ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps.
In vivo real-time assessment of the histology of diminutive (≤5 mm) colorectal polyps detected at colonoscopy can be achieved by means of an "optical biopsy" by using currently available endoscopic technologies. This systematic review and meta-analysis was performed by the American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee to specifically assess whether acceptable performance thresholds outlined by an ASGE Preservation and Incorporation of Valuable endoscopic Innovations (PIVI) document for clinical adoption of these technologies have been met. We conducted direct meta-analyses calculating the pooled negative predictive value (NPV) for narrow-band imaging (NBI), i-SCAN, and Fujinon Intelligent Color Enhancement (FICE)-assisted optical biopsy for predicting adenomatous polyp histology of small/diminutive colorectal polyps. We also calculated the pooled percentage agreement with histopathology when assigning postpolypectomy surveillance intervals based on combining real-time optical biopsy of colorectal polyps 5 mm or smaller with histopathologic assessment of polyps larger than 5 mm. Random-effects meta-analysis models were used. Statistical heterogeneity was evaluated by means of I(2) statistics. Our meta-analyses indicate that optical biopsy with NBI, exceeds the NPV threshold for adenomatous polyp histology, supporting a "diagnose-and-leave" strategy for diminutive predicted nonneoplastic polyps in the rectosigmoid colon. The pooled NPV of NBI for adenomatous polyp histology by using the random-effects model was 91% (95% confidence interval [CI], 88-94). This finding was associated with a high degree of heterogeneity (I(2) = 89%). Subgroup analysis indicated that the pooled NPV was greater than 90% for academic medical centers (91.8%; 95% CI, 89-94), for experts (93%; 95% CI, 91-96), and when the optical biopsy assessment was made with high confidence (93%; 95% CI, 90-96). Our meta-analyses also indicate that the agreement in assignment of postpolypectomy surveillance intervals based on optical biopsy with NBI of diminutive colorectal polyps is 90% or greater in academic settings (91%; 95% CI, 86-95), with experienced endoscopists (92%; 95% CI, 88-96) and when optical biopsy assessments are made with high confidence (91%; 95% CI, 88-95). Our systematic review and meta-analysis confirms that the thresholds established by the ASGE PIVI for real-time endoscopic assessment of the histology of diminutive polyps have been met, at least with NBI optical biopsy, with endoscopists who are expert in using this advanced imaging technology and when assessments are made with high confidence.


Experimental vulnerability analysis of QKD based on attack ratings.
Inspired by the methodology used for classical cryptographic hardware, we consider the use of attack ratings in the context of QKD security evaluation. To illustrate the relevance of this approach, we conduct an experimental vulnerability assessment of CV-QKD against saturation attacks, for two different attack strategies. The first strategy relies on inducing detector saturation by performing a large coherent displacement. This strategy is experimentally challenging and therefore translates into a high attack rating. We also propose and experimentally demonstrate a second attack strategy that simply consists in saturating the detector with an external laser. The low rating we obtain indicates that this attack constitutes a primary threat for practical CV-QKD systems. These results highlight the benefits of combining theoretical security considerations with vulnerability analysis based on attack ratings, in order to guide the design and engineering of practical QKD systems towards the highest possible security standards.


Delayed and incidental diagnosis of transverse testicular ectopia.
Transverse testicular ectopia is a rare malformation in which both testes are placed in the same inguinal region. Most of the patients are diagnosed incidentally during inguinal exploration. We here report three cases of transverse testicular ectopia and discuss the causes of delayed and incidental diagnosis of this infrequent malformation. Although the mean age at presentation was reported as 4 years, the mean age of our patients was 7.7 months. We detected the contralateral testis in the inguinal canal in all of our patients preoperatively. The most important diagnostic criteria are to be aware of this rare malformation and getting suspicious in patients with one side inguinal hernia and an empty hemiscrotum on the other side. It is essential to perform an ultrasound scan in patients with such a clinical presentation.


Sex differences in incidence and psychiatric comorbidity for alcohol dependence in patients with panic disorder.
Sex differences in the development of alcohol dependence (AD) among patients with panic disorder (PD) remain unexplored. The study investigated sex as an effect modifier in the incidence of AD among patients with PD. We included 9480 patients with PD from the Taiwan National Health Insurance Research Database. A total of 169 patients (89 men and 80 women) developed incident AD during the follow-up period. Standardized incidence ratios (SIRs) were used to represent the relative risks of incident AD compared with the general population. Based on a nested case-control study design, 10 controls were selected for each case. Medical utilization and psychiatric comorbidity before diagnosing AD were analyzed using conditional logistic regression. The SIR of incident AD was 3.36 for men and 6.29 for women. Women with PD and incident AD had more visits to the outpatient department than the controls did, whereas men exhibited no significant differences. Women with incident AD were more likely to comorbid with depressive disorder (adjusted risk ratio [aRR] = 2.94), personality disorder (aRR = 5.03), and sleep disorder (aRR = 1.72), whereas men with incident AD were more likely to comorbid with sleep disorder (aRR = 1.85) and other substance use disorders (aRR = 3.08). Patients with PD have an additional risk of developing AD compared with the general population, and that risk is higher in women. Women and men exhibited dissimilar patterns of medical utilization and psychiatric comorbidity before developing AD. Sex differences should be taken into consideration when establishing preventive measures.


Preventive action of green tea from changes in the liver antioxidant abilities of different aged rats intoxicated with ethanol.
The present study investigated the influence of green tea as a source of water-soluble antioxidants on the liver antioxidant potential of different aged rats chronically intoxicated with ethanol. Rats (2, 12, and 24 mo old) were fed for 5 wk on a control or an ethanol Lieber-DeCarli diet with and without green tea (7 g/L). The activity and level of enzymatic and non-enzymatic antioxidants and the level of markers of protein and lipid oxidation in the liver of rats were examined. The activities of superoxide dismutase and catalase and levels of vitamins C, E, A, and beta-carotene were significantly decreased, whereas activities of glutathione peroxidase and glutathione reductase and the level of reduced glutathione significantly increased during aging. The ethanol diet caused a significant decrease in activity of antioxidant enzymes and in the level of non-enzymatic antioxidants tested. Administration of green tea to ethanol-treated rats of different ages partly normalized the activity of enzymes and the level of non-enzymatic antioxidants. Changes in antioxidant ability observed during aging were accompanied by increased levels of markers of lipid and protein modifications that also were intensified by ethanol. Green tea caused a decrease in lipid and protein oxidation in aged and ethanol-treated rats. The protective effect of green tea was confirmed by the significantly lower activity of biomarkers of liver damage (alanine and aspartate aminotransferases) in the serum of rats that received green tea with ethanol compared with rats from the control ethanol group. The use of green tea appears to be beneficial to rat liver by decreasing oxidative stress caused by ethanol and/or aging.


