readings, central corneal thickness at the thinnest point (t-CCT), endothelial cell density (ECD) were assessed before and 12 months after CXL. The mean UCVA was increased (p = 0.001), while the mean BCVA did not show any difference (p > 0.05). The mean flattest and steepest K readings were decreased (p = 0.001). No change was observed in the mean t-CCT (p > 0.05). The mean ECD was decreased (p = 0.001). The mean pre-CXL and post-CXL percentages of polymegathism and pleomorphism did not show any significant difference (p > 0.05). CXL performed with customized epithelial debridement technique is successful in halting the progression of keratoconus in corneas thinner than 400 µm after 12 months of treatment. However, significant endothelial cell loss can occur after this procedure.


Streptococcus group B (GBS)--characteristic, occurrence in children and adolescents with type 1 diabetes mellitus.
Group B streptococcus causes infections in woman during pregnancy and confinement, perinatal infections in newborns related to mothers carrier-state and in adults, mostly in the elderly, with one or more predisposing to infections conditions. Diabetes mellitus is the most common underlying condition. The aim of the study was to determine the frequency of GBS occurrence and GBS antibiotic susceptibility in children and adolescents with type 1 diabetes mellitus. In years 2000--2002 occurrence of GBS in some clinical materials (urine, swabs from pharynx and urogenital tract) taken from 161 diabetics: 90 girls and 71 boys, hospitalized for newly diagnosed diabetes or insufficient metabolic control/longer duration of diabetes and 37 children with hypostatura (control group) aged from 5-17 years, was examined. Susceptibility of isolated GBS strains to ampicillin, erythromycin and clindamycin was determined. GBS were obtained from different materials from 36 (22.4%) diabetic children--25 girls (27.8%), and 11 boys (15.5%). In all examined groups GBS was detected significantly in children with insufficient metabolic control/longer duration of diabetes (27 of 36 children; p =0.029, chi2=4.773). GBS in girls was isolated mainly from vestibule of vagina (25 cases) and in few cases (4) from the pharynx. GBS in boys was grown from materials from urethra (6 cases) and pharynx (5 cases). In the control group, GBS colonization was observed only in one case. All isolates (40 strains) were susceptible to penicillins, however lower susceptibility to erythromycin (3 resistant and 1 moderately sensitive) and clindamycin (3 resistant) were observed. High percentage of carriers of GBS both in girls and boys with diabetes mellitus is the potential risk factor of infection caused by GBS.


Inequality and COVID-19 in Sweden: Relative risks of nine bad life events, by four social gradients, in pandemic vs. prepandemic years.
The COVID-19 pandemic struck societies directly and indirectly, not just challenging population health but disrupting many aspects of life. Different effects of the spreading virus-and the measures to fight it-are reported and discussed in different scientific fora, with hard-to-compare methods and metrics from different traditions. While the pandemic struck some groups more than others, it is difficult to assess the comprehensive impact on social inequalities. This paper gauges social inequalities using individual-level administrative data for Sweden's entire population. We describe and analyze the relative risks for different social groups in four dimensions-gender, education, income, and world region of birth-to experience three types of COVID-19 incidence, as well as six additional negative life outcomes that reflect general health, access to medical care, and economic strain. During the pandemic, the overall population faced severe morbidity and mortality from COVID-19 and saw higher all-cause mortality, income losses and unemployment risks, as well as reduced access to medical care. These burdens fell more heavily on individuals with low income or education and on immigrants. Although these vulnerable groups experienced larger absolute risks of suffering the direct and indirect consequences of the pandemic, the relative risks in pandemic years (2020 and 2021) were conspicuously similar to those in prepandemic years (2016 to 2019).


Oral epithelial dysplasia: Recognition, grading and clinical significance.
Histopathological grading of epithelial dysplasia remains the principal laboratory method for assessing the risk of malignant transformation in oral potentially malignant disorders (OPMDs). Current views on the molecular pathogenesis and histological interpretation of the features of epithelial dysplasia are described, and the use of grading systems for epithelial dysplasia is discussed. Changes to the current 2017 WHO criteria for diagnosis are proposed with emphasis on the architectural features of epithelial dysplasia. The predictive values of three-grade and binary systems are summarised, and categories of epithelial dysplasia are reviewed, including lichenoid and verrucous lesions, keratosis of unknown significance, HPV-associated dysplasia, differentiated and basaloid epithelial dysplasia. The implications of finding epithelial dysplasia in an oral biopsy for clinical management are discussed from the pathologists' viewpoint.


Utility of a patient survey in identifying fluctuations in early stage Parkinson's disease.
Motor and non-motor fluctuations are well known sequelae of dopaminergic therapies for Parkinson's disease (PD), particularly during the advanced stages. However, the prevalence of fluctuations early in the treatment course has been less well recognised and may be missed clinically if not specifically probed. We examined the used of a survey for this purpose. Patients to be surveyed were recruited by neurologists and geriatricians at 20 Australian centres. Patients had a diagnosis of idiopathic PD with a duration of fewer than 5 years and were considered by their treating physician to be non-fluctuating or had no change in their treatment plan in the prior 6 months. Patients, with or without assistance, completed a 19-item wearing-off questionnaire to assess the presence of motor and non-motor fluctuations that indicated early wearing-off. Investigators assessed the usefulness of the questionnaire in detecting fluctuations and guiding PD treatment. Of 105 patients recruited, 92 were eligible for analysis. There were 56 (61%) identified as having fluctuations. Patients with wearing-off were younger (mean 67 vs 72 years), and more likely to have had PD for more than 3 years. About half the patients (49%) were able to complete the questionnaire independently. Clinicians perceived the questionnaire as useful for detecting fluctuations and adjusting treatment. A simple and easily administered wearing-off questionnaire may be useful in the early detection of fluctuations in PD patients and assist in guiding therapy.


Mucosal microbiome dysbiosis in gastric carcinogenesis.
We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori-negative samples compared with H. pylori-positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis, D. pneumosintes, S. exigua, P. micra and S. anginosus in GC progression.


Developing the Supporting Choice Observational Tool (SCOT): A Formative Assessment Tool to Assist Nursing Home Staff in Realizing Resident Choice.
Quality of care in nursing homes has begun to address the importance of resident choice in daily life, yet there are no published tools to teach nursing home staff how to offer such choice. In the current study, a formative assessment tool was developed that can provide staff with detailed and concrete feedback on how to realize resident choice. The tool was created and refined through 22 hours of ethnographic observation in two Veterans Health Administration Community Living Centers (CLCs), 22 hours of developmental testing in two CLCs, review by a modified Delphi panel, and use of an algorithm to assess its logical structure. The resulting Supporting Choice Observational Tool (SCOT) documents how choice is or is not offered and is or is not enabled within a singular staff-resident interaction. SCOT findings could be used in clinical teaching, quality improvement, or research efforts intent on enhancing nursing home resident quality of life. [Res Gerontol Nurs. 2017; 10(3):129-138.].


Two-dimensional transition metal dichalcogenide nanomaterials for combination cancer therapy.
As demonstrated by preclinical and clinical studies, it is often difficult to eradicate tumors, particularly those that are deep-located, with photothermal therapy (PTT) alone because of the intrinsic drawbacks of optical therapy. To increase the therapeutic effect of PTT and reduce its significant side-effects, a new direction involving the combination of PTT with other therapeutic techniques is highly desirable. Recently, two-dimensional (2D) transition metal dichalcogenides (TMDCs), the typical ultrathin 2D layer nanomaterials, have gained tremendous interest in many different fields including biomedicine, due to their novel physicochemical properties. Benefitting from their intrinsic near-infrared absorbance properties and extremely large specific surface areas, many efforts are being devoted to fabricating 2D TMDC-based multifunctional nanoplatforms for combining PTT with other therapeutics in order to realize 2D TMDC-assisted combination therapy and thus achieve excellent anti-tumor therapeutic efficacy. In addition, various inorganic nanoparticles and fluorescent probes can be attached to the surface of 2D TMDCs to obtain nanocomposites with versatile optical and/or magnetic properties that are useful for multi-modal imaging and imaging-guided cancer therapy. In this review, we mainly summarize the latest advances in the utilization of 2D TMDCs for PTT combination cancer therapy, including PTT/photodynamic therapy, PTT/chemotherapy, PTT/radiotherapy, PTT/gene therapy, and imaging-guided cancer combination therapy, as well as the evaluation of their behaviors and toxicology both in vitro and in vivo. Furthermore, we address the principle for the design of 2D TMDC-assisted photothermal combination theranostics and the future prospects and challenges of using 2D TMDC-based nanomaterials for theranostic applications.


