Positive Aspects of Caregiving Are Associated With Lower Risk of Frailty and Sleep Disruption in the National Study of Caregiving.
Older adult caregivers have compounded risk for adverse health outcomes; however, evidence investigating the association between caregiving and frailty has been limited. In the National Study of Caregiving (NSOC), we examined the cross-sectional association between caregiving experiences and frailty and sleep disruption. We included 621 caregivers aged 65 and older from the 2011 NSOC round. They completed a phone interview, including 36 items about caregiving. Using principal component analysis, we identified 3 caregiving components: general burden, positive emotions, and financial-led burden. Frailty was assessed via low energy, shrinking, weakness, reduced activity, and poor self-rated health. Sleep disruption was assessed with 2 questions regarding sleep interruption and trouble falling back asleep. In models adjusted for age, sex, education, depression and anxiety symptoms, and medical conditions, positive emotions were associated with a reduced relative risk of frailty (relative risk [RR] = 0.94, 95% confidence interval [CI] 0.90, 0.99) while general burden (proportional odds ratio [POR] = 1.96, 95% CI 1.30, 2.93) and financial-led burden (POR = 1.94, 95% CI 1.22, 3.06) were associated with sleep interruption. Caregiver burden was associated with increased frailty and sleep interruption. Positive emotions were associated with decreased frailty risk. Interventions aimed at reducing the burden and increasing positive emotions in caregivers may improve frailty outcomes.


The kinetics of glomerular deposition of nephritogenic IgA.
Whether IgA nephropathy is attributable to mesangial IgA is unclear as there is no correlation between intensity of deposits and extent of glomerular injury and no clear mechanism explaining how these mesangial deposits induce hematuria and subsequent proteinuria. This hinders the development of a specific therapy. Thus, precise events during deposition still remain clinical challenge to clarify. Since no study assessed induction of IgA nephropathy by nephritogenic IgA, we analyzed sequential events involving nephritogenic IgA from IgA nephropathy-prone mice by real-time imaging systems. Immunofluorescence and electron microscopy showed that serum IgA from susceptible mice had strong affinity to mesangial, subepithelial, and subendothelial lesions, with effacement/actin aggregation in podocytes and arcade formation in endothelial cells. The deposits disappeared 24-h after single IgA injection. The data were supported by a fluorescence molecular tomography system and real-time and 3D in vivo imaging. In vivo imaging showed that IgA from the susceptible mice began depositing along the glomerular capillary from 1 min and accumulated until 2-h on the first stick in a focal and segmental manner. The findings indicate that glomerular IgA depositions in IgAN may be expressed under the balance between deposition and clearance. Since nephritogenic IgA showed mesangial as well as focal and segmental deposition along the capillary with acute cellular activation, all glomerular cellular elements are a plausible target for injury such as hematuria.


Metabolizable energy value of meat and bone meal for pigs.
Metabolizable energy and N-corrected ME (MEn) values of 12 samples of meat and bone meal (MBM) were determined using 288 barrows with an average BW of 35 +/- 3.1 kg. For each of 12 MBM samples, diets were formulated by substituting 0, 50, or 100 g/kg MBM (as-fed basis) in a basal 170 g of CP/kg corn-soybean meal diet; corn and soybean meal were adjusted at the same ratio to account for the substitution. Each diet was fed to eight barrows in individual metabolism crates in metabolism studies that used a 5-d acclimation, which was followed by a 5-d period of total, but separate, collection of feces and urine. The GE, CP, crude fat (CF), ash, Ca, and P contents of the MBM samples, per kilogram (DM basis), ranged from 3,493 to 4,732 kcal, 496.7 to 619.1 g, 91.1 to 151.2 g, 200.3 to 381.9 g, 54.3 to 145.8 g, and 25.6 to 61.7 g, respectively. For each of the 12 MBM samples, MBM intake and MBM contribution to ME and MEn increased linearly (P < 0.05) with increasing level of MBM in the diets. The ME and MEn content of each of the MBM samples was calculated from the slope of the regression of MBM contribution (in kilocalories) to ME and MEn intake, respectively, against quantity (in kilograms) of MBM intake. The ME and MEn of the 12 MBM samples ranged from 1,569 to 3,308 kcal/kg DM and 1,474 to 3,361 kcal/kg DM, respectively. The variation in ME was described by the regression equation: ME = 6,982 + 0.283 GE (kcal/kg) - 6.26 CP (g/kg) - 3.75 CF (g/kg) + 129.47 P (g/kg) - 54.91 Ca (g/kg) - 6.57 ash (g/kg), with an R2 of 0.612 and SD of 376. For MEn, the corresponding equation was: MEn = 3,937 + 1.089 GE (kcal/kg) - 8.74 CP (g/kg) + 3.58 CF (g/kg) + 60.89 P (g/kg) - 15.92 Ca (g/kg) - 9.57 ash (g/kg), with an R2 of 0.811 and SD of 314. Simpler regression equations describing variation in ME or MEn were 9,254 - 7.41 CP (g/kg) - 9.41 ash (g/kg), with R2 of 0.504 and SD of 278; or 12,504 - 10.71 CP (g/kg) - 13.44 ash (g/kg), with R2 of 0.723 and SD of 249. Pearson correlation analysis indicated that the variations in ME and MEn of the MBM samples were not related to any of the major chemical components. The results indicated that variation in each of the chemical components of MBM alone is not the sole determinant of ME or MEn content of MBM, but that the interactions among these components influence energy use in MBM for pigs.


Suppression of ammonia-induced swelling by aspartate but not by ornithine in primary cultures of rat astrocytes.
Cerebral edema with a rise in intracranial pressure is the hallmark of fulminant hepatic failure (FHF) and acute hyperammonemic (HA) states and is characterized by a poor survival rate. Astrocytes are the cells in brain which are swollen in these conditions. Several hypotheses have been proposed to explain the mechanism of cerebral edema in FHF and treatment strategies have evolved based on these putative mechanisms. Treatment with a mixture of ornithine and aspartate has been proven to be clinically beneficial as it reduces edema and improves the neurological status. It has been suggested that these two amino acids generate the glutamate required for the synthesis of glutamine and that they also enhance urea synthesis in surviving hepatocytes in FHF and HA. Presently, we report that of these two amino acids, only aspartate is effective in suppressing ammonia-induced swelling in primary cultures of astrocytes, while ornithine is ineffective. These results are discussed in relation to the metabolism of aspartate and ornithine in astrocytes, with an emphasis on glutamine synthesis and the malate-aspartate shuttle (MAS). We propose that the ability of aspartate to generate glutamate in the cytosol for glutamine synthesis and oxaloacetate in mitochondria to support the citric acid cycle play a role in its ability to reduce ammonia-induced swelling in astrocytes.


[Surgical resection for gastric cancer patients with liver metastasis].
Objective: To explore the surgical results and clinicopathological features of gastric cancer patients with liver metastases. Methods: The clinicopathological data and post-operative survival of 37 patients who underwent resection of liver metastasis from gastric cancer at our department from Dec. 2007 to Dec. 2014 were analyzed. Results: The 1-, 3-, and 5-year overall survival rates after resection were 91.4%, 57.9%, and 22.0%, respectively, with a median survival of 37 months. Univariate analysis revealed that lymph node metastasis, multiple hepatic metastases and no preoperative chemotherapy are unfavorable prognostic factors for overall survival. Multivariate analysis identified that lymph node metastasis and number of liver metastasis are independent prognostic factors. Conclusions: Gastric cancer patients with a solitary liver metastasis may be good candidates for gastric D2 resection combined with liver R0 resection.


Neurexophilins form a conserved family of neuropeptide-like glycoproteins.
Neurexophilin was discovered as a neuronal glycoprotein that is copurified with neurexin Ialpha during affinity chromatography on immobilized alpha-latrotoxin (Petrenko et al., 1996). We have now investigated how neurexophilin interacts with neurexins, whether it is post-translationally processed by site-specific cleavage similar to neuropeptides, and whether related neuropeptide-like proteins are expressed in brain. Our data show that mammalian brains contain four genes for neurexophilins the products of which share a common structure composed of five domains: an N-terminal signal peptide, a variable N-terminal domain, a highly conserved central domain that is N-glycosylated, a short linker region, and a conserved C-terminal domain that is cysteine-rich. When expressed in pheochromocytoma (PC12) cells with a replication-deficient adenovirus, neurexophilin 1 was rapidly N-glycosylated and then slowly processed to a smaller mature form, probably by endoproteolytic cleavage. Similar expression experiments in other neuron-like cells and in fibroblastic cells revealed that N-glycosylation of neurexophilin 1 occurred in all cell types tested, whereas proteolytic processing was observed only in neuron-like cells. Finally, only recombinant neurexin Ialpha and IIIalpha but not neurexin Ibeta interacted with neurexophilin 1 and were preferentially bound to the processed mature form of neurexophilin. Together our data demonstrate that neurexophilins form a family of related glycoproteins that are proteolytically processed after synthesis and bind to alpha-neurexins. The structure and characteristics of neurexophilins indicate that they function as neuropeptides that may signal via alpha-neurexins.


Autonomic nervous system dysfunction and serum levels of neurotoxic and neurotrophic cytokines in patients with cobalamin deficiency.
The imbalance between neurotoxic cytokine tumor necrosis factor-α (TNF-α) and neurotrophic cytokines epidermal growth factor (EGF) and interleukin-6 (IL-6) plays a role in the pathogenesis of cobalamin (Cbl) deficiency-induced neuropathy. The aim of this study was to evaluate autonomic nervous system dysfunction and to look for any relationship between autonomic nervous system disturbances and serum cytokine levels (TNF-α, EGF, IL-6) in patients with Cbl deficiency. Serum levels of TNF-α, EGF and IL-6 were studied in patients with Cbl deficiency (n=41) and a healthy control group (n=17) and after 3 months in patients who underwent Cbl replacement therapy (n=22). All patients with Cbl deficiency underwent electrophysiological studies (EPS) for the diagnosis of neuropathy. Statistical analysis was performed using SPSS for Windows 11.5 software. With EPS, 29 of 41 Cbl-deficient patients (70.73%) demonstrated neurological dysfunction [3 (7.32%), 19 (46.34%) and 7 (17.07%) patients with sensorimotor peripheral neuropathy, parasympathetic, and sympathetic autonomic dysfunction, respectively]. Although there was no significant difference in serum levels of EGF and IL-6 between patients with versus without autonomic dysfunction, levels were significantly lower in Cbl- deficient patients than healthy controls. Presence of autonomic dysfunction seems to be a frequent neurological finding in patients with Cbl deficiency. However, we could not find any relationship between serum cytokine levels and autonomic dysfunction by EPS.