Changes in Health Care Use Associated With the Introduction of Hospital Global Budgets in Maryland.
In 2014, the State of Maryland placed the majority of its hospitals under all-payer global budgets for inpatient, hospital outpatient, and emergency department care. Goals of the program included reducing unnecessary hospital utilization and encouraging greater use of primary care. To compare changes in hospital and primary care use through the first 2 years of Maryland's hospital global budget program among fee-for-service Medicare beneficiaries in Maryland vs matched control areas. We matched 8 Maryland counties (94 967 beneficiaries) with hospitals in the program to 27 non-Maryland control counties (206 389 beneficiaries). Using difference-in-differences analysis, we compared changes in hospital and primary care use in Maryland vs the control counties from before (2009-2013) to after (2014-2015) the payment change, using 2 different assumptions. First, we assumed that preintervention differences between Maryland and the control counties would have remained constant past 2014 had Maryland not implemented global budgets (parallel trend assumption). Second, we assumed that differences in preintervention trends would have continued without the payment change (differential trend assumption). Hospital stays (defined as admissions and observation stays); return hospital stays within 30 days of a prior hospital stay; emergency department visits that did not result in admission; price-standardized hospital outpatient department (HOPD) utilization; and visits with primary care physicians (overall and within 7 days of a hospital stay). We matched 8 Maryland counties with hospitals in the program (94 967 beneficiaries; 41.8% male; mean [SD] age, 72.3 [12.2] years) to 27 non-Maryland control counties (206 389 beneficiaries; 42.8% male; mean [SD] age, 71.7 [12.5] years). Assuming parallel trends, we estimated a differential change in Maryland of -0.47 annual hospital stays per 100 beneficiaries (95% CI, -1.65 to 0.72; P = .43) from the preintervention period (2009-2013) to 2015, but assuming differential trends, we estimated a differential change in Maryland of -1.24 stays per 100 beneficiaries (95% CI, -2.46 to -0.02; P = .047). Assuming parallel trends, we found a significant increase in primary care visits (+10.6 annual visits/100 beneficiaries; 95% CI, 4.6 to 16.6 annual visits/100 beneficiaries; P = .001), but assuming differential trends, we found no change (-0.8 visits/100 beneficiaries; 95% CI, -10.6 to 9.0 visits/100 beneficiaries; P = .87). Comparing estimates with both trend assumptions, we found no consistent changes in emergency department visits, return hospital stays, HOPD use, or posthospitalization primary care visits associated with Maryland's program. We did not find consistent evidence that Maryland's hospital global budget program was associated with reductions in hospital use or increases in primary care visits among fee-for-service Medicare beneficiaries after 2 years. Evaluations over longer periods should be pursued.


A small-molecule cell-based screen led to the identification of biphenylimidazoazines with highly potent and broad-spectrum anti-apicomplexan activity.
An in vitro screening of the anti-apicomplexan activity of 51 compounds, stemming from our chemical library and from chemical synthesis, was performed. As a study model, we used Toxoplasma gondii (T. gondii), expressing β-galactosidase for the colorimetric assessment of drug activity on parasites cultivated in vitro. This approach allowed the validation of a new series of molecules with a biphenylimidazoazine scaffold as inhibitors of T. gondii growth in vitro. Hence, 8 molecules significantly inhibited intracellular replication of T. gondii in vitro, with EC50 < 1 μM, while being non-toxic for human fibroblasts at these concentrations. Most attractive candidates were then selected for further biological investigations on other apicomplexan parasites (Neospora caninum, Besnoitia besnoiti, Eimeria tenella and Plasmodium falciparum). Finally, two compounds were able to inhibit growth of four different apicomplexans with EC50 in the submicromolar to nanomolar range, for each parasite. These data, including the broad anti-parasite spectrum of these inhibitors, define a new generation of potential anti-parasite compounds of wide interest, including for veterinary application. Studies realized on E. tenella suggest that these molecules act during the intracellular development steps of the parasite. Further experiments should be done to identify the molecular target(s) of these compounds.


Optical pumping of generalized laser active materials.
Results are presented of a computer-based study on the rate of excitation in the active cores of two types of optically pumped lasers as a function of a number of parameters of the active core. The absorption bands of the active materials are generated by Lorentzian and Gaussian functions. The excitation rate of the active core is proportional to the width of the absorption band at all depths of penetration. The plots of excitation rate as a function of frequency show curves similar to line reversal spectra and emphasize the importance of excitation some distance from the center of the absorption band in the slab model. In the cylindrical model, this wing pumping is even more important due to focusing. The effect of refractive index on the excitation rate is also described.


Legionella steelei sp. nov., isolated from human respiratory specimens in California, USA, and South Australia.
Legionella-like bacteria were isolated from the respiratory tract of two patients in California, USA, and South Australia, but were not thought to cause disease. These bacteria, strains F2632 and IMVS-3376(T), were found to have identical Legionella macrophage infectivity potentiator (mip) gene sequences and were therefore further characterized to determine their genetic and phenotypic relatedness and properties. Both of these Gram-negative-staining bacterial strains grew on buffered charcoal yeast extract medium, were cysteine auxotrophs and made a characteristic diffusible bright yellow fluorescent pigment, with one strain making a late appearing colony-bound blue-white fluorescent pigment. The optimal in vitro growth temperature was 35 °C, with very poor growth at 37 °C in broth or on solid media. There was no growth in human A549 cells at either 35 or 37 °C, but excellent growth in Acanthamoeba castellani at 30 °C and poorer growth at 35 °C. Phylogenetic analysis of these bacteria was performed by sequence analysis of 16S rRNA, mip, ribonuclease P, ribosomal polymerase B and zinc metalloprotease genes. These studies confirmed that the new strains represented a single novel species of the genus Legionella for which the name Legionella steelei sp. nov. is proposed. The type strain is IMVS-3376(T) ( = IMVS 3113(T) = ATCC BAA-2169(T)).