Provisional stenting strategies: systematic overview and implications for clinical decision-making.
Coronary stents reduce the rates of abrupt closure, emergency coronary artery bypass graft surgery and restenosis, but do not prevent myocardial infarction or death at six months. The financial burden of increased stent use and the difficulty in managing in-stent restenosis have provided the impetus to develop provisional stenting strategies. Patients at low risk for restenosis after balloon angioplasty may not derive additional benefit from stent implantation and may be successfully managed with percutaneous transluminal coronary angioplasty (PTCA) alone. Numerous patient, lesion and procedural predictors of restenosis have been identified. Postprocedural assessment using quantitative coronary angiography, intravascular ultrasound (IVUS), coronary flow velocity reserve (CVR) or fractional flow reserve (FFR) may further enhance the ability to predict adverse outcomes after PTCA. Several studies have been performed to investigate the feasibility of provisional stenting strategies using various modalities to identify low risk patients who could be managed with PTCA alone. An optimal or "stent-like" angiographic result after PTCA is associated with favorable clinical outcomes. Preliminary results of studies using IVUS or CVR to guide provisional stenting appear promising. Angiography alone may be inadequate to identify truly low risk patients and may need to be combined with clinical factors, assessment of recoil, IVUS or physiologic indexes. Strategies that avoid unnecessary stenting in even a small proportion of patients may have large impacts on health care costs. Provisional stenting may potentially reduce costs and rates of in-stent restenosis without compromising the quality of health care delivery.


Gastric epithelial atypia associated with hepatic arterial infusion chemotherapy. Its distinction from early gastric carcinoma.
Hepatic arterial infusion chemotherapy (HAIC) for metastatic colonic carcinoma has been associated with gastric ulceration and marked epithelial atypia which may be mistaken for carcinoma. The authors reviewed the gastric histopathologic features of seven patients who developed gastric ulcers following HAIC and compared them with 20 examples of "early" gastric carcinoma. The seven patients had primary colonic carcinomas with hepatic metastases; each had received combination chemotherapy with mitomycin C and 5-fluorouracil via percutaneously placed hepatic arterial catheter. The gastric ulcers became clinically apparent 10 to 45 days after initiation of the final course of HAIC, usually heralded by severe epigastric pain. Based on the authors' observations, histologic features which are indicative of HAIC-associated atypia rather than carcinoma include: preservation of mucosal architecture; atypia accentuated in the basilar gastric glands; bizarre atypia with cellular enlargement exceeding that seen in carcinoma; preservation of a low nuclear-cytoplasmic ratio; cytoplasmic eosinophilia with vacuolization; few or no mitotic figures; cytologic resemblance to radiation effect; similar atypia within fibroblasts and endothelial cells; and absence of intestinal metaplasia in adjacent gastric epithelium.


Microanalysis in biology and medicine: ultrastructural localization of aluminum.
Four methods for the ultrastructural tracing of elements in man and animal are discussed. In addition to histochemical staining, emphasis was put on three innovative sophisticated microanalytical techniques: electron probe X-ray microanalysis, secondary ion mass spectrometry, and laser microprobe mass analysis. The principles and merits of these methods for microanalysis are reviewed. The application of these techniques for the detection of aluminum at the microscopic level is described in detail because of the clinical importance of this metal in severe chronic renal failure. A literature survey concerning the microanalysis of aluminum in biology and medicine is presented.


PAGAS: Portable and Accurate Gait Analysis System.
Gait analysis systems are powerful tools in the monitoring and rehabilitation of many health conditions which result in an altered gait (such as Parkinson's disease and rheumatoid arthritis), along with the injury of lower limbs. However, current systems that provide accurate gait monitoring and analysis are large and expensive, and therefore are available only in professional settings. The goal of this research is to develop and test a Portable and Accurate Gait Analysis System, denoted PAGAS, which enables patients to monitor their own gait and track their progress and improvement over time. Moreover, PAGAS will enable therapists to follow the progress of their patients over time without the need for multiple visits required at a rehabilitation facility, thus saving significant healthcare costs. PAGAS includes footswitches and a micro-controller, which connects to an Android Smart-phone using Bluetooth communication. An application on the Smartphone analyzes the raw data to produce temporal gait parameters that are displayed to the user on a graphical user interface.


Administrative prevalence of insomnia and associated clinical features in patients with addiction during active substance use.
A bidirectional relation between substance use and insomnia has been described, although there are few studies examining insomnia in the population of people with addiction. The aim of this study was to describe the prevalence of insomnia during active substance use in patients with addiction and its associated clinical features. Descriptive study in patients diagnosed with substance dependence disorder admitted to a Hospital Detoxification Unit. The existence of insomnia prior to admission was assessed using the Oviedo Sleep Questionnaire (OSQ). Demographic variables, consumptionrelated clinical variables, and diagnostic variables were collected and the SCID-I and -II (Structured Clinical Interview for DSM-IV) and CAADID (Conners' Adult ADHD Diagnostic Interview for DSM-IV) were administered to evaluate the psychiatric diagnoses. Bivariate and multivariate analyses were made of the data. 481 patients (72.6% men, age 40.6±10.1 years) were enrolled. 64.3% of the patients reported insomnia during active substance use. The most common type of insomnia was fragmented nocturnal sleep (49.9%). The factors significantly associated with insomnia were polysubstance drug use, medical comorbidities (most notably, infectious diseases), anxiety disorder, personality disorder (particularly cluster C), a greater number of previous admissions for detoxication, and early age at onset of substance use. Insomnia is highly prevalent in patients with addiction during active use of the substance. Fragmented nocturnal sleep was the most common type of insomnia. Patients with addiction and comorbid anxiety disorder, medical comorbidity, and early onset of dependence were more likely to experience insomnia.


Low anthocyanin plum nectar does not impact cognition, blood pressure and gut microbiota in healthy older adults: A randomized crossover trial.
Queen Garnet plum (QGP), known for its high levels of anthocyanins, is a hybrid of the Japanese plum developed in Queensland, Australia. Anthocyanins provide the red, blue, and purple pigments in plants with demonstrated beneficial health effects. This study hypothesized that low-dose anthocyanin QGP intake will have a significant positive effect on cognition, blood pressure, and gut microbiota in healthy older adults. A randomized crossover trial was conducted to determine the effect and within subject variance on cognition and 24 hr. ambulatory blood pressure in older adults without cognitive impairment following daily consumption of 200 mL low-dose anthocyanin (5 mg/100 g) QGP nectar (intervention) or raspberry cordial (control). Secondary outcomes included inflammatory markers (C-reactive protein), nerve growth factor (BDNF), and gut microbiota (16S rRNA gene sequencing). Twenty-eight participants (55+ years) were recruited. Each randomized treatment arm lasted for 8 weeks with a 4-week washout period. Cognition, blood pressure, and urine samples were measured at each visit (5 total) while blood and fecal samples were collected at baseline, 8 weeks, and 20 weeks. Repeated-measures ANOVA was used to analyze the data. Across the treatments, no significant difference was observed for the different domains of cognition, blood pressure, or anti-inflammatory biomarkers. No intervention effect was found for genera or class of gut microbes. Low anthocyanin nectar derived from the QGP did not have any significant effects on cognition, blood pressure, or gut microbiota in healthy older adults.


Role of L-arginine in the vascular actions and development of tolerance to nitroglycerin.
The goal of this work was to test the role of nitric oxide synthase (NOS) and its substrate L-arginine in development of tolerance to nitroglycerin's (GTN) vasodilator actions. GTN's effects on NOS activity and NO formation were tested in cultured bovine aortic endothelial cells (BAECs). The arginine to citrulline conversion assay showed that GTN stimulated NOS basal activity in BAECs by approximately 40%, comparable with acetylcholine (ACh)-treated controls. Both effects were blocked by L-NMMA. Photometric assays showed that both GTN and ACh-stimulated NO formation. Both effects were potentiated by L-arginine and inhibited by L-NAME. L-NAME inhibited ACh responses approximately 80% compared with approximately 40% for GTN responses. The aortic ring assay showed that 2 h pretreatment with GTN caused substantial tolerance to GTN's vasodilating effects as evidenced by a 38 fold rightward shift of the concentration-relaxation curve. In contrast to D-arginine, addition of L-arginine substantially inhibited this effect, reducing the rightward shift to 4.4 fold of control values. GTN tolerance was associated with a 40% reduction in L-arginine tissue levels. GTN had a biphasic effect on BAEC uptake of L-arginine, stimulating uptake at 5 and 15 min, and suppressing uptake after 1 and 4 h In summary, acute GTN treatment stimulates endothelial NOS activity in producing NO and increases cellular uptake of L-arginine. Prolonged GTN exposure reduces GTN's vasodilator actions, decreases L-arginine tissue levels and depresses BAECs uptake of L-arginine. Supplementation of L-arginine reduces development of GTN tolerance. These data indicate that GTN tolerance depends in part on activation of the NOS pathway.