[A new disposable, self-retaining, single-bladed vaginal speculum (author's transl)].
A new, disposable vaginal speculum has been tested clinically. It consists of a thin, elastic plastic sheet which, rolled into the shape of a narrow tube, can be introduced into the vagina. Due to its inherent elasticity, it unfolds and allows examination of the cervix uteri. Of 507 patients investigated using this disposable speculum, cervical examination could be performed in 96%. In a comparative group of 138 patients using the usual metal speculum of Cusco, cervical examination was possible in 100%. The plastic speculum, developed for use in cancer screening tests, is suitable for routine vaginal examination after a little practice in the introduction technique.


Regulation of apoptosis and differentiation by p53 in human embryonic stem cells.
The essentially infinite expansion potential and pluripotency of human embryonic stem cells (hESCs) makes them attractive for cell-based therapeutics. In contrast to mouse embryonic stem cells (mESCs), hESCs normally undergo high rates of spontaneous apoptosis and differentiation, making them difficult to maintain in culture. Here we demonstrate that p53 protein accumulates in apoptotic hESCs induced by agents that damage DNA. However, despite the accumulation of p53, it nevertheless fails to activate the transcription of its target genes. This inability of p53 to activate its target genes has not been observed in other cell types, including mESCs. We further demonstrate that p53 induces apoptosis of hESCs through a mitochondrial pathway. Reducing p53 expression in hESCs in turn reduces both DNA damage-induced apoptosis as well as spontaneous apoptosis. Reducing p53 expression also reduces spontaneous differentiation and slows the differentiation rate of hESCs. Our studies reveal the important roles of p53 as a critical mediator of human embryonic stem cells survival and differentiation.


Pulse sequence considerations for quantification of pyruvate-to-lactate conversion kPL in hyperpolarized 13 C imaging.
Hyperpolarized 13 C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, kPL , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID-Delay,Crush /kPL,FID-Delay = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% kPL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum-TE version (kPL,FID-Delay /kPL,FID = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δωlactate /Δωpyruvate = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T2 *, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin-echo sequence that includes spin-echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE /kPL,FID = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL . The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies.


The age estimation practice related to illegal unaccompanied minors immigration in Italy.
The migrants arrived to the Italian coasts in 2016 were 181.436, 18% more than the previous year and 6% more than the highest number ever since. An "unaccompanied minor" (UAM) is a third-country national or a stateless person under eighteen years of age, who arrives on the territory of the Member State unaccompanied by an adult responsible for him/her whether by law or by the practice of the Member State concerned, and for as long as he or she is not effectively taken into the care of such a person; it includes a minor who is left unaccompanied after he/she entered the territory of the Member States. As many as 95.985 UAMs applied for international protection in an EU member country just in 2015, almost four times the number registered in the previous year. The UAMs arrived in Italy were 28.283 in 2016; 94% of them were males, 92% unaccompanied, 8% of them under 15; the 53,6% is 17; the individuals between 16 and 17 are instead the 82%. Many of them (50%), 6561 in 2016, escaped from the sanctuaries, thus avoiding to be formally identified and registered in Italy in the attempt to reach more easily northern Europe countries, since The Dublin Regulations (2003) state that the asylum application should be held in the EU country of entrance or where parents reside. The age assessment procedures can therefore be considered as a relevant task that weighs in on the shoulders of the forensic experts with all the related issues and the coming of age is the important threshold. In the EU laws on asylum, the minors are considered as one of the groups of vulnerable persons towards whom Member States have specific obligations. A proper EU common formal regulation in the matter of age estimation procedures still lacks. According to the Italian legal framework in the matter, a medical examination should have been always performed but a new law completely changed the approach to the procedures of age estimation of the migrant (excluding the criminal cases) with a better adherence to the notions and concepts of vulnerability and psychological and social maturity.


Exilibacterium tricleocarpae gen. nov., sp. nov., a marine bacterium from coralline algae Tricleocarpa sp.
A Gram-stain-negative, non-spore-forming, aerobic, curved rod-shaped bacterium, designed strain R142T, was isolated from a coralline algae Tricleocarpa sp. in the Beibu Gulf, China. Optimal growth occurred with 0-0.5 % (w/v) NaCl, at 25 °C and at pH 8. Global alignment based on 16S rRNA gene sequences indicated that strain R142T shared 93.8 % similarity with its closest type strain, Pseudomaricurvus alkylphenolicus KU14GT. Phylogenetic analyses showed that strain R142T forms a distinct branch alongside Maricurvus nonylphenolicus KU41ET, Pseudoteredinibacter isoporae SW-11T, Pseudomaricurvus alkylphenolicus KU14GT, Pseudomaricurvus alcaniphilus MEBiC06469T and Aestuariicella hydrocarbonica SM-6T. The major polar lipids of strain R142T were phosphatidylethanolamine and phosphatidylglycerol. The primary cellular fatty acids were C16 : 0, C16 : 1ω7c, C18 : 1ω7c, C18 : 0 and C14 : 0. The genome DNA G+C ratio was 56.4 mol%. The only detected respiratory quinone was ubiquinone 8. The low 16S rRNA gene sequence similarity and differences in cellular fatty acids readily distinguished strain R142T from all validly published type strains. Strain R142T is therefore suggested to represent a novel species of a new genus, for which the name Exilibacterium tricleocarpae gen. nov., sp. nov. is proposed. The type strain of Exilibacterium tricleocarpae is R142T (=MCCC 1K03816T=KCTC 72138T).


Dose and formulation of azithromycin in mass drug administration studies: a systematic review protocol.
Azithromycin has been given for tropical infectious diseases such as trachoma and yaws by mass drug administration (MDA). As well as controlling the infectious disease in question, MDA may have a beneficial effect in reducing mortality in young children. However, the dose, formulation, frequency and duration of azithromycin used in certain infectious diseases may vary in different studies, and these differences may have impacts on the effectiveness of azithromycin MDA. Furthermore, whether the dose, formulation, frequency and duration are associated with the effectiveness of azithromycin for reducing child mortality-if indeed this effect can be confirmed-remain unknown. In this study, we will investigate whether different strategies such as different dose, formulation, frequency and duration affect the effectiveness of azithromycin MDA on the prevalence of certain infectious diseases or child mortality. A narrative systematic review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be searched. No language restrictions will be applied. All randomised/quasi-controlled trials, observational studies (cross-sectional studies, cohort studies and case-control studies), case series and registered protocols will be considered. Dose, duration, frequency, rounds and formulations of azithromycin used in MDA will be collected and reviewed. The outcomes will be disease prevalence/control in children and child mortality. Data from the individual studies will not be pooled. Formal ethical approval is not required since data will be collected from published studies. This systematic review will be published in a peer-reviewed journal and presented at conference meetings. CRD42018114902.


Effects of layer-by-layer coating on activated carbon electrodes for capacitive deionization.
Recently, the need for obtaining, reusing, or purifying water has become a crucial issue. The capacitive deionization (CDI) method, which is based on the electric double layer (EDL) concept, can be applied to ion adsorption from an aqueous solution. This process is carried out by applying a potential difference to highly porous electrodes while pumping salty solution between them, partially removing the ions present in the solution and keeping them in the surface of the electrodes. The use of coated carbon electrodes with one polyelectrolyte layer, turning them into "soft electrodes" (SEs), has been proved to improve the efficiency of the system with respect to its original configuration. In this work, we investigate the effect on the ion adsorption and the efficiency of the process when implementing the coating technique known as layer-by-layer (LbL) on the electrode. This consists in successively coating the electrode surfaces with polyelectrolyte layers, alternating their charge polarity in each step. We tested the effect of the number of layers deposited, as well as the impact of this technique by using different carbons. We found that the second polyelectrolyte layer adheres more than the first layer, serving as a support or seed when it is not dense and uniformly distributed. In contrast, if the first layer is well adhered, a third layer is needed to observe improvements in adsorption and process efficiency. The adsorption of the polymer layers depends in any instance on the porosity of the carbon.


Prevalence and morphometric features of fossa navicularis on cone beam computed tomography in Turkish population.
The objective of this study is to determine the prevalence and morphometric features of fossa navicularis, a close radiographic anatomic variation of canalis basilaris medianus of the basiocciput, in a Turkish population, using cone beam computed tomography (CBCT). The study group consisted of 723 patients (female: 420, male: 303) having CBCT scans. The patients had no syndromes, history of neurological diseases or surgery in the area of interest. On the images that revealed a fossa navicularis, the depth, length, and width measurements were performed, and were compared to the age and gender of the patients. The shape and number of fossa navicularis were also recorded. Fossa navicularis was identified in 48 (6.6%) patients. Among these patients, 19 were female (4.5% of all female patients), whereas 29 were male (9.6% of all male patients), and their age ranged between 10 and 68 years (mean age: 34.0 ± 18.7). No significant difference was found between genders and age groups in terms of depth, length, and width measurements (p > 0.05). In 39 (5.4%) patients, fossa navicularis presented oval in shape. Even though the prevalence of fossa navicularis was found to be higher than previously reported, it still seems to be rare. Anatomical structure of the fossa navicularis can be studied effectively on CBCT images.