Experience with Quality Assurance in Two Store-and-Forward Telemedicine Networks.
Despite the increasing use of telemedicine around the world, little has been done to incorporate quality assurance (QA) into these operations. The purpose of the present study was to examine the feasibility of QA in store-and-forward teleconsulting using a previously published framework. During a 2-year study period, we examined the feasibility of using QA tools in two mature telemedicine networks [Médecins Sans Frontières (MSF) and New Zealand Teledermatology (NZT)]. The tools included performance reporting to assess trends, automated follow-up of patients to obtain outcomes data, automated surveying of referrers to obtain user feedback, and retrospective assessment of randomly selected cases to assess quality. In addition, the senior case coordinators in each network were responsible for identifying potential adverse events from email reports received from users. During the study period, there were 149 responses to the patient follow-up questions relating to the 1241 MSF cases (i.e., 12% of cases), and there were 271 responses to the follow-up questions relating to the 639 NZT cases (i.e., 42% of cases). The collection of user feedback reports was combined with the collection of patient follow-up data, thus producing the same response rates. The outcomes data suggested that the telemedicine advice proved useful for the referring doctor in the majority of cases and was likely to benefit the patient. The user feedback was overwhelmingly positive, over 90% of referrers in the two networks finding the advice received to be of educational benefit. The feedback also suggested that the teleconsultation had provided cost savings in about 20% of cases, either to the patient/family, or to the hospital/clinic treating the patient. Various problems were detected by regular monitoring, and certain adverse events were identified from email reports by the users. A single aberrant quality reading was detected by using a process control chart. The present study demonstrates that a QA program is feasible in store-and-forward telemedicine, and shows that it was useful in two different networks, because certain problems were detected (and then solved) that would not have been identified until much later. It seems likely that QA could be used much more widely in telemedicine generally to benefit patient care.


HIV risk behaviors in sub-Saharan Africa and Northern Thailand: baseline behavioral data from Project Accept.
Of 2.5 million new HIV infections worldwide in 2007, most occurred in sub-Saharan Africa and southeast Asia. We present the baseline data on HIV risk behaviors and HIV testing in sub-Saharan Africa and northern Thailand from Project Accept, a community-randomized controlled trial of community mobilization, mobile voluntary counseling and testing (VCT), and posttest support services. A random household probability sample of individuals aged 18-32 years yielded a sample of 14,657, with response rates ranging from 84%-94% across the 5 sites (Thailand, Zimbabwe, Tanzania, and 2 in South Africa). Individuals completed an interviewer-administered survey on demographic characteristics, HIV risk behaviors, and history of VCT. In multivariate analysis, females, married individuals, less educated with 1 sexual partner in the past 6 months were more likely to have had unprotected intercourse in the previous 6 months. Rates of lifetime HIV testing ranged from 5.4% among males in Zimbabwe to 52.6% among females in Soweto. Significant risk of HIV acquisition in Project Accept communities exists despite 2 decades of prevention efforts. Low levels of recent HIV testing suggest that increasing awareness of HIV status through accessible VCT services may reduce HIV transmission.


Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large community-based study.
Screening colonoscopy's effectiveness in reducing colorectal cancer mortality risk in community populations is unclear, particularly for right-colon cancers, leading to recommendations against its use for screening in some countries. This study aimed to determine whether, among average-risk people, receipt of screening colonoscopy reduces the risk of dying from both right-colon and left-colon/rectal cancers. We conducted a nested case-control study with incidence-density matching in screening-eligible Kaiser Permanente members. Patients who were 55-90 years old on their colorectal cancer death date during 2006-2012 were matched on diagnosis (reference) date to controls on age, sex, health plan enrolment duration and geographical region. We excluded patients at increased colorectal cancer risk, or with prior colorectal cancer diagnosis or colectomy. The association between screening colonoscopy receipt in the 10-year period before the reference date and colorectal cancer death risk was evaluated while accounting for other screening exposures. We analysed 1747 patients who died from colorectal cancer and 3460 colorectal cancer-free controls. Compared with no endoscopic screening, receipt of a screening colonoscopy was associated with a 67% reduction in the risk of death from any colorectal cancer (adjusted OR (aOR)=0.33, 95% CI 0.21 to 0.52). By cancer location, screening colonoscopy was associated with a 65% reduction in risk of death for right-colon cancers (aOR=0.35, CI 0.18 to 0.65) and a 75% reduction for left-colon/rectal cancers (aOR=0.25, CI 0.12 to 0.53). Screening colonoscopy was associated with a substantial and comparably decreased mortality risk for both right-sided and left-sided cancers within a large community-based population.


Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A.
Signaling pathways between cell surface receptors and the BCL-2 family of proteins regulate cell death. Survival factors induce the phosphorylation and inactivation of BAD, a proapoptotic member. Purification of BAD kinase(s) identified membrane-based cAMP-dependent protein kinase (PKA) as a BAD Ser-112 (S112) site-specific kinase. PKA-specific inhibitors blocked the IL-3-induced phosphorylation on S112 of endogenous BAD as well as mitochondria-based BAD S112 kinase activity. A blocking peptide that disrupts type II PKA holoenzyme association with A-kinase-anchoring proteins (AKAPs) also inhibited BAD phosphorylation and eliminated the BAD S112 kinase activity at mitochondria. Thus, the anchoring of PKA to mitochondria represents a focused subcellular kinase/substrate interaction that inactivates BAD at its target organelle in response to a survival factor.