Dithionite-Mediated Tandem Nitro Reduction/Imine Formation/Intramolecular Cyclization for the Synthesis of Dihydro-benzothiadiazine-1,1-dioxides.
A one-pot, tandem reductive annulation of 2-nitrobenzenesulfonamides with aldehydes to the synthesis of substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides in the presence of sodium dithionite (Na2S2O4) is reported under mild conditions. The method involves in situ reduction of the nitro group followed by condensation with aldehydes to form an imine, which upon subsequent intramolecular cyclization forms the product under one-pot conditions. The protocol features use of inexpensive Na2S2O4 as the exclusive reagent, appreciable functional group tolerance, broad substrate scope, high product yields, and scalability.


The origin, and application of somatosensory evoked potentials as a neurophysiological technique to investigate neuroplasticity.
Somatosensory evoked potentionals (SEPs) can be used to elucidate differences in cortical activity associated with a spinal manipulation (SM) intervention. The purpose of this narrative review is to overview the origin and application of SEPs, a neurophysiological technique to investigate neuroplasticity. Summaries of: 1) parameters for SEP generation and waveform recording; 2) SEP peak nomenclature, interpretation and generators; 3) peaks pertaining to tactile information processing (relevant to both chiropractic and other manual therapies); 4) utilization and application of SEPs; 5) SEPs concurrent with an experimental task and at baseline/control/pretest; 6) SEPs pain studies; and 7) SEPs design (pre/post) and neural reorganization/neuroplasticity; and 8) SEPs and future chiropractic research are all reviewed. Understanding what SEPs are, and their application allows chiropractors, educators, and other manual therapists interested in SM to understand the context, and importance of research findings from SM studies that involve SEPs.


Social Welfare Policy and Public Assistance for Low-Income Substance Abusers: The Impact of 1996 Welfare Reform Legislation on the Economic Security of Former Supplemental Security Income Drug Addiction and Alcoholism Beneficiaries.
Prior to January 1, 1997, individuals with drug- or alcohol-related disabilities could qualify for federal public assistance through the Supplemental Security Income (SSI) program. During the welfare reforms of the Clinton administration, this policy was changed resulting in lost income and health care benefits for many low-income substance abusers. This paper examines the historical underpinnings to the elimination of drug addiction and alcoholism (DA&A) as qualifying impairments for SSI disability payments. Following this, empirical evidence is presented on the effect this policy change had on the subsequent economic security of former SSI DA&A beneficiaries. Findings indicate that study participants that lost SSI benefits suffered increased economic hardship following the policy change. These findings have important implications for future social welfare policymaking decisions.


False-negative magnetic resonance angiography with extracranial internal carotid artery stenosis: a report of two cases and review of the literature.
Magnetic resonance angiography (MRA) is increasingly used as a noninvasive means to assess internal carotid artery (ICA) stenosis. When used alone, however, MRA may not be sufficiently accurate in certain settings to determine whether ICA disease meets surgical criteria. Although MRA has been recognized to overestimate the degree of stenosis, the authors present two cases in which it severely underestimated arterial stenosis. Two male patients, 70 and 40 years old, respectively, were admitted with crescendo transient ischemic attacks. Their MRA studies suggested nonsurgical lesions of the ICA. After the patients continued to demonstrate clinical evidence of embolic disease, digital subtraction angiography (DSA) was performed on one patient, and the other received a gadolinium contrast-enhanced MRA. These tests revealed critical stenosis in each patient. Each was taken to the operating room for awake carotid endarterectomy with heparin anticoagulation and electroencephalographic monitoring. At surgery, both patients were found to have severely stenosed ICAs with complex plaques. MRA to determine whether ICA stenosis meets surgical criteria may not be sufficiently accurate in certain clinical settings. Additional imaging studies, such as confirmatory digital ultrasonography, MRA with gadolinium contrast, or DSA, may be required to determine the extent of carotid artery stenosis accurately.


Anaphylactic responses of guinea-pig lung parenchymal strips: antigen concentration dependence and pharmacological modification.
The effects of mediator antagonists and synthesis inhibitors on anaphylactic responses of lung parenchymal strips from ovalbumin-sensitized guinea-pigs have been investigated. The dependence of the responses on the concentration of the antigen has been studied using a cumulative concentration-response technique. Anaphylactic contraction and histamine release were similar in response to cumulative and single additions of ovalbumin. Contractile responses to high doses of antigen (1 and 10 micrograms/ml) were slightly inhibited by mepyramine, whereas those to low doses (0.01 microgram/ml) were inhibited by leukotriene antagonist FPL 55712 and the lipoxygenase inhibitors nordihydroguaiaretic acid and BW 755C. Indomethacin potentiated both histamine release and contraction induced by ovalbumin. It is concluded that leukotrienes play a major role in anaphylactic responses to low antigen concentrations. Such responses may more closely resemble allergic bronchoconstriction in man. Histamine has a minor role in responses to higher antigen concentrations, where the major mediator of the responses may also be leukotrienes. This possibility cannot be proved with currently available leukotriene antagonists and synthesis inhibitors.


A Single-Center Experience with a Pregnant Immigrant Population and Zika Virus Serologic Screening in New York City.
Our institution is in an area of New York City with a large population of immigrants from Zika virus endemic areas. With the recent Zika virus outbreak, we sought to examine our center's experience with screening for Zika virus and outcomes among patients who tested positive for the disease during pregnancy. We performed a chart review of all pregnant patients who tested positive (positive serum or urine polymerase chain reaction [PCR]) or presumed positive (immunoglobulin M [IgM] enzyme-linked immunosorbent assay [ELISA] positive or IgM ELISA equivocal with positive plaque reduction neutralization test) for Zika virus. All tests were performed by the Department of Health (DOH) and followed Centers for Disease Control and Prevention guidelines in effect at the time of specimen collection. Testing of cord blood, placenta, and/or neonatal blood were/was performed by the DOH for New York County. Prenatal ultrasounds for fetal head size and surveillance for calcifications were performed by maternal-fetal medicine specialists. Infant head ultrasound results were included when available. Between March 2016 and April 2017, 70 pregnant patients were positive or presumed positive for Zika infection during pregnancy. Of those, 16 women had positive urine or serum PCR and the remaining 54 were presumed positive. Among positive cases, five women tested positive via urine PCR only, nine women tested positive via serum PCR only, and two women had both positive urine and serum PCR. Fifteen of 67 infants (22%) born during the study period were born to mothers with positive urine or serum PCR testing. Sixty-five newborns were clinically normal with normal head measurements. Of the intracranial ultrasound performed, one infant had a grade 1 intraventricular hemorrhage, four had incidental choroid plexus cysts, and one had severe ventriculomegaly that was also noted antenatally. There were 2 positive and 15 equivocal infant serum IgM samples and 1 positive placental PCR from these pregnancies. There were four pregnancy terminations and two cases with fetal anomalies in this population that were split evenly between patients who tested positive and those who tested presumed positive for Zika virus during pregnancy. We found no differences in pregnancy or neonatal outcomes between women who tested positive and presumed positive for Zika virus during pregnancy. Testing of infants and placenta tissue after delivery was largely inconclusive. Improvement in testing for Zika virus infection is needed to determine which pregnancies are at risk for congenital anomalies. Further research is still needed to determine which children are at risk for poor neurodevelopmental outcomes related to Zika virus and how to best coordinate care among the immigrant population during a new disease epidemic.


Sonographic assessment of a suspected biloma: A case report and review of the literature.
A biloma is a rare disease characterized by an abnormal intra- or extrahepatic bile collection due to a traumatic or spontaneous rupture of the biliary system. Laboratory findings are nonspecific. The diagnosis is usually suspected on the basis of a typical history (right upper quadrant abdominal pain, chills, fever and recent abdominal trauma or surgery) and is confirmed by detection of typical radiologic features. We report the case of a patient with a history of previous cholecystectomy for lithiasis who presented with clinical symptoms and laboratory data suggestive of acute pancreatitis. Imaging studies also revealed the presence of a chronic and asymptomatic biloma, which could be mistaken for a pseudocyst. The atypical location and ultrasound findings suggested an alternative diagnosis. We therefore reviewed the known literature for bilomas, focusing on the role of ultrasonography, which can reveal some typical aspects, such as location and imaging features. We conclude that ultrasound plays a key role in the assessment of a suspected biloma in patients with appropriate history and clinical features and provides valuable diagnostic clues even in the absence of these.


COVID-19 vaccination for people with severe mental illness: why, what, and how?
Psychiatric disorders, and especially severe mental illness, are associated with an increased risk of severe acute respiratory syndrome coronavirus 2 infection and COVID-19-related morbidity and mortality. People with severe mental illness should therefore be prioritised in vaccine allocation strategies. Here, we discuss the risk for worse COVID-19 outcomes in this vulnerable group, the effect of severe mental illness and psychotropic medications on vaccination response, the attitudes of people with severe mental illness towards vaccination, and, the potential barriers to, and possible solutions for, an efficient vaccination programme in this population.