Drug-Induced- or Rheumatic- Valvular Heart Disease in Patients Exposed to Benfluorex?
There is a risk of misdiagnosis between benfluorex-induced VHD and acute rheumatic fever (ARF)-related VHD due to common characteristics of both etiologies. We aimed at estimating the probability for a patient exposed to benfluorex presenting with VHD to have, at the same time, a history of ARF-related VHD. Such epidemiological approach could help at reducing the risk of misdiagnosis. We used INSEE data and related literature as well as various modeling hypotheses to drive and test a formula for calculating the probability of a patient presenting with VHD and a history of benfluorex intake to have a prior history of ARF-related VHD. Different scenarios were estimated by a Markov model on the life course of people born in France between 1940 and 1960. Sensitivity analyses were performed under these scenarios. According to the different scenarios and gender, the probability that a patient born between 1940 and 1960 presenting with VHD and a history of benfluorex intake would have had a prior history of ARF-related VHD varied from 0.2% to 2.7%. The probabilities by the year of birth were as follows: 0.8%-2.7% for a patient born in 1940, < 0.5% in all scenarios for patients born after 1955, and < 0.2% in all scenarios for patients, born in 1960. Our results indicate that the burden of ARF-related VHD is low in the patient population exposed to benfluorex. The probability of ARF related VHD should not be over-estimated in the diagnostic procedure of VHD.


[Impact of single disease payment system on hospital delivery service providers' behavior].
To find out whether single disease payment system would have an impact on hospital delivery service providers' behavior. Zhouzhi County in Shaanxi Province where there was a payment change from fee for service (FFS) to single disease payment in 2007 was selected as the treatment group, and Guangling County in Shanxi Province with FFS was selected as the control group. Using a difference-in-difference (DD) design, this study empirically examined the impact of single disease payment on the cost of hospital delivery and length of stay. The data of 1 050 samples were taken from the hospitalization medical records and list of charges in the hospitals between 2005-11-01 and 2010-12-31. When taking the expense as dependent variable, the estimated value of DD variable was -262.73 with parity, length of stay, delivery mode, and payment controlled, which was significant at the 1‰ level. It indicated that the expense had decreased by 262.73 yuan after single disease payment was introduced. When taking the length of stay as dependent variable, the estimated value of DD variable was 0.53, which was not significant at the 5% level,meaning that the length of stay was not different between single disease payment and FFS. The payment change from FFS to single disease payment has an impact on hospital delivery service providers' behavior. It could make hospitals try their best to reduce the expenses under the price ceiling to avoid paying for the exceeding cost, and it also can restrict induced demand, but it could not motivate hospitals to reduce length of stay. This research provides evidence for policy makers that compared with FFS, single disease payment system is an effective payment method for controlling the expense of hospital delivery under the new cooperative medical scheme (NCMS) and the policy of subsidy for rural hospital delivery (SRHD) .


Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation.
Oval cells are hepatocytic precursors that proliferate in late-stage cirrhosis and that give rise to a subset of human hepatocellular carcinomas. Although liver regeneration typically occurs through replication of existing hepatocytes, oval cells proliferate only when hepatocyte proliferation is inhibited. Transforming growth factor-beta (TGF-beta) is a key inhibitory cytokine for hepatocytes, both in vitro and in vivo. Because TGF-beta levels are elevated in chronic liver injury when oval cells arise, we hypothesized that oval cells may be less responsive to the growth inhibitory effects of this cytokine. To examine TGF-beta signaling in vivo in oval cells, we analyzed livers of rats fed a choline-deficient, ethionine-supplemented (CDE) diet for phospho-Smad2. Phospho-Smad2 was detected in more than 80% of hepatocytes, but staining was substantially reduced in oval cells. Ki67 staining, in contrast, was significantly more common in oval cells than hepatocytes. To understand the inverse relationship between TGF-beta signaling and proliferation in oval cells and hepatocytes, we examined TGF-beta signaling in vitro. TGF-beta caused marked growth inhibition in primary hepatocytes and the AML12 hepatocyte cell line. Two oval cell lines, LE/2 and LE/6, were less responsive. The greater sensitivity of the hepatocytes to TGF-beta-induced growth inhibition may result from the absence of Smad6 in these cells. Our results indicate that oval cells, both in vivo and in vitro, are less sensitive to TGF-beta-induced growth inhibition than hepatocytes. These findings further suggest an underlying mechanism for the proliferation of oval cells in an environment inhibitory to hepatocytic proliferation.


Serum level of Vitamin D is associated with COVID-19 mortality rate in hospitalized patients.
Due to widespread of coronavirus disease 2019 (COVID-19) infection, identification of its risk factors and clinical characteristics are important. The aim of the present study was to assess Vitamin D levels in individuals with severe acute respiratory syndrome coronavirus-19 infection and to report on its potential as a predictive marker. All patients, diagnosed with COVID-19 infection from February 16 to March 21, 2020, and referred to Firoozgar Hospital, Tehran, Iran, were enrolled in this study. Vitamin D analysis was undertaken on patient serum samples using a commercial kit (Pars Azmoon Co., Tehran, Iran). SPSS v. 22 was used for statistical analysis. Vitamin D serum concentration was analyzed in a total of 317 patients whose mean age ± standard deviation was 62.05 ± 15 years and with 62.5% being male. A significant association of Vitamin D level and death was observed. Higher levels of serum Vitamin D had protection against death (odds ratio = 0.955 [95% confidence interval = 0.923-0.988], P = 0.008). As a preliminary study in the Iranian population who suffered COVID-19 disease, we identified that Vitamin D deficiency was associated with a higher death rate and intensive care unit admission.


Calibration of optically trapped nanotools.
Holographically trapped nanotools can be used in a novel form of force microscopy. By measuring the displacement of the tool in the optical traps, the contact force experienced by the probe can be inferred. In the following paper we experimentally demonstrate the calibration of such a device and show that its behaviour is independent of small changes in the relative position of the optical traps. Furthermore, we explore more general aspects of the thermal motion of the tool.


Macrophage and nerve interaction in endometriosis.
Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and nerve fiber infiltration are the two major characteristics of this aberrant immune environment. First, the recruitment of macrophages and their polarization phenotype within the endometriotic lesion have been demonstrated to facilitate the development and maintenance of endometriosis. M1 phenotype of macrophages has the capacity to secrete multiple cytokines for inflammatory response, while M2 macrophage possesses an opposite property that can mediate the process of immunosuppression and neuroangiogenesis. Upon secretion of multiple abnormal signal molecules by the endometriotic lesion, macrophages could alter their location and phenotype. These changes facilitate the accommodation of the aberrant microenvironment and the exacerbation of disease progression. Second, the infiltration of nerve fibers and their abnormal distribution are proved to be involved in the generation of endometriosis-associated pain and inflammatory response. An imbalance in sensory and sympathetic innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis. Although endometriosis creates an inflammatory milieu promoting macrophage infiltration and an imbalanced innervation, interaction between macrophages and nerve fibers in this process remains unknown. The aim of this review is to highlight the role of macrophage and nerve interaction in endometriosis, where macrophage recruitment and neurogenesis can be the underlying mechanism of neuroinflammation and pathogenesis of endometriosis.


Choroideremia: a study of two families.
Choroideremia is a bilateral and progressive chorioretinal degenerative disease of X-linked inheritance. In Taiwan, the disease has rarely been reported. We recently found 8 male patients and 5 female carriers in two Chinese families with choroideremia and studied the clinical, psychophysical and electrophysiological properties of the disease. All patients revealed characteristic fundus and fluorescein angiographic changes in retinal pigment epithelium, and choroidal atrophy of variable extent. The severity of the functional impairments paralleled the fundus changes and the patients' age. However dark adaptation and the visual field were affected earlier than visual acuity and color sensation. In addition, rod cell impairment was found to be more severe than cone cell impairment in the electroretinographic studies. On the other hand, all carriers revealed similar diffuse punctate pigmentary changes and only mild abnormalities in dark adaptation. These findings may suggest that in choroideremia patients the photoreceptor cells are very sensitive to the influence of the choroidal atrophy, and that rod cells may be even more vulnerable than cone cells.


A cell-permeable phosphine-borane complex delays retinal ganglion cell death after axonal injury through activation of the pro-survival extracellular signal-regulated kinases 1/2 pathway.
The reactive oxygen species (ROS) superoxide has been recognized as a critical signal triggering retinal ganglion cell (RGC) death after axonal injury. Although the downstream targets of superoxide are unknown, chemical reduction of oxidized sulfhydryls has been shown to be neuroprotective for injured RGCs. On the basis of this, we developed novel phosphine-borane complex compounds that are cell permeable and highly stable. Here, we report that our lead compound, bis (3-propionic acid methyl ester) phenylphosphine borane complex 1 (PB1) promotes RGC survival in rat models of optic nerve axotomy and in experimental glaucoma. PB1-mediated RGC neuroprotection did not correlate with inhibition of stress-activated protein kinase signaling, including apoptosis stimulating kinase 1 (ASK1), c-jun NH2-terminal kinase (JNK) or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and downstream activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway. Pharmacological inhibition of ERK1/2 entirely blocked RGC neuroprotection induced by PB1. We conclude that PB1 protects damaged RGCs through activation of pro-survival signals. These data support a potential cross-talk between redox homeostasis and neurotrophin-related pathways leading to RGC survival after axonal injury.