SV40-mediated transformation and immortalization of human cells.
SV40 infection of human cells results in both transformation and lytic infection. We have used origin-defective viral mutants which are unable to replicate in permissive cells to help analysis of transformation. Expression of large T antigen (T ag) and small t antigen results in the altered growth phenotypes characteristic of transformation in other species. Human diploid fibroblasts (HF) have a limited lifespan and undergo senescence; T ag results in extension of lifespan but only in rare cases are the cells capable of continuous growth and are immortal. We have developed matched sets of non-immortal and immortal transformed HF for assessment of the steps required for immortalization. Results are summarized to characterize both T-dependent and T-independent functions. A novel growth suppressor gene SEN6 has been identified, the inactivation of which is required for immortalization; it may also serve as a marker to distinguish cells in which SV40 is replicating from those in which it is responsible for tumorigenesis.


The effects of electronic cigarette vapor on placental trophoblast cell function.
Despite evidence that maternal smoking is associated with numerous adverse outcomes, 10-35% of women still smoke during pregnancy. Recently, many smokers have turned to electronic cigarettes (e-cigarettes) as a smoking cessation tool. However, there is considerable uncertainty regarding their safety for use during pregnancy. The goal of this study was to examine the effects of e-cigarette vapour on placental trophoblast function. HTR-8/SVneo cells were exposed to unflavored e-cigarette vapour-conditioned media with and without nicotine to assess cell viability, proliferation, migration (wound healing assay), invasion (transwell extracellular matrix invasion assay), and tube formation, a surrogate for angiogenesis. While there was no effect on cell viability, proliferation or migration (all p > 0.05), e-cigarette conditioned media significantly reduced trophoblast invasion and tube formation; these effects could not be solely attributed to the presence of nicotine. These results suggest that an evaluation of the safety of e-cigarette use during pregnancy is urgently required.


Endothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea.
Endothelin-1 (ET-1), a potent vasoconstrictor, is released mainly by vascular endothelial cells under the influence of hypoxia and other stimuli. ET-1 is related to endothelial dysfunction, as well as arterial and pulmonary hypertension, all of which are thought to be associated with obstructive sleep apnoea (OSA). This study evaluated venous plasma concentrations of ET-1 and noradrenaline and 24-h systemic blood pressure in 29 patients with OSA (age=56.9+/-1.6 yrs; body mass index=29.5+/-0.7 kg x m2 (mean+/-SEM)). Blood samples were taken in the morning, evening and during sleep. In the same way, the patients were assessed during a night of continuous positive airway pressure (CPAP) and after 13.9+/-1.4 months while still on CPAP. ET-1 levels were compared to those of control subjects, who were selected from in- and outpatients and were matched to patients for age, sex, presence of arterial hypertension and coronary artery disease. ET-1 plasma levels were not elevated in the patients compared to the controls (41.6+/-2.2 and 44.9+/-1.3 pg x mL(-1), respectively, p=0.20). The ET-1 concentration did not change significantly, neither during sleep nor in the first night on CPAP therapy, nor under long-term treatment with CPAP. ET-1 neither correlated to the severity of OSA nor to that of systemic hypertension. The results suggest that endothelin-1 does not play a crucial role in the pathophysiology of obstructive sleep apnoea.


Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy.
Paclitaxel (Taxol®) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone.


Bark Beetle-Associated Blue-Stain Fungi Increase Antioxidant Enzyme Activities and Monoterpene Concentrations in Pinus yunnanensis.
Yunnan pine is the most important tree species in SW China in both economical and ecological terms, but it is often killed by pine shoot beetles (Tomicus spp.). Tomicus beetles are secondary pests in temperate regions and the aggressiveness of the beetles in SW China is considered to be due to the warm subtropical climates as well as the beetles' virulent fungal associates. Here, we assessed the virulence of three blue-stain fungi (Leptographium wushanense, L. sinense and Ophiostoma canum) associated with pine shoot beetles to Yunnan pine (Pinus yunnanensis) in SW China. Following fungal inoculation, we measured necrotic lesion lengths, antioxidant enzyme activities and monoterpene concentrations in the stem phloem of Yunnan pine. Leptographium wushanense induced twice as long lesions as L. sinense and O. canum, and all three fungi induced significantly longer lesions than sterile agar control inoculations. The activity of three tested antioxidant enzymes (peroxidase, polyphenol oxidase, and superoxide dismutase) increased after both fungal inoculation and control inoculation. However, L. wushanense and L. sinense generally caused a greater increase in enzyme activities than O. canum and the control treatment. Fungal inoculation induced stronger increases in six major monoterpenes than the control treatment, but the difference was significant only for some fungus-monoterpene combinations. Overall, our results show that L. wushanense and L. sinense elicit stronger defense responses and thus are more virulent to Yunnan pine than O. canum. The two Leptographium species may thus contribute to the aggressiveness of their beetle vectors and could damage Yunnan pine across SW China if they spread from the restricted geographical area they have been found in so far.


Improved uniformity in high-performance organic photovoltaics enabled by (3-aminopropyl)triethoxysilane cathode functionalization.
Organic photovoltaics have the potential to serve as lightweight, low-cost, mechanically flexible solar cells. However, losses in efficiency as laboratory cells are scaled up to the module level have to date impeded large scale deployment. Here, we report that a 3-aminopropyltriethoxysilane (APTES) cathode interfacial treatment significantly enhances performance reproducibility in inverted high-efficiency PTB7:PC71BM organic photovoltaic cells, as demonstrated by the fabrication of 100 APTES-treated devices versus 100 untreated controls. The APTES-treated devices achieve a power conversion efficiency of 8.08 ± 0.12% with histogram skewness of -0.291, whereas the untreated controls achieve 7.80 ± 0.26% with histogram skewness of -1.86. By substantially suppressing the interfacial origins of underperforming cells, the APTES treatment offers a pathway for fabricating large-area modules with high spatial performance uniformity.