Long-term dietary cadmium intake and postmenopausal endometrial cancer incidence: a population-based prospective cohort study.
Environmental pollutants mimicking the effects of estrogen are suggested to contribute to the high incidence of hormone-related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-alpha, has been shown in vivo. We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population-based prospective cohort of 30,210 postmenopausal women free of cancer diagnose at baseline (1987) and who completed a food frequency questionnaire at baseline and in 1997. We estimated the dietary cadmium intake based on the questionnaire data and the cadmium content in all foods. During 16.0 years (484,274 person-years) of follow-up between the baseline and mid-2006, we ascertained 378 incident cases of endometrioid adenocarcinoma. The average estimated dietary cadmium intake was 15 mug/day (80% from cereals and vegetables). Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women; the multivariate relative risk (RR) was 1.39 [95% confidence interval (CI), 1.04-1.86; P(trend) = 0.019], comparing highest tertile versus lowest. Among never-smoking women with body mass index (BMI) of <27 kg/m(2), the RR was 1.86 (95% CI, 1.13-3.08; P(trend) = 0.009). We observed a 2.9-fold increased risk (95% CI, 1.05-7.79) associated with long-term cadmium intake consistently above the median at both baseline 1987 and in 1997 in never-smoking women with low bioavailable estrogen (BMI of <27 kg/m(2) and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers.


Design, synthesis, and structure-activity relationship exploration of 1-substituted 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one analogues as inhibitors of the annexin A2-S100A10 protein interaction.
S100 proteins are small adaptors that regulate the activity of partner proteins by virtue of direct protein interactions. Here, we describe the first small molecule blockers of the interaction between S100A10 and annexin A2. Molecular docking yielded candidate blockers that were screened for competition of the binding of an annexin A2 peptide to S100A10. Several inhibitory clusters were identified with some containing compounds with potency in the lower micromolar range. We chose 3-hydroxy-1-(2-hydroxypropyl)-5-(4-isopropylphenyl)-4-(4-methylbenzoyl)-1H-pyrrol-2(5H)-one (1a) as a starting point for structure-activity studies. These confirmed the hypothetical binding mode from the virtual screen for this series of molecules. Selected compounds disrupted the physiological complex of annexin A2 and S100A10, both in a broken cell preparation and inside MDA-MB-231 breast cancer cells. Thus, this class of compounds has promising properties as inhibitors of the interaction between annexin A2 and S100A10 and may help to elucidate the cellular function of this protein interaction.


The role of the medullary collecting ducts in postobstructive diuresis.
Medullary collecting duct function was studied by direct microcatheterization techniques in rats undergoing postobstructive diuresis. Significant net addition of water and sodium to the duct was demonstrated during postobstructive diuresis after relief of 24-h bilateral ureteral ligation. This striking abnormality in function was associated with reduced delivery of sodium and water to the collecting duct compared to sham-operated controls. To examine the role of circulating factors in this phenomenon, another group of rats was studied that underwent 24 h of total urine reinfusion into the femoral vein. Natriuresis and diuresis were similar to the postobstructive group, but absolute collecting duct reabsorption of sodium and water was normal. The natriuresis and diuresis in rats with urine reinfusion resulted from increased delivery of fluid and sodium to the medullary collecting duct. A third group of rats was studied with 24-h unilateral ureteral ligation as well as urine reinfusion from the contralateral normal kidney. Without urine reinfusion there was no diuresis-natriuresis but with urine reinfusion the diuresis and natriuresis after relief of unilateral obstruction was similar to that after relief of bilateral obstruction. Moreover, net addition of sodium and no significant water reabsorption were demonstrated in the medullary collecting duct of such animals. The results indicate that (a) the medullary collecting duct is the critical nephron segment affected by ureteral obstruction, since postobstructive diuresis occurred despite reduced delivery of fluid from the more proximal nephron; (b) the net addition of sodium to the medullary collecting duct observed during postobstructive diuresis is probably a direct effect of obstruction, since it was found during postobstructive diuresis after relief of bilateral or unilateral ureteral ligation, but not with urine reinfusion alone; and (c) blood-borne factors are important in the development of postobstructive natriuresis and diuresis, and probably act by increasing the fraction of filtered sodium and water delivered from the proximal and distal tubule to the collecting duct.


Tracking lysozyme unfolding during salt-induced precipitation with hydrogen exchange and mass spectrometry.
We utilized electrospray ionization mass spectrometry (ESI-MS) and hydrogen-deuterium exchange (HX) to detect unfolding of hen egg white lysozyme during salt-induced precipitation. Deuterated lysozyme was dissolved in protonated buffer at pH 2.16 and precipitated with ammonium sulfate, sodium chloride, and potassium thiocyanate. ESI-MS was used to detect mass differences in lysozyme due to the loss of deuterons for solvent protons, providing insight on the conformational history of the protein during the labeling experiment. Precipitation with ammonium sulfate and sodium chloride did not unfold lysozyme, consistent with the known stabilizing effects of kosmotropic salts. Potassium thiocyanate, an aggressive chaotrope, was an effective precipitant at 0.2 M, but also disrupted lysozyme structure and caused the formation of precipitate fractions that did not readily redissolve into aqueous solution without the use of a chemical denaturant. Precipitation with 1.0 M thiocyanate resulted in faster rates of unfolding and larger amounts of the insoluble precipitate. The unfolding kinetics were biphasic, exhibiting a slow phase after a few hours that presumably reflected a smaller propensity for lysozyme to unfold in the precipitated state. Bimodal mass distributions in the ESI-MS spectra for the thiocyanate precipitates indicate two states for lysozyme in this system, a native and a molten globule-like partially unfolded state. ESI-MS analysis of the insoluble precipitates indicated that they consisted primarily of protein molecules that had unfolded. Investigation of the HX behavior of lysozyme in a KSCN solution at low protein concentrations confirmed the destabilizing effect of the salt on the protein structure, even when there was almost no solid phase present. The HX/ESI-MS results provide insight into the mechanism combining precipitation and denaturation for such a system, both in terms of obtaining quantitative kinetic and stability information and the identification of the conformers present.


Cyanide ion complexation by a cationic borane.
While we have previously reported that [1-(Mes2B)-8-(Me3NCH2)-C10H6]+ ([2]+) complexes fluoride ions to form [1-(Mes2FB)-8-(Me3NCH2)-C10H6] (2-F), we now show that this cationic borane also complexes cyanide to form [1-(Mes2(NC)B)-8-(Me3NCH2)-C10H6] (2-CN). This reaction also occurs under biphasic conditions (H2O-CHCl3) and may serve to transport cyanide in organic phases. The zwitterionic cyanoborate 2-CN has been fully characterized and its crystal structure determined. UV-vis titration experiments carried out in THF indicate that [2]+ has a higher affinity for fluoride (K > 10(8) M(-1)) than cyanide (K = 8.0 (+/-0.5) x 10(5) M(-1)). Steric effects which impede cyanide binding to the sterically congested boron center of [2]+ are most likely at the origin of this selectivity. Finally, electrochemical studies indicate that [2]+ is significantly more electrophilic than its neutral precursor 1-(Mes2B)-8-(Me2NCH2)-(C10H6) (1). These studies also show that reduction of [2]+ is irreversible, possibly because of elimination of the NMe3 moiety under reductive conditions. In fact, [2]OTf reacts with NaBH4 to afford 1-(Mes2B)-8-(CH3)-(C10H6) (4) which has also been fully characterized.


Lead-Free Organic-Perovskite Hybrid Quantum Wells for Highly Stable Light-Emitting Diodes.
Two-dimensional perovskites that could be regarded as natural organic-inorganic hybrid quantum wells (HQWs) are promising for light-emitting diode (LED) applications. High photoluminescence quantum efficiencies (approaching 80%) and extremely narrow emission bandwidth (less than 20 nm) have been demonstrated in their single crystals; however, a reliable electrically driven LED device has not been realized owing to inefficient charge injection and extremely poor stability. Furthermore, the use of toxic lead raises concerns. Here, we report Sn(II)-based organic-perovskite HQWs employing molecularly tailored organic semiconducting barrier layers for efficient and stable LEDs. Utilizing femtosecond transient absorption spectroscopy, we demonstrate the energy transfer from organic barrier to inorganic perovskite emitter occurs faster than the intramolecular charge transfer in the organic layer. Consequently, this process allows efficient conversion of lower-energy emission associated with the organic layer into higher-energy emission from the perovskite layer. This greatly broadened the candidate pool for the organic layer. Incorporating a bulky small bandgap organic barrier in the HQW, charge transport is enhanced and ion migration is greatly suppressed. We demonstrate a HQW-LED device with pure red emission, a maximum luminance of 3466 cd m-2, a peak external quantum efficiency up to 3.33%, and an operational stability of over 150 h, which are significantly better than previously reported lead-free perovskite LEDs.