Current possibilities of liquid chromatography for the characterization of antibody-drug conjugates.
Antibody Drug Conjugates (ADCs) are innovative biopharmaceuticals gaining increasing attention over the last two decades. The concept of ADCs lead to new therapy approaches in numerous oncological indications as well in infectious diseases. Currently, around 60 CECs are in clinical trials indicating the expanding importance of this class of protein therapeutics. ADCs show unprecedented intrinsic heterogeneity and address new quality attributes which have to be assessed. Liquid chromatography is one of the most frequently used analytical method for the characterization of ADCs. This review summarizes recent results in the chromatographic characterization of ADCs and supposed to provide a general overview on the possibilities and limitations of current approaches for the evaluation of drug load distribution, determination of average drug to antibody ratio (DARav), and for the analysis of process/storage related impurities. Hydrophobic interaction chromatography (HIC), reversed phase liquid chromatography (RPLC), size exclusion chromatography (SEC) and multidimensional separations are discussed focusing on the analysis of marketed ADCs. Fundamentals and aspects of method development are illustrated with applications for each technique. Future perspectives in hydrophilic interaction chromatography (HILIC), HIC, SEC and ion exchange chromatography (IEX) are also discussed.


Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs.
Familial Hypertrophic Cardiomyopathy (HCM) is the most common inherited cardiac disease. About 30% of the patients are heterozygous for mutations in the MYH7 gene encoding the ß-myosin heavy chain (MyHC). Hallmarks of HCM are cardiomyocyte disarray and hypertrophy of the left ventricle, the symptoms range from slight arrhythmias to sudden cardiac death or heart failure. To gain insight into the underlying mechanisms of the diseases' etiology we aimed to generate genome edited pigs with an HCM-mutation. We used TALEN-mediated genome editing and successfully introduced the HCM-point mutation R723G into the MYH7 gene of porcine fibroblasts and subsequently cloned pigs that were heterozygous for the HCM-mutation R723G. No off-target effects were determined in the R723G-pigs. Surprisingly, the animals died within 24 h post partem, probably due to heart failure as indicated by a shift in the a/ß-MyHC ratio in the left ventricle. Most interestingly, the neonatal pigs displayed features of HCM, including mild myocyte disarray, malformed nuclei, and MYH7-overexpression. The finding of HCM-specific pathology in neonatal R723G-piglets suggests a very early onset of the disease and highlights the importance of novel large animal models for studying causative mechanisms and long-term progression of human cardiac diseases.


Aspiration and tetracycline sclerotherapy: a novel method for management of vaginal and vulval Gartner cysts.
Fifteen patients suffering from symptomatic Gartner cysts were subjected to cyst fluid aspiration and 5% tetracycline injection of a similar volume (as that of aspirated cyst fluid) under local analgesia. Twenty-four hours later the injected tetracycline was re-aspirated until the cyst walls collapsed. The procedure was easy, inexpensive, acceptable by all patients with no operative or postoperative complaints or complications and no cyst reformation. This novel technique is an ideal, safe and effective simple office procedure for management of symptomatic Gartner cysts.


Modifying the Power and Performance of 2-Dimensional MoS2 Field Effect Transistors.
Over the past 60 years, the semiconductor industry has been the core driver for the development of information technology, contributing to the birth of integrated circuits, Internet, artificial intelligence, and Internet of Things. Semiconductor technology has been evolving in structure and material with co-optimization of performance-power-area-cost until the state-of-the-art sub-5-nm node. Two-dimensional (2D) semiconductors are recognized by the industry and academia as a hopeful solution to break through the quantum confinement for the future technology nodes. In the recent 10 years, the key issues on 2D semiconductors regarding material, processing, and integration have been overcome in sequence, making 2D semiconductors already on the verge of application. In this paper, the evolution of transistors is reviewed by outlining the potential of 2D semiconductors as a technological option beyond the scaled metal oxide semiconductor field-effect transistors. We mainly focus on the optimization strategies of mobility (μ), equivalent oxide thickness (EOT), and contact resistance (RC ), which enables high ON current (Ion ) with reduced driving voltage (Vdd ). Finally, we prospect the semiconductor technology roadmap by summarizing the technological development of 2D semiconductors over the past decade.


Unveiling the development of intracranial injury using dynamic brain EIT: an evaluation of current reconstruction algorithms.
Dynamic brain electrical impedance tomography (EIT) is a promising technique for continuously monitoring the development of cerebral injury. While there are many reconstruction algorithms available for brain EIT, there is still a lack of study to compare their performance in the context of dynamic brain monitoring. To address this problem, we develop a framework for evaluating different current algorithms with their ability to correctly identify small intracranial conductivity changes. Firstly, a simulation 3D head phantom with realistic layered structure and impedance distribution is developed. Next several reconstructing algorithms, such as back projection (BP), damped least-square (DLS), Bayesian, split Bregman (SB) and GREIT are introduced. We investigate their temporal response, noise performance, location and shape error with respect to different noise levels on the simulation phantom. The results show that the SB algorithm demonstrates superior performance in reducing image error. To further improve the location accuracy, we optimize SB by incorporating the brain structure-based conductivity distribution priors, in which differences of the conductivities between different brain tissues and the inhomogeneous conductivity distribution of the skull are considered. We compare this novel algorithm (called SB-IBCD) with SB and DLS using anatomically correct head shaped phantoms with spatial varying skull conductivity. Main results and Significance: The results showed that SB-IBCD is the most effective in unveiling small intracranial conductivity changes, where it can reduce the image error by an average of 30.0% compared to DLS.


Right ventricular perforation: a rare complication of pulmonary artery catheterization.
A 70 years old male underwent Coronary Artery Bypass and Graft (CABG) surgery. After induction, a Pulmonary Artery Catheter (PAC) was inserted via right IJV with some difficulty in achieving PA tracing. During distal RCA anastomosis, surgeon noticed PAC tip coming out of Right Ventricular (RV) surface. Resistance was felt on trying to pull PAC, so it was left there. Cardiac surgeon then opened the Right Atrium (RA) and pulled out the catheter. Multiple attempts during insertion of PA catheter should always raise the suspicion of PAC tip slipping back into the RV. It should be closely monitored during surgery and communicated to the surgeon.


Anti-apoptotic effect of insulin in the control of cell death and neurologic deficit after acute spinal cord injury in rats.
Recent studies confirmed that the new cell survival signal pathway of Insulin-PI3K-Akt exerted cyto-protective actions involving anti-apoptosis. This study was undertaken to investigate the potential neuroprotective effects of insulin in the pathogenesis of spinal cord injury (SCI) and evaluate its therapeutic effects in adult rats. SCI was produced by extradural compression using modified Allen's stall with damage energy of 40 g-cm force. One group of rats was subjected to SCI in combination with the administration of recombinant human insulin dissolved in 50% glucose solution at the dose of 1 IU/kg day, for 7 days. At the same time, another group of rats was subjected to SCI in combination with the administration of an equal volume of sterile saline solution. Functional recovery was evaluated using open-field walking, inclined plane tests, and motor evoked potentials (MEPs) during the first 14 days post-trauma. Levels of protein for B-cell lymphoma/leukemia-2 gene (Bcl-2), Caspase-3, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified in the injured spinal cord by Western blot analysis. Neuronal apoptosis was detected by TUNEL, and spinal cord blood flow (SCBF) was measured by laser-Doppler flowmetry (LDF). Ultimately, the data established the effectiveness of insulin treatment in improving neurologic recovery, increasing the expression of anti-apoptotic bcl-2 proteins, inhibiting caspase-3 expression decreasing neuronal apoptosis, reducing the expression of proinflammatory cytokines iNOS and COX-2, and ameliorating microcirculation of injured spinal cord after moderate contusive SCI in rats. In sum, this study reported the beneficial effects of insulin in the treatment of SCI, with the suggestion that insulin should be considered as a potential therapeutic agent.


Hypertension and its management: a problem in need of new treatment strategies.
Although treatments of hypertension have significantly decreased morbidity and mortality from cerebrovascular disease, the associated reductions in coronary artery disease have been very disappointing. Hypertension is a complex inherited syndrome of cardiovascular risk factors, all of which contribute to the development of heart disease. Angiotensin II receptor blockers (ARBs), such as the highly selective ARB valsartan, provide an alternative treatment strategy to address the multiple issues in coronary artery disease. These agents are well-tolerated and have a once-daily regimen that improves compliance. They bring multiple cardiovascular benefits beyond blood pressure (BP) control, such as renoprotection and cardiovascular growth reduction.


Relating ocean temperatures to frontal ablation rates at Svalbard tidewater glaciers: Insights from glacier proximal datasets.
Fjord-terminating glaciers in Svalbard lose mass through submarine melt and calving (collectively: frontal ablation), and surface melt. With the recently observed Atlantification of water masses in the Barents Sea, warmer waters enter these fjords and may reach glacier fronts, where their role in accelerating frontal ablation remains insufficiently understood. Here, the impact of ocean temperatures on frontal ablation at two glaciers is assessed using time series of water temperature at depth, analysed alongside meteorological and glaciological variables. Ocean temperatures at depth are harvested at distances of 1 km from the calving fronts of the glaciers Kronebreen and Tunabreen, western Svalbard, from 2016 to 2017. We find ocean temperature at depth to control c. 50% of frontal ablation, making it the most important factor. However, its absolute importance is considerably less than found by a 2013-2014 study, where temperatures were sampled much further away from the glaciers. In light of evidence that accelerating levels of global mass loss from marine terminating glaciers are being driven by frontal ablation, our findings illustrate the importance of sampling calving front proximal water masses.


Disruption of aldo-keto reductase genes leads to elevated markers of oxidative stress and inositol auxotrophy in Saccharomyces cerevisiae.
A large family of aldo-keto reductases with similar kinetic and structural properties but unknown physiological roles is expressed in the yeast Saccharomyces cerevisiae. Strains with one or two AKR genes disrupted have apparently normal phenotypes, but disruption of at least three AKR genes results in a heat shock phenotype and slow growth in inositol-deficient culture medium (Ino(-)). The present study was carried out to identify metabolic or signaling defects that may underlie phenotypes that emerge in AKR deficient strains. Here we demonstrate that pretreatment of a pentuple AKR null mutant with the anti-oxidative agent N-acetyl-cysteine rescues the heat shock phenotype. This indicates that AKR gene disruption may be associated with defects in oxidative stress response. We observed additional markers of oxidative stress in AKR-deficient strains, including reduced glutathione levels, constitutive nuclear localization of the oxidation-sensitive transcription factor Yap1 and upregulation of a set of Yap1 target genes whose function as a group is primarily involved in response to oxidative stress and redox balance. Genetic analysis of the Ino(-) phenotype of the null mutants showed that defects in transcriptional regulation of the INO1, which encodes for inositol-1-phosphate synthase, can be rescued through ectopic expression of a functional INO1. Taken together, these results suggest potential roles for AKRs in oxidative defense and transcriptional regulation.