Diverse spatial, temporal, and sexual expression of recently duplicated androgen-binding protein genes in Mus musculus.
The genes for salivary androgen-binding protein (ABP) subunits have been evolving rapidly in ancestors of the house mouse Mus musculus, as evidenced both by recent and extensive gene duplication and by high ratios of nonsynonymous to synonymous nucleotide substitution rates. This makes ABP an appropriate model system with which to investigate how recent adaptive evolution of paralogous genes results in functional innovation (neofunctionalization). It was our goal to find evidence for the expression of as many of the Abp paralogues in the mouse genome as possible. We observed expression of six Abpa paralogues and five Abpbg paralogues in ten glands and other organs located predominantly in the head and neck (olfactory lobe of the brain, three salivary glands, lacrimal gland, Harderian gland, vomeronasal organ, and major olfactory epithelium). These Abp paralogues differed dramatically in their specific expression in these different glands and in their sexual dimorphism of expression. We also studied the appearance of expression in both late-stage embryos and postnatal animals prior to puberty and found significantly different timing of the onset of expression among the various paralogues. The multiple changes in the spatial expression profile of these genes resulting in various combinations of expression in glands and other organs in the head and face of the mouse strongly suggest that neofunctionalization of these genes, driven by adaptive evolution, has occurred following duplication. The extensive diversification in expression of this family of proteins provides two lines of evidence for a pheromonal role for ABP: 1) different patterns of Abpa/Abpbg expression in different glands; and 2) sexual dimorphism in the expression of the paralogues in a subset of those glands. These expression patterns differ dramatically among various glands that are located almost exclusively in the head and neck, where the sensory organs are located. Since mice are nocturnal, it is expected that they will make extensive use of olfactory as opposed to visual cues. The glands expressing Abp paralogues produce secretions (lacrimal and salivary) or detect odors (MOE and VNO) and thus it appears highly likely that ABP proteins play a role in olfactory communication.


An assessment of routine liver scanning in patients with breast cancer.
A retrospective review of the value of routine perioperative liver scanning for patients with breast cancer was performed. The liver was considered to be normal in 231 of 234 patients. The hepatoscan uncovered only one patient with unsuspected metastases. There were eight false-positive studies. Measurements of liver function, SGOT, SGPT, alkaline phosphatase, and bilirubin levels separated true positive from false-positive hepatoscans for all except one patient. Abnormal liver chemistry studies also identified liver metastases in an additional follow-up group of 192 patients. The low yield of detection of hepatic metastases during the initial work-up of breast cancer patients suggests that routine hepatoscanning be abandoned unless there is evidence of abnormal liver function.


Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels.
Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that overexpression of dopamine D2 receptors in medium spiny neurons increases their membrane excitability and decreases the complexity and length of their dendritic arbors. These changes can be reversed in the adult animal after restoring D2 receptors to wild-type levels, demonstrating a remarkable degree of structural plasticity in the adult striatum. Increased excitability and decreased dendritic arborization are associated with downregulation of inward rectifier potassium channels (Kir2.1/2.3). Downregulation of Kir2 function is critical for the neurophysiological and morphological changes in vivo because virally mediated expression of a dominant-negative Kir2 channel is sufficient to recapitulate the changes in D2 transgenic mice. These findings may have important implications for the understanding of basal ganglia disorders, and more specifically schizophrenia, in which excessive activation of striatal D2 receptors has long been hypothesized to be of pathophysiologic significance.


Importance of Assessing Cardiorespiratory Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign: A Scientific Statement From the American Heart Association.
Mounting evidence has firmly established that low levels of cardiorespiratory fitness (CRF) are associated with a high risk of cardiovascular disease, all-cause mortality, and mortality rates attributable to various cancers. A growing body of epidemiological and clinical evidence demonstrates not only that CRF is a potentially stronger predictor of mortality than established risk factors such as smoking, hypertension, high cholesterol, and type 2 diabetes mellitus, but that the addition of CRF to traditional risk factors significantly improves the reclassification of risk for adverse outcomes. The purpose of this statement is to review current knowledge related to the association between CRF and health outcomes, increase awareness of the added value of CRF to improve risk prediction, and suggest future directions in research. Although the statement is not intended to be a comprehensive review, critical references that address important advances in the field are highlighted. The underlying premise of this statement is that the addition of CRF for risk classification presents health professionals with unique opportunities to improve patient management and to encourage lifestyle-based strategies designed to reduce cardiovascular risk. These opportunities must be realized to optimize the prevention and treatment of cardiovascular disease and hence meet the American Heart Association's 2020 goals.


Temperature dependence and counter effect of the correlations of folding rate with chain length and with native topology.
There is a controversy about the major determinants of the folding rate of small single-domain proteins. To shed light on this issue, we examined a possibility that the major determinants may change depending on temperature by conducting molecular dynamics simulations for 17 small single-domain proteins using an off-lattice Go-like model over a wide range of temperature. It was shown that the rank order of the folding rates is temperature dependent, which indicates that the major determinants are dependent on temperature. It was also found that as temperature is decreased, the correlation of the folding rate with the chain length becomes weakened, whereas that with the native topology becomes enhanced. Our simulation results, therefore, may provide a clue to reconcile the apparent controversy between the study by Plaxco based on experimental data and the previous theoretical and subsequent simulation studies: the former showed that the folding rate of two-state folders does not correlate with the chain length but correlates well with the native topology, whereas the latter showed that the folding rate does correlate with the chain length. We propose a possible scenario reconciling the controversy, explaining the reason why the correlation of the folding rate with the chain length became weakened and that with the native topology became enhanced with decreasing temperature.


Posttraumatic Stress Symptoms in Patients With Cancer During the COVID-19 Pandemic: A One-Year Longitudinal Study.
Patients with cancer may be particularly vulnerable to psychological consequences of the COVID-19 pandemic. We studied the prevalence and evolution of posttraumatic stress symptoms (PTSS) in patients with cancer during the pandemic waves, and we investigated factors associated with high symptoms. COVIPACT is a 1-year longitudinal prospective study of French patients with solid/hematologic malignancies receiving treatment during the first nationwide lockdown. PTSS were measured every 3 months from April 2020 using the Impact of Event Scale-Revised. Patients also completed questionnaires on their quality of life, cognitive complaints, insomnia, and COVID-19 lockdown experience. Longitudinal analyses involved 386 patients with at least one PTSS assessment after baseline (median age, 63 years; 76% female). Among them, 21.5% had moderate/severe PTSS during the first lockdown. The rate of patients reporting PTSS decreased at lockdown release (13.6%), increased again at second lockdown (23.2%), and slightly declined from the second release period (22.7%) to the third lockdown (17.5%). Patients were grouped into 3 trajectories of evolution. Most patients had stable low symptoms throughout the period, 6% had high baseline symptoms slowly decreasing over time, and 17.6% had moderate symptoms worsening during the second lockdown. Female sex, feeling socially isolated, worrying about COVID-19 infection, and using psychotropic drugs were associated with PTSS. PTSS were associated with impaired quality of life, sleep, and cognition. Approximately one-fourth of patients with cancer experienced high and persistent PTSS over the first year of the COVID-19 pandemic and may benefit from psychological support. gov identifier: NCT04366154.