In vitro diagnosis of cow's milk protein sensitive enteropathy by organ culture method.
The criteria that are used at present to diagnose cow's milk protein sensitive enteropathy (CMPSE) are based on an in vivo milk challenge which can be hazardous and life threatening. We have used an organ culture model to determine the usefulness of this technique in establishing the diagnosis of CMPSE on the basis of a single biopsy with in vitro milk challenge. Fourteen infants with diarrhoea clinically suspected to have CMPSE were studied prospectively. On the basis of milk challenge studies seven infants had CMPSE. They had clinical reaction to cow's milk with associated histological changes and depression of alkaline phosphatase levels in the jejunal mucosa. In all seven cases parallel changes in alkaline phosphatase levels were noted in the organ culture specimens of initial biopsy subjected to in vitro challenge. The seven control infants tolerated cow's milk and did not have histological changes. The alkaline phosphatase levels were moderately increased in the jejunal mucosa in five of the seven infants. The alkaline phosphatase levels in the organ culture specimens of initial biopsy were increased after in vitro challenge in all seven infants. This study suggests that organ culture methods may be useful in the vitro diagnosis of CMPSE, and also obviate the need for in vivo oral milk challenges and repeated biopsies.


Nickel complexes based on BIAN ligands: transformation and catalysis on ethylene polymerization.
Treatment of bis(arylimino)acenaphthene (ArBIAN) with Ni(COD)2 in toluene afforded dmpBIANNi(COD) (2a, dmp = 2,6-Me2C6H3) and dippBIANNi(COD) (2b, dipp = 2,6-iPrC6H3), respectively, in moderate yields. Complexes 2a and 2b can be oxidized by a small amount of oxygen at low temperature leading to oxygen-bridged dinuclear Ni(ii) complexes (dmpBIANNi)2(μ-O)2 (4a) and (dippBIANNi)2(μ-O)2 (4b), respectively, as a purple powder. The reaction of ArBIAN with 0.5 equiv of Ni(COD)2 or Ni(Ph3P)4 gave bisligated complexes (dmpBIAN)2Ni (3a) and (dippBIAN)2Ni (3b), which can be considered as Ni(0) complexes supported by two neutral BIAN ligands. Oxidation of the bisligated nickel complexes 3a and 3b with [Cp2Fe][B(C6F5)4] afforded cationic Ni(i) complexes [(dmpBIAN)2Ni][B(C6F5)4] (5a) and [(dippBIAN)2Ni][B(C6F5)4] (5b), respectively, in which the Ni(i) centre is chelated by two neutral Ar-BIAN ligands. These complexes were characterized by NMR and IR spectroscopy and DFT calculation, and the molecular structures of 3b, 4b, and 5b were well established by X-ray diffraction analysis. These complexes were evaluated as catalysts for ethylene polymerization in which 2b showed high activity in the presence of AlMe3. 13C NMR analysis of polymers showed that the 2b/AlMe3 catalytic system gave less-branched polymers when compared to that obtained with dippBIANNiBr2 under the same conditions.


Electrostatic and lipid anchor contributions to the interaction of transducin with membranes: mechanistic implications for activation and translocation.
The heterotrimeric G protein transducin is a key component of the vertebrate phototransduction cascade. Transducin is peripherally attached to membranes of the rod outer segment, where it interacts with other proteins at the membrane-cytosol interface. However, upon sustained activation by light, the dissociated G(t)alpha and Gbeta(1)gamma(1) subunits of transducin translocate from the outer segment to other parts of the rod cell. Here we used a computational approach to analyze the interaction strength of transducin and its subunits with acidic lipid bilayers, as well as the range of orientations that they are allowed to occupy on the membrane surface. Our results suggest that the combined constraints of electrostatics and lipid anchors substantially limit the rotational degrees of freedom of the membrane-bound transducin heterotrimer. This may contribute to a faster transducin activation rate by accelerating transducin-rhodopsin complex formation. Notably, the membrane interactions of the dissociated transducin subunits are very different from those of the heterotrimer. As shown previously, Gbeta(1)gamma(1) experiences significant attractive interactions with negatively charged membranes, whereas our new results suggest that G(t)alpha is electrostatically repelled by such membranes. We suggest that this repulsion could facilitate the membrane dissociation and intracellular translocation of G(t)alpha. Moreover, based on similarities in sequence and electrostatic properties, we propose that the properties described for transducin are common to its homologs within the G(i) subfamily. In a broader view, this work exemplifies how the activity-dependent association and dissociation of a G protein can change both the affinity for membranes and the range of allowed orientations, thereby modulating G protein function.


Cost-effectiveness of clozapine monitoring after the first 6 months.
Clozapine is effective in treating patients with schizophrenia who do not respond to conventional neuroleptic drugs. The drug is unique in that it is available only with a US Food and Drug Administration-mandated system for weekly monitoring of patients' white blood cell counts. No study has been conducted to evaluate the cost-effectiveness of this mandatory monitoring system. A benchmark case was established by utilizing cumulative incidence rates of agranulocytosis from a recent study with a large sample of clozapine-treated patients. We assumed a 20% mortality among patients with agranulocytosis, $30.61 in monitoring costs each week, and 14.4 years of remaining life expectancy after detection of agranulocytosis. Based on these bench-mark assumptions, cost-effectiveness ratios in dollars per quality-adjusted life-year were calculated for the first, second, and third 6-month periods during which a patient was receiving clozapine. Sensitivity analyses were performed with more conservative assumptions in 5 alternative scenarios. In the benchmark case, costs per quality-adjusted life-year gained were $61,694, $925,418, and $420,644 for the first, second, and third 6-month periods of clozapine treatment, respectively. In the alternative scenarios, these costs ranged from $7923 to $46,056 for the first 6-month period and from $54,025 to $690,850 for the second and third 6-month periods. While the costs of monitoring patients with schizophrenia in the first 6-month period of clozapine treatment seem to be justifiable, monitoring thereafter may not be cost-effective because of the very low incidence of agranulocytosis in the later periods.


Risk of hospitalization among survivors of childhood and adolescent acute lymphoblastic leukemia compared to siblings and a general population sample.
Acute Lymphoblastic Leukemia (ALL) has a high survival rate, but cancer-related late effects in the early post-treatment years need documentation. Hospitalizations are an indicator of the burden of late effects. We identify rates and risk factors for hospitalization from five to ten years after diagnosis for childhood and adolescent ALL survivors compared to siblings and a matched population sample. 176 ALL survivors were diagnosed at ≤22 years between 1998 and 2008 and treated at an Intermountain Healthcare facility. The Utah Population Database identified siblings, an age- and sex-matched sample of the Utah population, and statewide inpatient hospital discharges. Sex- and birth year-adjusted Poisson models with Generalized Estimating Equations and robust standard errors calculated rates and rate ratios. Cox proportional hazards models identified demographic and clinical risk factors for hospitalizations among survivors. Hospitalization rates for survivors (Rate:3.76, 95% CI=2.22-6.36) were higher than siblings (Rate:2.69, 95% CI=1.01-7.18) and the population sample (Rate:1.87, 95% CI=1.13-3.09). Compared to siblings and population comparisons, rate ratios (RR) were significantly higher for survivors diagnosed between age 6 and 22 years (RR:2.87, 95% CI=1.03-7.97 vs siblings; RR:2.66, 95% CI=1.17-6.04 vs population comparisons). Rate ratios for diagnosis between 2004 and 2008 were significantly higher compared to the population sample (RR:4.29, 95% CI=1.49, 12.32), but not siblings (RR:2.73, 95% CI=0.54, 13.68). Survivors originally diagnosed with high-risk ALL did not have a significantly higher risk than siblings or population comparators. However, high-risk ALL survivors (Hazard ratio [HR]:3.36, 95% CI=1.33-8.45) and survivors diagnosed from 2004 to 2008 (HR:9.48, 95% CI=1.93-46.59) had the highest risk compared to their survivor counterparts. Five to ten years after diagnosis is a sensitive time period for hospitalizations in the ALL population. Survivors of childhood ALL require better long-term surveillance.


Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection.
Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts. Reconstitution of DNA protection in vitro revealed that the defect arises directly due to altered RAD51 properties. Both mutations induce pronounced structural changes and RAD51 filament destabilization that is not rescued by prevention of ATP hydrolysis due to aberrant ATP binding. Our results further interconnect the FA pathway with DNA replication and provide mechanistic insight into the role of RAD51 in recombination-independent mechanisms of genome maintenance.