Screening of factors influencing catheter rotation of a vascular interventional surgical robot using design of experiment approach.
Over the past decades, Vascular Interventional Surgery Robots (VISR) have been developed to address the risks associated with X-rays used in minimally invasive vascular surgery procedures. Manipulation of over-the-wire catheters is necessary to perform complex surgery but requires high forces on the robot's end effector during rotational movements. The VISR under study mimics the physician's fingers by rolling the catheter between two planar surfaces to rotate it. In this study, an experimental set-up is used to replicate this grasping method, also used in other VISR [1, 2]. The parameters of the gripping surfaces are investigated to maximise the torque delivered to the catheter and minimise the forces required at the robot's end-effector. The implemented design of experiment (DOE) demonstrated that large and soft gripping surfaces could achieve this compromise. By adjusting these parameters, sufficient torque can be achieved on the catheter.


Protection of Exogenous Phosphocreatine for Myocardium in Percutaneous Coronary Intervention Related to Inflammation.
Although injury of myocardium after percutaneous coronary intervention (PCI) has been reported, the mechanism and effect of exogenous phosphocreatine (PCr) supplementation on the injury are yet to be elucidated. Biomarkers, such as interleukin-6 (IL-6) and variations in white blood cells for inflammation, and serum cardiac troponin I (cTnI) for myocardial injury are examined. A total of 105 patients undergoing PCI were included and randomly divided into two groups: control (treated with routine hydration therapy) and PCr (treated with additional intravenous infusion of exogenous PCr). The serum levels of biomarkers were detected at administration and 4, 12, 24, and 48 h after PCI, with natural logarithmic (loge) transformation of data when modeling assumptions were not fulfilled. The level of loge-transformed IL-6 increased in both groups, especially at 12 and 24 h after the operation, and that of PCr group was less than the control group at 48 h. The content of loge-transformed cTnI was significantly increased in both groups, while that of the PCr group was markedly lower than the control group at all time points after PCI. Moreover, the ratio of neutrophils was elevated at all time points after PCI, while that of the PCr group was lower at 48 h, and the variations in the ratio of lymphocytes showed opposite results. Exogenous phosphocreatine reduces stent implantation, triggers inflammation manifested as decreased serum levels of IL-6 and the aggregation of neutrophils, and protects the myocardium of the patients undergoing PCI. These findings provided the potential mechanism and treatment for myocardial injury associated with PCI.


Hepatic steatosis and its relationship to transplantation.
Fatty infiltration of the liver is common in the brain-dead donor population and has a strong correlation with primary nonfunction after cold preservation, a condition that is catastrophic to liver transplant recipients. This literature review examines factors associated with the development, diagnosis, quantification, and clinical management of this difficult condition.


Vertebral fractures usually affect the cranial endplate because it is thinner and supported by less-dense trabecular bone.
Cranial endplates of human vertebrae are injured more often than caudal, in both young and elderly spines. We hypothesise that cranial endplates are inherently vulnerable to compressive loading because of structural asymmetries in the vertebrae. Sixty-two "motion segments" (two vertebrae and the intervening disc and ligaments) were obtained post-mortem from thirty-five human spines (17F/18M, age 48-92 yrs, all spinal levels from T8-9 to L4-5). Specimens were compressed to failure while positioned in 2-6 degrees of flexion, and the resulting damage characterised from radiographs and at dissection. 2 mm-thick slices of 94 vertebral bodies (at least one from each motion segment) were cut in the mid-sagittal plane, and in a para-sagittal plane through the pedicles. Microradiographs of the slices were subjected to image analysis to determine the thickness of each endplate at 10 locations. Optical density of the endplates and adjacent trabecular bone was also measured. Measurements obtained in cranial and caudal regions, and in mid-sagittal and pedicle slices, were compared using repeated measures ANOVA with age, level and gender included as between-subject factors. Linear regression was used to determine significant predictors of compressive strength (failure stress). Fracture affected the cranial endplate in 55/62 specimens. Cranial endplates were thinner than caudal (p=0.003) by 14% and 11% on average, in mid-sagittal and pedicle slices respectively. Caudal but not cranial endplates were thicker at lower spinal levels (p=0.01). Optical density of trabecular bone adjacent to the endplates was 6% lower cranially than caudally (p=0.004), and the average optical density of trabecular bone in mid-sagittal slices was 10% lower in women than in men (p=0.025). Vertebral yield stress (mean 2.22 MPa, SD 0.77 MPa) was best predicted by the density of trabecular bone underlying the cranial endplate of the mid-sagittal slice of the fractured vertebra (r(2)=0.67, p=0.0006). When vertebrae are compressed naturally by adjacent intervertebral discs, cranial endplates usually fail before caudal endplates because they are thinner and supported by less dense trabecular bone.


Advances in MRI of the myelin bilayer.
Myelin plays a key role in the function of the central nervous system and is involved in many neurodegenerative diseases. Hence, depiction of myelin is desired for both research and diagnosis. However, MRI of the lipid bilayer constituting the myelin membrane is hampered by extremely rapid signal decay and cannot be accomplished with conventional sequences. Dedicated short-T2 techniques have therefore been employed, yet with extended sequence timings not well matched to the rapid transverse relaxation in the bilayer, which leads to signal loss and blurring. In the present work, capture and encoding of the ultra-short-T2 signals in the myelin bilayer is considerably improved by employing advanced short-T2 methodology and hardware, in particular a high-performance human-sized gradient insert. The approach is applied to tissue samples excised from porcine brain and in vivo in a human volunteer. It is found that the rapidly decaying non-aqueous components in the brain can indeed be depicted with MRI at useful resolution. As a considerable fraction of these signals is related to the myelin bilayer, the presented approach has strong potential to contribute to myelin research and diagnosis.


The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects.
We previously have shown that ingested beef protein is just as potent as glucose in stimulating a rise in insulin concentration in type II diabetic patients. A synergistic effect was seen when given with glucose. Therefore, we considered it important to determine if other common dietary proteins also strongly stimulate an increase in insulin concentration when given with glucose. Seventeen type II (non-insulin-dependent) untreated diabetic subjects were given single breakfast meals consisting of 50 g glucose, or 50 g glucose plus 25 g protein in the form of lean beef, turkey, gelatin, egg white, cottage cheese, fish, or soy. The peripheral plasma concentrations of glucose, insulin, glucagon, alpha amino nitrogen, urea nitrogen, free fatty acids, and triglycerides were measured. Following ingestion of the meals containing protein, the plasma insulin concentration was increased further and remained elevated longer compared with the meal containing glucose alone. The relative area under the insulin response curve was greatest following ingestion of the meal containing cottage cheese (360%) and was least with egg white (190%) compared with that following glucose alone (100%). The glucose response was diminished following ingestion of the meals containing protein with the exception of the egg white meals. The peripheral glucagon concentration was decreased following ingestion of glucose alone and increased following all the meals containing protein. The alpha amino nitrogen concentration varied considerably. It was decreased after glucose alone, was unchanged after egg white ingestion, and was greatest after ingestion of gelatin. The free fatty acid concentration decrease was 4- to 8-fold greater after the ingestion of protein with glucose compared with ingestion of glucose alone.


Plasma exchange for two patients with autoimmune GFAP astrocytopathy with rapid progression to respiratory failure: a case report.
Patients with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy can present with early neurological deterioration, but rapidly progressive respiratory failure is rarely reported. We present the cases of two patients with autoimmune GFAP astrocytopathy who experienced rapid progression to respiratory failure and were effectively treated using plasma exchange therapy. Two patients were diagnosed with autoimmune GFAP astrocytopathy. Their initial symptoms were consistent with those of previously observed cases of autoimmune GFAP astrocytopathy. However, they experienced rapid progression to respiratory failure due to their lesion location. Specifically, case 1 had lesions in the medulla oblongata, and case 2 had lesions in the high cervical spinal cord, which are both common sites of lesions causing respiratory failure. The patients did not respond well to intravenous methylprednisolone and intravenous immunoglobulin initially and could not be withdrawn from ventilator support. Fortunately, subsequent plasma exchange therapy led to significant clinical improvements and successful withdrawal from ventilator support. Patients with autoimmune GFAP astrocytopathy can present with rapidly progressive respiratory failure. Early treatment with plasma exchange can be beneficial in withdrawing patients from ventilator support.


Results, potential effects, and implementation issues of the Resource-Based Relative Value Scale.
This article presents the overall results of the Resource-Based Relative Value Scale (RBRVS) study. We present resource-based relative values for selected services in each of the 18 specialties we studied. We found that preservice and postservice work represents close to 50% of total work for invasive services and 33% of total work for evaluation/management services. We also found that the work per unit time (a measure of intensity) for invasive services is about three times that of evaluation/management. We developed a simple model and simulated an RBRVS-based fee schedule for the Medicare program under a "budget-neutral" assumption. Results for 30 commonly performed services show that office visit fees for evaluation/management services could rise by 70%, while some surgical fees could drop by 60%. We also simulated what the Medicare outlays would have been in 1986 for categories of medical services under an RBRVS-based fee schedule. We found that total Medicare payments for evaluation/management services would have increased by about 56%. Invasive, imaging, and laboratory services would have decreased by 42%, 30%, and 5%, respectively. We also discuss implementation issues related to an RBRVS-based fee schedule, such as the determination of a monetary conversion factor, practice costs, billing codes, and the need to evaluate the potential impacts of an RBRVS-based payment system on the cost and quality of health care.