Stability of photodiodes under irradiation with a 157-nm pulsed excimer laser.
We have measured the stability of a variety of photodiodes exposed to 157-nm light from a pulsed excimer laser by using a radiometry beamline at the Synchrotron Ultraviolet Radiation Facility at the National Institute of Standards and Technology. The intense, pulsed laser light exposed the photodiodes, whereas the low-intensity, continuously tunable light from the synchrotron source measured changes in the characteristics of the photodiodes, such as in the responsivity and the reflectance from the surface of a photodiode. Photodiodes studied include both silicon pn-junction and Schottky-barrier types. Among these photodiodes, we found that the damage mechanism for photodiodes with SiO2-based passivating layers is mainly the buildup of SiO2-Si interface trap states. The interface trap state buildup is well known for other semiconductor devices and is generally recognized as a product induced by radiation with an energy more than the 9-eV SiO2 bandgap energy rather than the 7.9-eV energy of the 157-nm radiation. Based on the generation of interface trap states, a model is proposed to describe the dependence of detector responsivity on exposure to 157-nm radiation. We also observed slow recovery in some of the damaged photodiodes, confirming that some of the interface trap states are only semipermanent. Radiation damage induced by low-power continuous 157-nm synchrotron light was also studied. As for the other photodiodes with no SiO2 layers, measurement results support the assumption that the changes in responsivity are due mainly to the deposition of thin layers on the tops of the detectors during laser irradiation.


Does Acute Fatigue Negatively Affect Intrinsic Risk Factors of the Lower Extremity Injury Risk Profile? A Systematic and Critical Review.
Acute fatigue is hypothesized to alter lower extremity injury risk profiles by affecting intrinsic risk factors (i.e. single leg postural control, hamstring strength). However, no systematic overview exists that merges the insights into prospective lower extremity injury risk profiling with the effect of acute fatigue on functional test performance. The objective of this review is to identify the influence of acute fatigue on prospectively determined modifiable intrinsic risk factors for lower extremity injuries. Systematic review. PubMed (MEDLINE), Web of Science, PEDro, and Cochrane Library were searched until 29 May 2019. Studies were eligible when the study outcomes encompassed intrinsic modifiable risk factors for lower extremity injury, an acute fatigue intervention, and included healthy athletes or physically active people. Intrinsic modifiable risk factors were identified through recent systematic reviews and meta-analyses, and the referenced original research papers were used to determine outcome measures associated with increased injury risk. Forty-three studies reported acute fatigue effects on modifiable risk factors, with eight studies matching all criteria for data-extraction. Acute fatigue can decrease single leg postural control, decrease ankle joint position sense, decrease isokinetic strength of hamstring and quadriceps muscles and can affect isokinetic hamstring:quadriceps ratios. Acute fatigue affects prospective intrinsic modifiable risk factors for lower extremity injury, indicating an altered injury risk profile for lateral ankle sprain, patellofemoral pain syndrome and hamstring injuries. Future research should allow for individual fatiguability as a relevant outcome, and merge insights from athlete-centred injury risk profiling and fatigue.


Transverse-junction superluminescent diodes at the 1.1 microm wavelength regime.
We demonstrate, for the first time to our knowledge, GaAs-based transverse-junction (TJ) superluminescent diodes (SLDs) that operate at a wavelength of 1.1 microm. Due to lateral current injection by use of TJ, specified as transverse carrier flow spread in each quantum well horizontally instead of vertical well-by-well injection, nonuniform carrier distribution can be minimized among different multiple quantum wells (MQWs), which is a problem in vertical-junction (VJ) SLDs whose electroluminescent (EL) spectrum is governed by the center wavelength of QWs near the p side. In contrast with a VJ SLD, the EL spectrum of our device is determined by QWs that have a larger differential gain than the positions of QWs neighbored with a p side layer.


Auditory attention at the onset of West syndrome: correlation with EEG patterns and visual function.
At the onset of West syndrome a specific impairment of visual function has been clearly demonstrated, while other aspects of sensorial development, and in particular of the auditory function, have been less studied. The aim of this study was to evaluate auditory function and orienting responses at the onset of West syndrome, and to relate the results with EEG patterns, visual function and neurodevelopmental competence. A prospective multicentric study was performed on 25 successively enrolled infants with West syndrome; all the patients underwent a full clinical assessment, including MRI and video-EEG, visual function and auditory orienting responses (AORs) as well as Griffiths' developmental scales. The whole assessment performed at the onset of spasms (T0) was repeated after two months (T1). AORs resulted significantly impaired both at T0 and T1. At the onset of spasms a highly significant relationship of auditory attention with visual function and neurodevelopmental competence was shown in both cryptogenic and symptomatic forms, but it was no longer present after two months. Our results may suggest a possible pervasive effect of the epileptic disorder on sensory processing, associated to a deficit of neurodevelopment. Although we failed to show a significant correlation between auditory orienting responses and EEG patterns, some evidence seems to support at least partially an influence of the epileptic disorder per se on the genesis of the sensorial impairment. A longer follow up and a larger cohort will be useful for a better clarification of these findings.