Tailoring amphotericin B as an ionic liquid: an upfront strategy to potentiate the biological activity of antifungal drugs.
Aspergillus species are the primary cause of invasive aspergillosis, which afflicts hundreds of thousands of patients yearly, with high mortality rates. Amphotericin B is considered the gold standard in antifungal drug therapy, due to its broad-spectrum activity and rarely reported resistance. However, low solubility and permeability, as well as considerable toxicity, challenge its administration. Lipid formulations of amphotericin B have been used to promote its slow release and diminish toxicity, but these are expensive and adverse health effects of their prolonged use have been reported. In the past decades, great interest emerged on converting biologically active molecules into an ionic liquid form to overcome limitations such as low solubility or polymorphisms. In this study, we evaluated the biological activity of novel ionic liquid formulations where the cholinium, cetylpyridinium or trihexyltetradecylphosphonium cations were combined with an anionic form of amphotericin B. We observed that two formulations increased the antifungal activity of the drug, while maintaining its mode of action. Molecular dynamics simulations showed that higher biological activity was due to increased interaction of the ionic liquid with the fungal membrane ergosterol compared with amphotericin B alone. Increased cytotoxicity could also be observed, probably due to greater interaction of the cation with cholesterol, the main sterol in animal cells. Importantly, one formulation also displayed antibacterial activity (dual functionality), likely preserved from the cation. Collectively, the data set ground for the guided development of ionic liquid formulations that could improve the administration, efficacy and safety of antifungal drugs or even the exploitation of their dual functionality.


Evaluation of Risk Perception of Smoking after the Implementation of California's Tobacco 21 Law.
Decreasing smoking initiation remains a public health priority. In 2016, California, in the United States, enacted the Tobacco 21 law, which raised the minimum age for the purchase of tobacco products from age 18 to age 21. This paper evaluates whether the enactment and implementation of the Tobacco 21 law changed how young adults perceive the risk(s) of smoking. Data were drawn from a cohort of emerging adults (n = 575) in California who were non-daily smokers at enrollment and followed quarterly for 3 years. Data were collected during 2015-2019. Piecewise multilevel regression models were used to test for changes in smoking status and perceived risks of cigarettes after Tobacco 21 enforcement began. Findings indicated that the prevalence of current smoking and perceived risks of smoking both declined following Tobacco 21 implementation (ps < 0.001). Post-hoc analyses suggested that post-implementation changes in perceived risk occurred primarily among ongoing smokers. Findings suggest that Tobacco 21 and associated public health measures have been effective, but additional research is needed to disentangle the effects of specific components. Understanding the impact and efficacy of tobacco laws provides great social value to research and implement policies that create intervention(s) on reducing tobacco use initiation.


Postoperative maladaptive behavioral changes in children.
Induction of anesthesia can be a very stressful period for a child and his family and can be associated with increased risk of psychological disturbances. These disturbances are categorized as preoperative anxiety, emergence delirium and postoperative behavioral changes. Several tools have been developed to measure these psychological manifestations as well as the baseline personality traits of these patients. Postoperative negative behavioral changes, such as sleep and eating disorders, separation anxiety, temper tantrum, aggression toward authorities, may occur in up to 60% of all children undergoing general anesthesia. Several studies found a strong association between these postoperative behavioral changes, the distress of the child on induction and his individual personality characteristics, although a cause-effect relationship could not be determined. Understanding the risk factors for behavior changes helps us determine the best way for prevention and treatment of these changes in the perioperative period.


Adaptation of the geminivirus bean yellow dwarf virus to dicotyledonous hosts involves both virion-sense and complementary-sense genes.
Bean yellow dwarf virus (BeYDV) and maize streak virus (MSV) belong to the geminivirus genus Mastrevirus and have host ranges confined to dicotyledonous and monocotyledonous species, respectively. To investigate viral determinants of host range specificity, chimeras were constructed by exchanging their coding and non-coding regions. BeYDV chimeras containing MSV ORF V1, ORF V2 or small intergenic region sequences, either individually or in various sequential combinations, replicated and produced virus particles in Nicotiana tabacum protoplasts. BeYDV chimeras containing MSV ORFs C1 and C2 and/or the large intergenic region were unable to replicate. None of the chimeras was able to systemically infect either N. benthamiana or maize. Complementation experiments using BeYDV chimeras containing MSV ORF V1 and/or ORF V2 suggest that expression of MSV movement protein and/or coat protein prevents BeYDV movement. The results demonstrate that factors involved in both viral DNA replication and virus movement are exclusively adapted to either monocotyledonous or dicotyledonous host backgrounds.


Modified Pfeffer Questionnaire for Functional Assessment in Parkinson Disease.
It was proposed to modify the Pfeffer questionnaire (PQ) for functional assessment in patients with Parkinson disease (PD). To determine the cutoff score for diagnosis of functional impairment in patients with PD by modified PQ (mPQ). A total of 110 patients with PD were enrolled into the study, and a neuropsychological test battery was performed to assess their cognitive status. Regarding functional assessment, the mPQ has been applied, and their results were compared to the functional assessment by Informant Questionnaire on Cognitive Decline in the Elderly adapted for use in Brazil (IQCODE-BR). The statistical analysis was accomplished through receiver operating characteristic (ROC) curve with evaluation of the area under the curve, sensitivity, and specificity of the new cutoff point. Eighty-nine patients with PD were evaluated with a mean age of 63.69 ± 9.14 years. Cognitive status categorization was 28.10% as normal, 44.94% as mild cognitive impairment, and 26.96% of patients as dementia associated with PD. The average score on PQ was 3.49 ± 4.79 and on the mPQ 2.56 ± 3.49. In IQCODE-BR, the average score was 6.75 ± 32.72. The ROC curve for the new cutoff point presented 47.4% sensitivity, 88.10% specificity, and 0.757 of area under the curve, with a standard deviation of 0.055 (95% confidence interval: 0.650-0.864). 3.5 is proposed as the cutoff point to define functional impairment in patients with PD by mPQ.


FRAME - reflections on the future and challenges to success.
FRAME is 40 years of age and has contributed much to reasoned debate on the need to use animals in responsible scientific enquiry. It has done this through the promotion of good science as best practice, as well as promotion of the Three Rs of Reduction, Refinement and Replacement of animal experimentation. However, unless the debate widens to question society at large over its attitudes to personal risk, to accepting responsibility rather than apportioning blame, and to its simplistic adoption of regulation as the panacea, we could see the pursuit of the Three Rs degenerate into a formulaic process, leading to imperfect animal models being replaced by imperfect alternatives which would not serve to improve our science. We must not lose sight of the ultimate goal of conducting good science without the need to use animals.


Frontobasal fractures: anatomical classification and clinical significance.
Frontobasal injury is a classic craniomaxillofacial fracture affecting the anterior cranial base. No data exist regarding the degree of frontobasal injury and associated midfacial fractures. The authors propose a classification of frontobasal and midface fractures involving the cranial base based on cadaveric experiments and comprehensive clinical experience. An institutional review board-approved retrospective review was conducted on patients with frontobasal fractures from 1995 to 2005. Fractures were categorized by pattern, location, midfacial involvement (impure), and complications compiled. One hundred five cadaveric heads underwent blunt impact to the frontal bone and upper midface. Calvarial vault, cranial base, and midface fracture patterns were categorized. Three frontobasal fracture patterns were identified. Isolated linear cranial base fractures constitute type I. Vertical-linear fractures of the skull vault (frontal bone) occur in combination with base fractures, representing type II (vault and base). Comminution of the frontolateral skull vault and orbital roof in association with a linear base fracture constitute type III. Two hundred ninety patients were identified with 49 complications (cerebrospinal fistula, 24; and infectious 25). Type III (n = 159) had the highest complication rate (impure, 29 percent; pure, 17 percent), followed by type II (impure, 19 percent; pure, 5 percent). There is essentially no extension of midface fractures to the cranial vault. Frontobasal fractures have three unique and reproducible patterns based on vector, location, and force. This new classification scheme, paired with known patterns of midfacial injuries, assists in fully understanding frontofaciobasal injury and its complications. Overwhelmingly, impure type II and any type III fractures are associated with a high rate of complications and must be carefully managed.


Accuracy of the abdominal examination for identifying children with blunt intra-abdominal injuries.
To determine the accuracy of complaints of abdominal pain and findings of abdominal tenderness for identifying children with intra-abdominal injury (IAI) stratified by Glasgow Coma Scale (GCS) score. This was a prospective, multicenter observational study of children with blunt torso trauma and a GCS score ≥13. We calculated the sensitivity of abdominal findings for IAI with 95% CI stratified by GCS score. We examined the association of isolated abdominal pain or tenderness with IAI and that undergoing acute intervention (therapeutic laparotomy, angiographic embolization, blood transfusion, or ≥2 nights of intravenous fluid therapy). Among the 12 044 patients evaluated, 11 277 (94%) had a GCS score of ≥13 and were included in this analysis. Sensitivity of abdominal pain for IAI was 79% (95% CI, 76%-83%) for patients with a GCS score of 15, 51% (95% CI, 37%-65%) for patients with a GCS score of 14, and 32% (95% CI, 14%-55%) for patients with a GCS score of 13. Sensitivity of abdominal tenderness for IAI also decreased with decreasing GCS score: 79% (95% CI, 75%-82%) for a GCS score of 15, 57% (95% CI, 42%-70%) for a GCS score of 14, and 37% (95% CI, 19%-58%) for a GCS score of 13. Among patients with isolated abdominal pain and/or tenderness, the rate of IAI was 8% (95% CI, 6%-9%) and the rate of IAI undergoing acute intervention was 1% (95% CI, 1%-2%). The sensitivity of abdominal findings for IAI decreases as GCS score decreases. Although abdominal computed tomography is not mandatory, the risk of IAI is sufficiently high that diagnostic evaluation is warranted in children with isolated abdominal pain or tenderness.