The three-second "subjective present": A critical review and a new proposal.
It has been argued that there is a "subjective present" or "experienced moment" of about 3 seconds in duration, involving automatic binding of events into perceptual units on that time scale. Research on topics that have been taken as relevant to this proposal is reviewed. The topics include accuracy in reproduction of stimulus durations, synchronization of behavior with a regular beat, mental rhythmization of a regular beat, time units in behavior, segmentation of observed behavior into meaningful units, time scale of reversals of perception with bistable ambiguous figures, time scale of inhibition of return in visual search, and EEG responses to deviant stimuli in series of repeating stimuli. Most of the research findings were not consistent with the 3 s window hypothesis. The small amount of supportive evidence is better interpreted as effects of specific processing mechanisms, not as showing general temporal integration. The evidence shows that temporal integration occurs on multiple time scales and no particular duration is special, and that windows of temporal integration are defined in terms of information density, not in terms of duration. The subjective present is constructed through local temporal integration on multiple time scales, further integrated into a coherent global representation of what is going on. (PsycINFO Database Record


Congenitally corrected transposition of great arteries with severe rhythm disturbances.
Within recent years, much scientific attention has been devoted to adults with congenital heart disease (CHD) and probable complications. Congenitally corrected transposition of the great arteries (CCTGA) is a rare, complex form of congenital heart defects. CCTGA is characterized by atrioventricular (AV) and ventriculoarterial (VA) discordance and, hence, by a physiologically normal direction of blood flow. The development of complete AV block and global ventricular dysfunction has been identified as the cause of cardiac death. Although the development of arrhythmias represents a major cause of morbidity and mortality in patients with CHD, the account of all implantations of pacemakers and implantable cardioverter defibrillators (ICD) is less than one percent. This paper presents a case of CCTGA with severe rhythm disorders, discusses probable treatment options, and offers indications of ICD implantation in patients with CHD.


The prevalence of dental fear and avoidance: expanded adult and recent adolescent surveys.
This study evaluates the current incidence of dental fear and avoidance in a general population of adults and adolescents. Two adult samples were collected. The consisted of 1,882 individuals who were contacted randomly by telephone; the second sample consisted of 357 junior high and secondary school teachers who received a questionnaire. The adolescent sample, also surveyed by questionnaire, consisted of 641 junior high school students and 801 secondary school students. Results indicate that 11.2% to 12.3% of the adults reported high dental fear; 17.5% to 18.2% reported moderate dental fear. Similar rates were found among the adolescents. A major new finding was that more adolescents than adults had not seen a dentist in a year or more.


[Proteins, nucleic acids and acid hydrolases in the chick embryo tail bud].
During the 3d and 4th days of incubation the tail bud displays cell degeneration which result in the complete involution of both postanal gut and primitive streak. In spite of the degenerations the amounts of DNA, RNA and proteins are still growing. Over this period the activities of acid phosphatase and cathepsin are changing. The specific activity of phosphatase reaches a maximum when the tissue resorption is most intensive. The specific activity of cathepsin is then at its lowest level but it has passed earlier through a maximum.


Immediate loading of an implant following implant site development using forced eruption: a case report.
In restoring periodontally involved hopeless teeth, implant treatment has been widely used with combinations of various grafting techniques or guided bone regeneration. Instead of traditional surgical procedures, forced tooth eruption may be used successfully for implant site development. In this case, the authors orthodontically erupted a hopeless central incisor with an angular bony defect. Subsequently, they placed an implant immediately after tooth extraction and immediately loaded it with a temporary resin restoration.


Laser generated guided waves and finite element modeling for the thickness gauging of thin layers.
In this paper, nondestructive testing has been performed on a thin gold layer deposited on a 2 in. silicon wafer. Guided waves were generated and studied using a laser ultrasonic setup and a two-dimensional fast Fourier transform technique was employed to obtain the dispersion curves. A gold layer thickness of 1.33 microm has been determined with a +/-5% margin of error using the shape of the two first propagating modes, assuming for the substrate and the layer an uncertainty on the elastic parameters of +/-2.5%. A finite element model has been implemented to validate the data post-treatment and the experimental results. A good agreement between the numerical simulation, the analytical modeling and the experimentations has been observed. This method was considered suitable for thickness layer higher than 0.7 microm.


Hepatitis B Virus X Protein Stimulates Proliferation, Wound Closure and Inhibits Apoptosis of HuH-7 Cells via CDC42.
Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played by the HBx protein in HBV induced carcinogenesis remains controversial. CDC42, a member of the Rho GTPase family, has been reported to be overexpressed in several different cancers, including HBV-related HCC. However, the specific role of CDC42 in HCC development remains unclear. Here, we investigated the cellular mechanisms by which CDC42 was responsible for the higher proliferation of HuH-7 cells mediated by HBx. We found that the expression level of CDC42 and its activity were significantly increased in HuH-7-HBx cells. The deficiency of CDC42 using the CRISPR/Cas9 system and inhibition by specific inhibitor CASIN led to the reduction of HBx-mediated proliferation. Furthermore, we observed that IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), the downstream mediator of the CDC42 pathway, might be involved in the carcinogenesis induced by HBx. Therefore, the HBx/CDC42/IQGAP1 signaling pathway may potentially play an important role in HBx-mediated carcinogenesis.


[Current issues and future prospects of gastric mass survey].
In general, it is necessary to consider morbidity rate and mortality in the population at risk when mass survey for cancer is performed. From our long-term follow-up study, it is clearly suggested that gastric mass survey contributed toward reducing the mortality from stomach cancer. However, the effectiveness of gastric mass survey depends on the screening system. The screening system with a low grade in its accuracy and reliability may also cause spoil the effectiveness of mass survey.


Long-Term β-Blocker Therapy Decreases Blood Lactate Concentration in Severely Septic Patients.
Measurement of blood lactate concentration in the early management of sepsis is an important step in severity assessment. High blood lactate levels in the early phase of sepsis have classically been thought to be related to tissue hypoxia, but other factors could intervene. We hypothesized that the activation of glycolysis through β-adrenergic stimulation by endogenous catecholamines plays an important role in lactate production and that long-term β-blocker therapy could affect the lactate concentration in patients with severe sepsis and septic shock. Retrospective cohort study. Emergency department. Two hundred sixty patients with severe sepsis or septic shock were included. Twenty-five percent were previously treated with β-blockers. None. We recorded initial vital signs, the source of infection, mortality at 28 days, blood lactate concentration, and Predisposition Insult Response of Organ failure and Sequential Organ Failure Assessment scores using an electronic database. Blood lactate concentration was significantly lower in patients previously treated with β-blockers (3.9 ± 2.3 mmol/L vs 5.6 ± 3.6 mmol/L; p < 0.001). This difference was still significant after controlling for mortality (p < 0.005), for the level of the Predisposition Insult Response of Organ failure (p < 0.05) and Sequential Organ Failure Assessment (p < 0.05) scores, and for the source of infection (p < 0.05). Nearly four times more patients treated with β-blockers had normal blood lactate levels (p< 0.001). Only two factors were significantly and independently associated with normal blood lactate concentration during severe sepsis and septic shock: survival (p = 0.03) and β-blocker therapy (p = 0.01). Long-term β-blocker therapy decreases blood lactate concentration of severely ill septic patients at presentation. We conclude that the use of blood lactate measurement as a triage tool in the initial assessment of septic patients with β-blocker therapy may underestimate the severity of the sepsis.


Panton-Valentine leukocidin is expressed at toxic levels in human skin abscesses.
Pus samples were prospectively collected from patients with Staphylococcus aureus skin infections and tested for Panton-Valentine leukocidin (PVL). PVL was detected at concentrations that were toxic for rabbit skin in all specimens from patients infected with strains harbouring PVL genes.


Superparamagnetic colloids in a rotating field: Transition state from chains to disks.
When exposed to an external magnetic field, 2D layers of spherical superparamagnetic colloids form specific structures which depend on the features of the external field. If the magnetic field is constant along time, superparamagnetic colloids self-organize into chains oriented in the direction of the field. If the magnetic field is rotating in the plane of the suspension, below a critical frequency, the superparamagnetic beads still aggregate into chains, but these chains rotate with the magnetic field. When the rotation reaches a certain speed, the colloids aggregate in rotating disklike clusters. In this work, we focused on the early stages of the disklike clusters' aggregation and the dynamics of this process. In particular, we observed experimentally that before clustering into disklike structures, the colloids were aggregating into rotating chains, just as they did in suspensions submitted to a magnetic field rotating at a lower rate. Over time, the chains interact with one another and aggregate into disklike clusters, resulting in a mixture of chains and disks in the sample. Finally, we propose a model to characterize the suspension over time in terms of the proportion of chains and disklike clusters, and report its deduced temporal evolution for different frequencies and volume fractions.


Ductal carcinoma in situ: biology, diagnosis, and new therapies.
The incidence of ductal carcinoma in situ (DCIS) has markedly increased as a result of the use of screening mammography. Whether DCIS is a premalignant lesion or a cancer remains a cause of debate, but evidence supports the idea that DCIS evolves into invasive breast cancer based on histologic patterns, similar risk factors, and genetic similarities. Microcalcifications identified during mammography generally raise the suspicion of DCIS, and biopsy, often by core needle, confirms such a diagnosis. The extent of disease can be further delineated by breast magnetic resonance imaging. Radiation therapy in breast-conserving treatment, along with tamoxifen, decreases the overall rate of local recurrence in patients with DCIS. Studies in the treatment of DCIS exploring partial breast radiation and trastuzumab are under way. Ongoing investigations with comparative genomic hybridization suggest that there are independent, evolutionary genetic pathways within DCIS. Genome-wide microarray-based gene expression analyses are now providing new opportunities to discover genes that are specifically activated or inactivated during the course of breast cancer progression.