Physiological and neurocognitive correlates of adaptive behavior in preschool among children in Head Start.
This study examined physiological and neurocognitive correlates of teacherreported adaptive behavior in preschool among children in Head Start. Child physiology was assessed by cardiac vagal tone and was measured during a baseline period and during the administration of a mildly effortful cognitive task. Neurocognitive function was measured using two tasks of executive function, which require children to inhibit a prepotent response, while remembering and executing the rule for correct responding. Parents reported on aspects of child negative emotionality associated with fear and anger. Information on child receptive language ability was also collected. Although correlates of teacher-reported social competence and on-task behavior were expected to be similar, some evidence for differentiation was obtained. Results indicated that higher resting vagal tone, vagal increase during the administration of the cognitive task, and higher levels of fearful emotionality were related to higher ratings of social competence, after adjusting for levels of on-task behavior. In contrast, lower resting vagal tone, vagal suppression in response to the cognitive task, and higher levels of executive function were associated with higher teacher ratings of on-task behavior, adjusted for social competence. Implications are considered of findings for developmental relations between social and academic competence and adaptation to preschool among children in Head Start.


Early versus delayed endocrine therapy for prostate cancer.
Endocrine treatment (ET) has in the past been shown to be beneficial in delaying clinical progression in all stages of prostate cancer, leading to an improvement of progression free survival in virtually all trials ever conducted. The first observations on this issue date back to the studies of the Veterans Administration Cooperative Urological Research Group in the 1960s. The period of time during which ET and the resulting side effects can be avoided is strongly dependent on the clinical stage of the disease. This treatment period is long in men who have minimal disease, such as a rising prostate-specific antigen after potentially curative management; however, it is considerably shorter in men who initially present with metastatic disease. In these situations, the potential benefit in quality of life, and avoidance of adverse events must be matched against the benefit in terms of gaining progression free time for the individual patient. This difficult task is supported by information supplied in this review. Locally advanced and regional (lymph node positive; stage T3N0-1M0Gx) disease is the domain of adjuvant ET. In this field, important progress has recently been made due to trials, which combine aggressive treatment of the primary tumor with adjuvant ET initiated at the same time. Therefore, in locally advanced and regional disease, radiotherapy or surgery combined with adjuvant ET must be considered state-of-the-art.


Outcome of first-episode acute and transient psychotic disorder in Hong Kong Chinese: a 20-year retrospective follow-up study.
'Acute and transient psychotic disorder' (ATPD) is a category in ICD-10 marked by psychosis with acute onset and early remission. It remains relatively under-researched, despite controversies over its nosological status in the current classification system. (1) To assess the changes in diagnosis over time in patients initially diagnosed as ATPD. (2) To identify factors predicting changes in diagnosis, and compare the long-term outcomes of various patterns of diagnostic shift. (3) To make recommendations on the classification and treatment of ATPD based on the findings of the study. This was a retrospective longitudinal study based on review of medical records of patients first admitted to a regional hospital in Hong Kong for ATPD during the period from 1990-2000. Of the 87 subjects initially diagnosed as ATPD, 64.4% had their diagnoses revised over an average of 20 years, mostly to bipolar disorder and schizophrenia. Among those with diagnosis of ATPD unchanged, 54.8% had one single episode, while the remaining 45.2% had recurrence. Subjects with diagnostic shift had significantly younger age of onset, more first-degree relatives with a history of mental illness, and more subsequent psychiatric admissions. ATPD is likely a composite category consisting of clinically distinct outcome groups, for which further research is warranted to identify diagnostic features that distinguish them at initial presentation and revise the current nosological status of ATPD. Long-term follow-up, judicial use of antipsychotics, and education on prognosis are of paramount importance in managing patients diagnosed with ATPD.


Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice.
We tested the hypothesis that endothelial nitric oxide (NO) synthase (eNOS)-derived NO modulates rho-kinase-mediated vascular contraction. Because 3-hydroxy-3-methylglutaryl (HMG)-CoA-reductase inhibition can both upregulate eNOS expression and inhibit rhoA/rho-kinase function, a second hypothesis tested was that statin treatment modulates rho-kinase-mediated contraction and that this can occur independently of eNOS. Contractile responses to the receptor-dependent agonists serotonin and phenylephrine but not to the receptor-independent agent KCl were greater in aortic rings from eNOS-null (eNOS(-/-)) vs. wild-type (eNOS(+/+)) mice. Similarly enhanced responses were seen in eNOS(+/+) rings after acute NOS inhibition. The rho-kinase inhibitor Y-27632 abolished or profoundly attenuated responses to receptor agonists in both eNOS(+/+) and eNOS(-/-) rings, but responses in eNOS(+/+) were more sensitive to Y-27632. Mevastatin treatment (20 mg/kg sc per day, 14 days) reduced responses to serotonin and phenylephrine in female mice of both strains. KCl-induced contractions were slightly smaller in eNOS(+/+)-derived aortic rings only. Levels of plasma cholesterol, and aortic expression of rhoA and rho-kinase, did not differ between groups. Thus eNOS-derived NO suppresses rhoA/rho-kinase-mediated vascular contraction. Moreover, a similar suppressive effect on rho-kinase-mediated vasoconstriction by statin therapy occurs independently of effects on eNOS or plasma cholesterol.


Adsorption of Kinetic Hydrate Inhibitors on Growing Surfaces: A Molecular Dynamics Study.
We investigate the mechanism of a typical kinetic hydrate inhibitor (KHI), polyvinylcaprolactam (PVCap), which has been applied to prevent hydrate plugs from forming in gas pipe lines, using molecular dynamics simulations of crystal growth of ethylene oxide hydrate. Water-soluble ethylene oxide is chosen as a guest species to avoid problems associated with the presence of the gas phase in the simulation cell such as slow crystal growth. A PVCap dodecamer adsorbs irreversibly on the hydrate surface which grows at supercooling of 3 K when the hydrophobic part of two pendent groups are trapped in open cages at the surface. The amide hydrogen bonds make no contribution to the adsorption. PVCap can adsorb on various crystallographic planes of sI hydrate. This is in contrast to antifreeze proteins, each of which prefers a specific plane of ice. The trapped PVCap gives rise to necessarily the concave surface of the hydrate. The crystal growth rate decreases with increasing surface curvature, indicating that the inhibition by PVCap is explained by the Gibbs-Thomson effect.