Developmental maturation of D-glucose transport by rat jejunal brush-border membrane vesicles.
D-Glucose uptake into jejunal brush-border membrane vesicles was studied in suckling (2-wk-old), weanling (3-wk-old), and adolescent (6-wk-old) rats. The purity of the membrane vesicles from all age groups was validated by the finding that the specific activity of brush-border enzyme markers was severalfold greater in membrane vesicles compared with corresponding values in mucosal homogenate. D-Glucose uptake was inversely related to increasing medium osmolality, indicating that uptake of D-glucose was into the intravesicular space rather than binding. D-Glucose uptake was sodium dependent at all age groups; however, the initial uptake at 20 s was significantly greater in adolescent rats compared with suckling rats. The addition of valinomycin to KCl-preincubated vesicles in the presence of Na+ gradient resulted in a severalfold increase in D-glucose initial uptake over Na+ gradient alone, indicating that D-glucose uptake was electrogenic at all age groups. To delineate the mechanism for the decrease in the initial uptake in suckling rats, two experiments were performed: 1) an exchange tracer study that indicated the activity of D-glucose-Na+ transporters was similar in suckling and adolescent rats, and 2) a study that indicated 22Na uptake, as an indicator for Na+ permeability, was significantly greater in suckling rats compared with adolescent rats. These findings suggest that a Na+-dependent, electrogenic D-glucose uptake is already developed in the suckling period; however, because of the increased permeability to Na+, the Na+ gradient dissipates faster, resulting in a decrease in initial uptake.


Sphericity index and E-point-to-septal-separation (EPSS) to diagnose dilated cardiomyopathy in Doberman Pinschers.
E-point-to-septal-separation (EPSS) and the sphericity index (SI) are echocardiographic parameters that are recommended in the ESVC-DCM guidelines. However, SI cutoff values to diagnose dilated cardiomyopathy (DCM) have never been evaluated. To establish reference ranges, calculate cutoff values, and assess the clinical value of SI and EPSS to diagnose DCM in Doberman Pinschers. One hundred seventy-nine client-owned Doberman Pinschers. Three groups were formed in this prospective longitudinal study according to established Holter and echocardiographic criteria using the Simpson method of disk (SMOD): control group (97 dogs), DCM with echocardiographic changes (75 dogs) and "last normal" group (n = 7), which included dogs that developed DCM within 1.5 years, but were still normal at this time point. In a substudy, dogs with early DCM based upon SMOD values above the reference range but still normal M-Mode measurements were selected, to evaluate if EPSS or SI were abnormal using the established cutoff values. ROC-curve analysis determined <1.65 for the SI (sensitivity 86.8%; specificity 87.6%) and >6.5 mm for EPSS (sensitivity 100%; specificity 99.0%) as optimal cutoff values to diagnose DCM. Both parameters were significantly different between the control group and the DCM group (P < 0.001), but were not abnormal in the "last normal" group. In the substudy, EPSS was abnormal in 13/13 dogs and SI in 2/13 dogs. E-point-to-septal-separation is a valuable additional parameter for the diagnosis of DCM, which can enhance diagnostic capabilities of M-Mode and which performs similar as well as SMOD.


A characterization of the immunosuppressive activity of adriamycin and daunomycin on humoral antibody production and tumor allograft rejection.
The effects of adriamycin (AM) and its analog daunomycin (DM) on immunological responsiveness have been investigated in an effort to elucidate whether a differential interaction of the two drugs with the immune system could play a role in the higher antineoplastic activity of AM. It was found that AM induced a greater reduction in the number of antibody-producing cells after primary stimulation with sheep erythrocytes, whereas DM was more suppressive on the secondary response to the same antigen. Primary reactivity to the T-independent antigen S-III was reduced by AM, whereas DM was ineffective in the same conditions even at high doses. In addition, when a tumor allograft model was investigated, DM was significantly more immunosuppressive than was AM administered at equitoxic doses. In contrast, these agents displayed similar activity in reducing bone marrow stem cells and in inhibiting DNA synthesis in this organ. The possibility that the different immunosuppressive capacity of AM and DM contributes to the greater antitumoral activity of the former is advanced.


Evaluation of children with chronic cough including obstructive sleep apnea: a single-center experience.
Chronic cough in children may be due to a diverse range of etiologies. We aimed to evaluate children with chronic cough following a standardized cough algorithm and assess obstructive sleep apnea (OSA) as a possible etiology. In addition, cough resolution rates of two different treatment protocols in children with non-specific cough were compared. A total of 237 children referred for chronic cough were assessed and classified according to etiologies. Children with non-specific cough were assigned either in the early-arm (group-1, n = 13) or delayed arm (group-2, n = 23). The presence of OSA was evaluated using a pediatric sleep questionnaire, and polysomnography was handled in indicated patients. Asthma (n = 82) and protracted bacterial bronchitis (PBB) (n = 73) were the most frequent etiologies. Cough resolution was higher in group-1 (100%) compared with group-2 (50%) (absolute risk reduction (rr) = 43.48% [95% CI 21.38-65.58%]). Polysomnography revealed mild (n = 6), moderate (n = 7), or severe (n = 5) OSA in 18 children, with adenoid/adenotonsillary hypertrophy as the leading cause.Conclusion: We recognized asthma and PBB as the most frequent causes of chronic cough in our cohort. Early treatment of patients with high parental anxiety might be beneficial. We also believe that further studies including larger series might eventuate in incorporation of assessment of OSA to standardized algorithms. What is known? • Chronic cough in children may be due to a diverse range of etiologies, including serious respiratory disorders. Thus, its correct diagnosis and treatment are essential. • Although a well-defined reason of chronic cough in adults, obstructive sleep apnea (OSA) has not been been evaluated so far in children with chronic cough. What is new? • We examined OSA for the first time as a possible cause of chronic cough in children and detected OSA with polysomnography in cases who scored high pediatric sleep questionnaire (PSQ) scores. • We believe that studies including larger series might eventuate in incorporation of assessment of OSA to standardized algorithms for children with chronic cough.


Calciphylaxis in a patient with hypoparathyroidism and MEN-1 syndrome.
Calciphylaxis is a rare disorder characterised by the development of painful necrotic skin lesions. Occlusion of cutaneous arterioles due to ectopic calcification leads to potentially life-threatening widespread skin loss. Most cases occur in patients with chronic renal disease, which leads to dysregulation of calcium and phosphate homeostasis. Only a handful of case reports exist describing calciphylaxis occurring in patients without chronic renal disease but with hypoparathyroidism. We report on a unique case of a 53-year-old man with multiple endocrine neoplasia type 1 syndrome and acquired hypoparathyroidism due to total parathyroidectomy who went on to develop calciphylaxis following cardiac surgery. Calciphylaxis most commonly occurs in the context of chronic renal disease but can rarely occur in its absence as a consequence of calcium and phosphate dysregulation. Patients who develop necrotic skin lesions in the presence of hypoparathyroidism require an urgent dermatological opinion. Mortality from calciphylaxis is high, with the majority of deaths occurring secondary to sepsis. Management of calciphylaxis requires a multidisciplinary team approach to manage wound healing, infections and pain. Recovery with full rehabilitation from calciphylaxis can take months to years.


Predictive factors for secondary intensive care unit admission within 48 hours after hospitalization in a medical ward from the emergency room.
Unplanned transfer to an ICU within 48 hours of admission from the emergency department (ED) can be considered an adverse event. Screening at risk for such an event is a challenge for ED staff. Our purpose was to identify the clinical and biological variables which may be identified in the ED setting and can predict short-term unplanned secondary transfer to the intensive care setting. This was a three-year retrospective case controlled monocentric study. The cases were patients transferred to a medical ICU within 48 hours of admission to the general wards from the ED. Each case was matched to two controls (patients not transferred to the ICU) based on age, gender, year of admission, and hospital unit. A conditional logistic regression was performed. Three hundred nineteen patients, including 107 cases and 212 controls, were studied. Community-acquired pneumonia (CAP) was the most frequent diagnosis (23% of cases) followed by sepsis (16%). We identified six predictive factors of an unplanned short-term transfer to the ICU. Former smoking status, fever between 38°C and 40°C, dyspnea as the chief complaint in the ED, a lower MEDS score, an elevated acute physiology age chronic health evaluation score, and the ordering of an arterial blood gas each correlate with secondary transfer to an intensive care setting. We report a higher risk of short-term unscheduled ICU transfer in patients meeting these criteria. These patients should be closely monitored and frequently re-evaluated before being transferred to a general ward.