Epithelioid inflammatory myofibroblastic sarcoma: a case report and brief literature review.
Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare variant of the inflammatory myofibroblastic tumor, characterized by more aggressive clinical course and nuclear membrane staining of anaplastic lymphoma kinase (ALK) with ALK rearrangement. An elderly male came to the clinic because of an accidental abdominal mass. Abdominal and pelvic enhanced CT revealed a tumor apparently orginated from mesenchymal tissue. Subsequently, the abdominal mass and multiple organ resection was performed, and the mass was pathologically confirmed as EIMS. The patient developed Clavien-Dindo Grade III postoperative complications and was discharged after his condition improved. He received doxorubicin monotherapy after operation, but only one cycle was administered due to severe vomiting. The follow-up of 5 months after operation showed no evidence of recurrence. Given the rarity of EIMS, and ALk inhibitors have a long and robust effect on patients with ALK gene tumors, it is very important for clinicians to be familiar with the clinicopathological features of EIMS, which will contribute to the accurate diagnosis of EIMS and reduce misdiagnosis.


Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering.
The primary cause of death among chronic diseases worldwide is ischemic cardiovascular diseases, such as stroke and myocardial infarction. Recent evidence indicates that adult stem cell therapies involving cardiovascular regeneration represent promising strategies to treat cardiovascular diseases. Owing to their immunomodulatory properties and vascular repair capabilities, mesenchymal stem cells (MSCs) are strong candidate therapeutic stem cells for use in cardiovascular regeneration. However, major limitations must be overcome, including their very low survival rate in ischemic lesion. Various attempts have been made to improve the poor survival and longevity of engrafted MSCs. In order to develop novel therapeutic strategies, it is necessary to first identify stem cell modulators for intracellular signal triggering or niche activation. One promising therapeutic strategy is the priming of therapeutic MSCs with stem cell modulators before transplantation. Another is a tissue engineering-based therapeutic strategy involving a cell scaffold, a cell-protein-scaffold architecture made of biomaterials such as ECM or hydrogel, and cell patch- and 3D printing-based tissue engineering. This review focuses on the current clinical applications of MSCs for treating cardiovascular diseases and highlights several therapeutic strategies for promoting the therapeutic efficacy of MSCs in vitro or in vivo from cell priming to tissue engineering strategies, for use in cardiovascular regeneration.


PI3K/Akt/mTOR signalling pathway activation in patients with ER-positive, metachronous, contralateral breast cancer treated with hormone therapy.
Oestrogen receptor (ER)-positive, metachronous, contralateral breast cancer (MCBC) sometimes develops during or soon after completion of hormone therapy (HT), but it is uncertain whether it is HT-resistant. We examined the association between ER-positive second cancer and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, which are associated with HT resistance. We examined the treatment-free interval (time after completion of HT for initial cancer) in 41 patients with ER-positive MCBC with a history of adjuvant HT for initial cancer (HT group), and initial-to-second period duration (time after operation of initial cancer to onset of second cancer) in 17 patients with ER-positive MCBC in whom adjuvant HT was not applied to the initial tumour (control group or no HT group). Phosphorylated S6 (pS6) and phosphorylated MAPK (pMAPK) were used as indicators of PI3K/Akt/mTOR and MAPK pathway activity, respectively. Tumours were classified as showing negative, positive or strongly positive staining, and the correlation between staining and treatment-free interval or initial-to-second period duration was evaluated using the Spearman's rank correlation coefficient (ρ). Treatment-free interval and pS6 staining showed a negative correlation (ρ=-0.5355; P=0.0003) in the HT group. There was no correlation between initial-to-second period duration and pS6 staining in the no HT group (ρ=-0.0814; P=0.756). There was no correlation between pMAPK signalling and the treatment-free interval in the HT group (ρ=-0.1560; P=0.330) or the initial-to-second period duration in the no HT group (ρ=-0.0116; P=0.965). Development of a second ER-positive cancer during or soon after completion of HT for the initial cancer may be associated with activation of the PI3K/Akt/mTOR pathway. Care should be taken during follow-up and when selecting adjuvant therapy for second cancer.


Effects of the Oxygen-Carrying Solution OxyVita C on the Cerebral Microcirculation and Systemic Blood Pressures in Healthy Rats.
The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with a high molecular weight (~17 MDa). The large molecular weight is believed to prevent extravasation and limit NO scavenging and vasoconstriction. The aim of this study was to assess vasoactive effects of OxyVita C on systemic blood pressures and cerebral pial arteriole diameters. Anesthetized healthy rats received four intravenous (IV) infusions of an increasing dose of OxyVita C (2, 25, 50, 100 mg/kg) and hemodynamic parameters and pial arteriolar diameters were measured pre- and post-infusion. Normal saline was used as a volume-matched control. Systemic blood pressures increased (P ≤ 0.05) with increasing doses of OxyVita C, but not with saline. There was no vasoconstriction in small (<50 µm) and medium-sized (50-100 µm) pial arterioles in the OxyVita C group. In contrast, small and medium-sized pial arterioles vasoconstricted in the control group. Compared to saline, OxyVita C showed no cerebral vasoconstriction after any of the four doses evaluated in this rat model despite increases in blood pressure.


Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.
On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.


Association of the Asp1312Gly Thyroglobulin Gene Polymorphism with Susceptibility to Differentiated Thyroid Cancer in an Iranian Population
Background and aim: While the causes of thyroid cancer in most patients remain largely unknown, it has recently been reported that there may be links to particular chromosome regions. In particular, polymorphisms (SNPs) in the thyroglobulin (TG) gene could be susceptibility factors. Methods: In this case-control study, any association of the Asp1312Gly single nucleotide polymorphism (SNP) in the TG gene (rs2069556) with susceptibility to differentiated thyroid cancer (DTC) was investigated among 103 Iranian patients and 100 controls who had no history of any type of cancer. Genomic DNA was extracted from the whole blood by salting out procedure. High Resolution Melting (HRM) technique was used to detect this SNP. Results: Data were analyzed with SPSS software and the results showed that the recessive GG genotype was associated with an increased risk of differentiated thyroid carcinoma when compared to the AA+AG genotypes (OR: 2.06; CI: 1.09-3.89; P-value: 0.025). Conclusion: Although our study demonstrated that differentiated thyroid cancer is significantly associated with this polymorphism, further studies with larger populations are required to confirm our findings.


Western blot analysis of serological response in Helicobacter pylori in acid peptic diseases.
A prospective study was undertaken in 70 patients presenting with acid peptic disease with the objective of characterising the serological response to Helicobacter pylori and finding antigens specific for the serodiagnosis of H. pylori infection. H. pylori status was assessed by smear microscopy, rapid urease activity, culture and histopathology of endoscopic gastric antral biopsy specimens. Serological characterisation was carried out by using western blotting of various antigenic components of H. pylori and subsequent enzymatic detection of antibodies against them. Four reactive bands in the molecular weight range of 45-65 kDa were present in all subjects irrespective of H. pylori status. Four to six immunoreactive bands in the molecular weight range of 21-45 kDa were found only in patients with positive H. pylori status and histopathologically proven gastritis. These immunoreactive components may be valuable in specific immunodiagnosis of H. pylori infection.


Performance of Four Commercial Wearable Sleep-Tracking Devices Tested Under Unrestricted Conditions at Home in Healthy Young Adults.
Commercial wearable sleep-tracking devices are growing in popularity and in recent studies have performed well against gold standard sleep measurement techniques. However, most studies were conducted in controlled laboratory conditions. We therefore aimed to test the performance of devices under naturalistic unrestricted home sleep conditions. Healthy young adults (n = 21; 12 women, 9 men; 29.0 ± 5.0 years, mean ± SD) slept at home under unrestricted conditions for 1 week using a set of commercial wearable sleep-tracking devices and completed daily sleep diaries. Devices included the Fatigue Science Readiband, Fitbit Inspire HR, Oura ring, and Polar Vantage V Titan. Participants also wore a research-grade actigraphy watch (Philips Respironics Actiwatch 2) for comparison. To assess performance, all devices were compared with a high performing mobile sleep electroencephalography headband device (Dreem 2). Analyses included epoch-by-epoch and sleep summary agreement comparisons. Devices accurately tracked sleep-wake summary metrics (ie, time in bed, total sleep time, sleep efficiency, sleep latency, wake after sleep onset) on most nights but performed best on nights with higher sleep efficiency. Epoch-by-epoch sensitivity (for sleep) and specificity (for wake), respectively, were as follows: Actiwatch (0.95, 0.35), Fatigue Science (0.94, 0.40), Fitbit (0.93, 0.45), Oura (0.94, 0.41), and Polar (0.96, 0.35). Sleep stage-tracking performance was mixed, with high variability. As in previous studies, all devices were better at detecting sleep than wake, and most devices compared favorably to actigraphy in wake detection. Devices performed best on nights with more consolidated sleep patterns. Unrestricted sleep TIB differences were accurately tracked on most nights. High variability in sleep stage-tracking performance suggests that these devices, in their current form, are still best utilized for tracking sleep-wake outcomes and not sleep stages. Most commercial wearables exhibited promising performance for tracking sleep-wake in real-world conditions, further supporting their consideration as an alternative to actigraphy.


Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis.
Zygomycosis is an emerging frequently fatal opportunistic mycosis whose immunopathogenesis is poorly understood. We developed a zygomycosis model by injecting Drosophila melanogaster flies with a standardized amount of fungal spores from clinical Zygomycetes isolates to study virulence and host defense mechanisms. We found that, as opposed to most other fungi, which are nonpathogenic in D. melanogaster (e.g., Aspergillus fumigatus), Zygomycetes rapidly infect and kill wild-type flies. Toll-deficient flies exhibited increased susceptibility to Zygomycetes, whereas constitutive overexpression of the antifungal peptide Drosomycin in transgenic flies partially restored resistance to zygomycosis. D. melanogaster Schneider 2 phagocytic cells displayed decreased phagocytosis and caused less hyphal damage to Zygomycetes compared with that to A. fumigatus. Furthermore, phagocytosis-defective eater mutant flies displayed increased susceptibility to Zygomycetes infection. Classic enhancers of Zygomycetes virulence in humans, such as corticosteroids, increased iron supply, and iron availability through treatment with deferoxamine dramatically increased Zygomycetes pathogenicity in our model. In contrast, iron starvation induced by treatment with the iron chelator deferasirox significantly protected flies infected with Zygomycetes. Whole-genome expression profiling in wild-type flies after infection with Zygomycetes vs. A. fumigatus identified genes selectively down-regulated by Zygomycetes, which act in pathogen recognition, immune defense, stress response, detoxification, steroid metabolism, or tissue repair or have unknown functions. Our results provide insights into the factors that mediate host-pathogen interactions in zygomycosis and establish D. melanogaster as a promising model to study this important mycosis.


Therapists-in-training experiences of working with transfer clients: One relationship terminates and another begins.
Data from interviews with 12 graduate-level trainees about their experiences of working with clients who had been transferred to them from another therapist were analyzed using consensual qualitative research. Trainees reported a range of helpful and hindering aspects about the transfer experience related to the client (e.g., client had experienced a prior termination and transfer, client had severe character pathology), the prior therapist (e.g., prior therapist prepared client for transfer, prior therapists did not process their termination with client), themselves (e.g., participant was open to addressing grief, participant was fearful of rejection), supervision (e.g., the supervisor provided important feedback on dealing with loss, the supervisor failed to address the unique nature of transferring), training (e.g., there was not adequate readings on termination and transfer, there was no readings on transfers), and clinic practices (e.g., meeting with the prior therapist and current therapist facilitated process, having clients end treatment with debt hindered the development of the new relationship). Participants also provided recommendations for improving the transfer process. Implications of these findings for clinical practice, training, and research are addressed. (PsycINFO Database Record


Organometallic-Derived Carbon (ODC)-Metal Nano-Oxide Composites as Improved Electrode Materials for Supercapacitors.
In the search for the new generation of electrochemical energy storage materials, a novel and straightforward synthetic route for porous carbons and metal oxide nanoparticle composites based on the chlorination of the organometallic compounds Ni(C5H5)2 and Mn(C5H7O2)2 at moderate temperatures, followed by hydrothermal treatment, has been developed. Electrochemical measurements in a three-electrode configuration show that, in both composites NiO@ODC and Mn3O4@ODC, a synergistic effect between the capacitive and pseudocapacitive energy storage mechanisms is observed, thereby improving their electrochemical performance vs pure carbon materials. Electrochemical evaluation of symmetric cells gave gravimetric capacitances of 124 and 130 F g-1 for NiO@ODC and Mn3O4@ODC, respectively. However, the porous structure of the carbon matrix and the higher conductivity of Mn3O4, together, were found to be responsible for the superior electrochemical performance of Mn3O4@ODC.


CRISPR guide RNA design for research applications.
The rapid rise of CRISPR as a technology for genome engineering and related research applications has created a need for algorithms and associated online tools that facilitate design of on-target and effective guide RNAs (gRNAs). Here, we review the state of the art in CRISPR gRNA design for research applications of the CRISPR-Cas9 system, including knockout, activation, and inhibition. Notably, achieving good gRNA design is not solely dependent on innovations in CRISPR technology. Good design and design tools also rely on availability of high-quality genome sequence and gene annotations, as well as on availability of accumulated data regarding off-targets and effectiveness metrics.


'Placement budgets' for supported employment: impact on employment rates in a multicentre randomised controlled trial.
The most effective rehabilitation model for job (re-)entry of people with mental illness is supported employment. A barrier to introducing supported employment into standard care is its temporally unlimited provision, which conflicts with health and social legislation in many European countries. To test the impact of different 'placement budgets', i.e. a predefined maximum time budget for job seeking until take-up of competitive employment. Participants (116) were randomly assigned to 25 h, 40 h or 55 h placement budgets in an intent-to-treat analysis. We applied the individual placement and support model over 24 months, following participants for 36 months. Primary outcome was employment in the labour market for at least 3 months. The proportion of participants obtaining competitive employment was 55.1% in the 25 h group, 37.8% in the 40 h group and 35.8% in the 55 h group. In a Cox regression analysis, time to employment was slightly lower in the 25 h group relative to the 40 h (hazard ratio 1.78, 95% CI 0.88-3.57, P = 0.107) and 55 h groups (hazard ratio 1.74, 95% CI 0.86-3.49, P = 0.122), but this was not statistically significant. The vast majority of all participants who found a job did so within the first 12 months (80.4%). A restricted time budget for job finding and placement does not affect the rate of successful employment. In accordance with legislation, a restriction of care provision seems justified and enhances the chances of supported employment being introduced in statutory services.


[Effects of electroacupuncture on cochlea morphology and expression of aquaporins in guinea pigs with endolymphatic hydrops].
To observe the effects of electroacupuncture (EA) on cochlea morphology and expression of aquaporin 1 (AQP1) in guinea pigs with endolymphatic hydrops, so as to explore the possible mechanism of EA on endolymphatic hydrops. Forty guinea pigs were randomly divided into a blank group, a model group, a medication group and an EA group, 10 guinea pigs in each one. Model of endolymphatic hydrops was established by using intraperitoneal injection of aldosterone. Guinea pigs in the blank group and model group were treated with identical immobilization as EA group but no treatment was given; guinea pigs in the medication group were treated with intragastric administration of hydrochlorothiazide at a dose of 5 mg/kg, once a day for consecutive 10 days; guinea pigs in the EA group were treated with' EA at "Baihui" (GV 20) and "Tinggong"(SI 19), once a day for consecutive 10 days. The serum ionic concentration in each group was tested by turbidimetric method; hematoxylin-eosin staining was used to measure the severity of cochlea hydrops; immunohistochemical method was used to observe the expression of AQP1 in the cochlea. (1) There was no endolymphatic hydrops in the blank group, moderate-severe endolymphatic hydrops in the model group and slight endolymphatic hydrops in the EA group and medication group. (2) The concentration of K+ and Ca2+ in the EA group was higher than that in the model group and medication group (all P<0. 01); the concentration of Na+ was lower than that in the model group (P< 0. 01) but higher than that in the medication group (P<0. 01); the concentration of Cl- was higher than that in the medication group (P<0. 01), but not significantly different from the model group (P>0. 05). (3) The ratio of expression area of AQP1 in the model group was lower than that in the blank group (P<0. 01); the ratio of expression area of AQP1 in the EA group was higher than that in the model group (P<0. 01), and lower than that in the medication group without significant difference (P>0. 05). EA could relieve the endolymphatic hydrops in guinea pigs; the mechanism is likely to be related with up-regulating the expression of AQP1 in cochlea and ion concentration might be an important factor involved.


Clinicopathological Presentation of Retinoblastoma in Ethiopia.
Introduction: The presenting symptoms of retinoblastoma in Ethiopia, as well as their relationship to the stage of the disease, are poorly understood, but they could be important as background knowledge for creating early detection initiatives. This study aimed to describe the clinical and histopathological characteristics of retinoblastoma among Ethiopian patients. Methods: A hospital-based cross-sectional analysis of all children with newly diagnosed retinoblastoma during the study period of May 2015 to December 2019, inclusive, who presented to a tertiary referral center during were included. Demographic, clinical, and histological characteristics were collected and descriptive statistics were done using SPSS Version 20.0 software. Results: A total of 217 patients (unilateral 84.3%, bilateral 15.7%) were studied. The median age at presentation was 29 months (34 months vs. 19.5 months in unilateral and bilateral cases, respectively, p < 0.001). Among all patients, 57.8% were male. Leukocoria was the most common presenting sign (37.3%) and followed by fungating mass (31.8%). Tumors were extraocular in 40.1% of cases. From the intraocular cases, 73.3% were advanced International Intraocular Retinoblastoma Classification Group D or E disease. Sixty-two (54.4%) of the eyes had high-risk pathological features. The median lag time was significantly shorter for intraocular versus extraocular cases (5 months vs. 12 months, respectively, p < 0.001). Conclusion: Our results show that the majority of Ethiopian children with retinoblastoma have delayed presentation and late stage at diagnosis. This suggests that national health promotion campaigns to increase public knowledge on the presenting signs of retinoblastoma may be critical to achieving early diagnosis. Furthermore, the development of standard management guidelines informed by this study will be helpful in managing the complex and advanced cases currently observed.


The easiest children to reach are most likely to be infected with ocular Chlamydia trachomatis in trachoma endemic areas of Niger.
Control programs for trachoma use mass antibiotic distributions to treat ocular Chlamydia trachomatis in an effort to eliminate this disease worldwide. To determine whether children infected with ocular Chlamydia are more likely to present later for examination than those who are uninfected, we compare the order of presentation for examination of children 0-5 years, and the presence of ocular Chlamydia by PCR in 4 villages in Niger where trachoma is endemic. We conducted a cluster-randomized, controlled trial where 48 randomly selected villages in Niger are divided into 4 study arms of different mass treatment strategies. In a substudy of the main trial, we randomly selected 1 village from each of the 4 study arms (4 total villages) and we evaluated the odds of ocular Chlamydia versus the rank order of presentation for examination and laboratory assessment before treatment was offered. We found the odds of harboring ocular Chlamydia dropped by more than 70% from the first child examined to the last child examined (OR 0.27, 95% CI 0.13-0.59, P = 0.001) in the 4 randomly selected villages. We found the odds of active trachoma dropped by 80% from the first child examined to the last child examined (OR 0.20, 95% CI 0.10-0.4, P<0.0001) in the 48 villages in the main trial. This study demonstrates that even if the WHO recommended 80% treatment coverage is not reached in certain settings, children 0-5 years with the greatest probability of ocular Chlamydia have higher odds of receiving attention because they are the first to present. These results suggest there may be diminishing returns when using scarce resources to track down the last few children in a mass treatment program. ClinicalTrials.gov NCT00792922.