USBDAN: Unsupervised Scale-aware and Boundary-aware Domain Adaptive Network for Gastric Tumor Segmentation.
Accurate segmentation of gastric tumors from computed tomography (CT) images provides useful image information for guiding the diagnosis and treatment of gastric cancer. Researchers typically collect datasets from multiple medical centers to increase sample size and representation, but this raises the issue of data heterogeneity. To this end, we propose a new cross-center 3D tumor segmentation method named unsupervised scale-aware and boundary-aware domain adaptive network (USBDAN), which includes a new 3D neural network that efficiently bridges an Anisotropic neural network and a Transformer (AsTr) for extracting multi-scale features from the CT images with anisotropic resolution, and a scale-aware and boundary-aware domain alignment (SaBaDA) module for adaptively aligning multi-scale features between two domains and enhancing tumor boundary drawing based on location-related information drawn from each sample across all domains. We evaluate the proposed method on an in-house CT image dataset collected from four medical centers. Our results demonstrate that the proposed method outperforms several state-of-the-art methods.


Wheat dependent exercise induced anaphylaxis: is this an appropriate terminology?
The presentation of wheat dependent exercise induced anaphylaxis (WDEIA) can be variable. A high index of clinical suspicion is required to initiate the investigation pathway. Double blind placebo controlled food-exercise challenge is the gold standard investigation but the practicality of this test limits its application. To critically analyse the symptoms of WDEIA and their correlation with serum specific IgE (sIgE) to romega-5-gliadin. 17 patients were tested for serum sIgE to romega-5-gliadin. The clinical response to a diet/exercise intervention protocol was used to assess specificity of a positive sIgE to romega-5-gliadin. Length of time to diagnosis, clinical likelihood scores, exercise intensity involved and the severity of allergic reactions were examined retrospectively. 8/10 patients with positive sIgE to romega-5-gliadin had a confirmed diagnosis of WDEIA. Half of the WDEIA patients had a prolonged time lag to diagnosis (32-62 months) and were initially diagnosed with idiopathic anaphylaxis or chronic idiopathic urticaria and angioedema. Only three patients had experienced life threatening symptoms (Mueller grading 4). A close association was observed between requirements of lower exercise intensity to provoke a reaction and diagnostic delay. Specific IgE to romega-5-gliadin can provide supportive evidence for WDEIA without the need of a food-exercise challenge. The wheat-exercise association is not obvious in many patients, highlighting the need to consider WDEIA in the differential diagnosis of all patients presenting with idiopathic systemic reactions. The term anaphylaxis may be inappropriate and it is therefore worth considering an alternative terminology such as 'activity dependent wheat allergy' to describe this condition.


Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats.
To investigate whether activation and translocation of extracellular signal-regulated kinase (ERK) is involved in the induction and maintenance of neuropathic pain, and effects of activation and translocation of ERK on expression of pCREB and Fos in the chronic neuropathic pain. Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciaticaos trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered every 12 h, 1 d pre-chronic constriction injury (CCI) and 3 d post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The expression of pERK, pCREB, and Fos were assessed by both Western blotting and immunohistochemical analysis. Intrathecal injection of U0126 or ERK antisense ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of p-ERK-IR neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK expression showed that the levels of both cytosol and nuclear pERK, but not total ERK, were increased at all points after CCI and reached a peak level on postoperative d 5. CCI also significantly increased the expression of pCREB and Fos. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord and Fos was expressed in laminae I and II of the ipsilateral spinal dorsal horn. Intrathecal injection of U0126 or ERK antisense ODN markedly suppressed the increase of CCI-induced pERK, pCREB and c-Fos expression in the spinal cord. The activation of ERK pathways contributes to neuropathic pain in CCI rats, and the function of pERK may partly be accomplished via the cAMP response element binding protein (CREB)-dependent gene expression.


Error-free continuously-tunable delay at 10 Gbit/s in a reconfigurable on-chip delay-line.
A coupled-resonator optical waveguide (CROW) consisting of a chain of directly coupled ring-resonators (RRs) fabricated in 4.5%-indexcontrast silicon oxynitride technology is employed to control the delay of optical pulses with continuity and over several bit-slots. The moderate deterioration of the signal quality versus the delay is demonstrated by the observation of error-free transmission (BER < 10(-9)) at 10 Gbit/s for fractional delays of up to 3 bits, with fractional losses below 1 dB per bit-delay. The high storage efficiency of the device, exceeding 0.5 bit/RR, enables an easy management of the delay and the reduction of the footprint down to 7 mm(2). The presented reconfiguration scheme is hitless with respect to data transmission, since the CROW delay can be tuned without halting the data flow, while preserving the signal quality.


Contemporary anesthesia management for liver transplantation: a comparison of American and European methods.
This review article compares the organization of liver transplantation programs, anesthesia management and postoperative care in the United States and Europe. Liver transplantation is a definitive treatment for end-stage liver disease. The procedure is extremely complex and requires excellent surgical technique and experienced anesthesiologists who are able to provide precise management. Liver transplantation programs, which first started in the United States and a few years later in Europe, have quickly been able to achieve remarkable results. In the United States one organization, the United Network for Organ Sharing (UNOS) is responsible for the allocation of organs and data collection; in Europe there are various organizations with different levels of cooperation. The major difference between anesthesia management in the United States and Europe is the number of medications available for coagulation improvement. Substances such as prothrombin complex concentrate, fibrinogen, and antithrombin III allow for a greater flexibility in European anesthesia management. Thromboelastography, which is routinely used in the United States for overseeing coagulation, is now increasingly being used in Europe, and seems to be highly effective in providing precise information about coagulation. The overall ICU stay in Europe is longer than in the United States, and services such as maintenance of critical care, immunosuppression and nutrition are not separated in Europe. Despite these differences in liver transplantation programs, overall one-year patient survival rate is similar in the United States and in Europe, exceeding 85% in both.


Maraba virus as a potent oncolytic vaccine vector.
The rhabdovirus Maraba has recently been characterized as a potent oncolytic virus. In the present study, we engineered an attenuated Maraba strain, defined as MG1, to express a melanoma-associated tumor antigen. Its ability to mount an antitumor immunity was evaluated in tumor-free and melanoma tumor-bearing mice. Alone, the MG1 vaccine appeared insufficient to prime detectable adaptive immunity against the tumor antigen. However, when used as a boosting vector in a heterologous prime-boost regimen, MG1 vaccine rapidly generated strong antigen-specific T-cell immune responses. Once applied for treating syngeneic murine melanoma tumors, our oncolytic prime-boost vaccination protocol involving Maraba MG1 dramatically extended median survival and allowed complete remission in more than 20% of the animals treated. This work describes Maraba virus MG1 as a potent vaccine vector for cancer immunotherapy displaying both oncolytic activity and a remarkable ability to boost adaptive antitumor immunity.


Defining the appropriate use of community hospital beds.
Patients of GPs who have access to community hospitals (CHs) as well as district general hospitals (DGHs) tend to spend on average more days in hospital each year. Increasing attention is being paid to the efficient management of medical admissions; however, there has been no previous prospective study investigating the appropriateness of CH admissions. To develop a protocol to assess the clinical appropriateness of admission and length of stay of patients in CHs and to simultaneously compare the appropriateness of admissions to all DGHs and CHs in the county. A protocol named Community Hospital Appropriateness Evaluation Protocol (CHAEP) was developed to assess CH admissions through a process of consultation and a series of pilot studies. The appropriateness evaluation protocol (AEP) was also reviewed and used to assess DGH admissions. A prospective cohort of 440 DGH admissions from five DGH sites and 440 CH admissions from nine CHs. The admissions were assessed and followed for 28 days. If an admission failed to satisfy any of the criteria then the researcher interviewed the clinician to decide whether it was justified to override the protocol and still classify the admission as appropriate. To assess validity, a proportion of these 'clinical overrides' and the researcher's classifications were reviewed retrospectively by a clinical panel. The kappa statistic was used to assess the level of agreement. Applying the CHAEP, 82% of CH admissions satisfied a criterion for admission and a further 3% were given clinical overrides. A lower intensity of care was required for the majority of the remainder while three admissions required DGH care according to AEP criteria. Sixty-eight per cent of bed days satisfied day-of-care criteria within CHAEP and only a further 2% were given clinical override. These results were similar to those found with the AEP at the DGHs where 75% of admissions (plus 16% given clinical override) and 55% of days-of-care (plus 20% given clinical override) satisfied the AEP criteria. The review panel generally did not agree with the clinician's use of the clinical override at the CHs. Agreement between research nurse and review panel was better for the AEP and DGH (kappa = 0.9, 95% confidence interval (CI) = 0.7-1.0) than for the CHAEP and CH (kappa = 0.37, 95% CI = 0.1-0.8). The CHAEP could be used to audit the appropriateness of admission and length of stay in CHs. Other health communities would need to review the CHAEP before it could be applied within their context.