Bariatric surgery in women of reproductive age: special concerns for pregnancy.
The use of bariatric surgery for treating severe obesity has increased dramatically over the past 10 years; about half of patients who undergo these procedures are women of reproductive age. This report was commissioned to measure the incidence of bariatric surgery in this population and review the evidence on the impact of bariatric surgery on fertility and subsequent pregnancy. To measure the incidence of contemporary bariatric surgery procedures in women age 18-45 and to assess its impact on fertility, contraception, prepregnancy risk factors, and pregnancy outcomes, including those of neonates. Nationwide Inpatient Sample (NIS), a national sample of over 1,000 hospitals, to measure the trend in the number of women of reproductive age who underwent bariatric procedures from 1998-2005. We searched numerous electronic databases, including MEDLINE and Embase, for potentially relevant studies involving bariatric surgery (gastric bypass, laparoscopic adjustable gastric band, vertical-banded gastroplasty, biliopancreatic diversion), and consequent fertility, contraception, pregnancy, weight management, maternal and neonatal outcomes, and nutritional deficiencies. We scanned reference lists for additional relevant articles and contacted experts in the fields of bariatric surgery and obstetrics/gynecology (OB/GYN). Of 223 screened articles, we accepted 57 that reported on fertility following surgery (19 articles), contraception use/recommendations (11), maternal weight or nutrition management (28), maternal outcomes including morbidity and mortality (48), cesarean-section rates (16), and neonatal outcomes (44). These articles included reports on gastric bypass, both open and laparoscopic (27 articles), laparoscopic adjustable band (15), biliopancreatic diversion (16), and vertical-banded gastroplasty (6). Studies could contribute to one or more analyses. We found one case-control study and the observational data accepted included 12 cohort studies, 21 case series, and 23 individual case reports. We abstracted information about study design, fertility history, fertility outcomes, prepregnancy weight loss, nutritional management, outcomes following pregnancy, and adverse events (during pregnancy) related to surgery. Nationally representative data showed a six-fold increase in bariatric surgery inpatient procedures from 1998 to 2005. Women age 18-45 accounted for about half of the patients undergoing bariatric surgery; over 50,000 have these procedures as inpatients annually. An unknown number have outpatient bariatric procedures. We identified one case-control study that directly addressed some of the key questions, but no randomized controlled trials or prospective cohort studies, which would be the strongest study designs to answer questions about effectiveness, risk and prognosis. Consequently, all of our conclusions are limited by the available data, and are cautious.The evidence suggests that bariatric surgery results in improved fertility; the strongest evidence is in women with the polycystic ovarian syndrome, where biochemical studies showing normalization of hormones after surgery support case series data. Observational studies (retrospective cohorts and case series) suggest that fertility improves following bariatric procedures and weight loss; similar to that seen when obese women lose weight through nonsurgical means. There is almost no evidence on post-surgical contraceptive efficacy or use. Research is needed to determine whether differences in absorption, particularly for oral contraceptives, affect contraceptive efficacy. Nutrient deficiencies were reported in infants born to women who underwent procedures that resulted in malabsorption, as well as women who did not take prenatal vitamins or had difficulty with their own nutrition (i.e., from chronic vomiting). Literature suggests that gastric bypass and laparoscopic adjustable band procedures confer only minimal, if any, increased risk of nutritional or congenital problems if supplemental vitamins are taken and maternal nutrition is otherwise adequate. Biliopancreatic diversion has an appreciable risk for nutritional problems in some patients. Women who have undergone bariatric surgery may have less risk than obese women for certain pregnancy complications such as gestational diabetes, preeclampsia, and pregnancy induced hypertension. There is no evidence that cesarean section rates and delivery complications are higher in the post-surgery group, but data are limited. Weight loss procedures are being performed more frequently to treat morbid obesity, with a six-fold increase over a recent 7-year time span; almost half of all patients are women of reproductive age. The level of evidence on fertility, contraception, and pregnancy outcomes is limited to observational studies. Data suggest that fertility improves after bariatric surgical procedures, nutritional deficiencies for mother and child are minimal, and maternal and neonatal outcomes are acceptable with laparoscopic adjustable band and gastric bypass as long as adequate maternal nutrition and vitamin supplementation are maintained. There is no evidence that delivery complications are higher in post-surgery pregnancies.


Stenting of the right ventricular outflow tract in the high-risk infant with cyanotic teratology of Fallot.
Neonatal tetralogy of Fallot (TOF) repair carries an increased risk of low birthweight or premature infants. Studies are investigating stents in the right ventricular outflow tract (RVOT) as an alternative to aortopulmonary shunts. The authors review their institutional experience with RVOT stenting in the high-risk infant with TOF. Data on sequential patients who received RVOT stents were reviewed, with collection of their surgical, echocardiographic, and catheterization data. Size-matched control subjects were identified and outcomes compared. Six infants went to the catheterization lab for RVOT stenting from 2008 to 2010. Five of these patients had placement of an RVOT stent after balloon dilation. The median saturations were 71% on 48% fraction of inspired oxygen (FiO2), with improvement to 94% (p < 0.001) on 39% FiO2 24 h after stent placement. As shown by echocardiography, the diameter of the median right pulmonary artery (RPA) was 2.6 mm (z-score, -3.3), and the diameter of the left pulmonary artery (LPA) was 2.0 mm (z-score, -4.5). Repeat echocardiography before surgery showed a statistically significant increase in RPA and LPA size as well as a modified McGoon ratio (p < 0.05). Four of the five patients subsequently underwent TOF repair. No stent fractures occurred. One patient had repair 10 days after stent placement secondary to stent malposition and tricuspid valve injury. The authors' experience with stents in the RVOT of TOF patients has yielded good results, with significant improvement in oxygen saturations. Patients had successful elective surgical repair and stent removal without longer cardiopulmonary bypass times or recognizable complications compared with shunted patients.


Development of murine lupus involves the combined genetic contribution of the SLAM and FcgammaR intervals within the Nba2 autoimmune susceptibility locus.
Autoantibodies are of central importance in the pathogenesis of Ab-mediated autoimmune disorders. The murine lupus susceptibility locus Nba2 on chromosome 1 and the syntenic human locus are associated with a loss of immune tolerance that leads to antinuclear Ab production. To identify gene intervals within Nba2 that control the development of autoantibody-producing B cells and to determine the cellular components through which Nba2 genes accomplish this, we generated congenic mice expressing various Nba2 intervals where genes for the FcgammaR, SLAM, and IFN-inducible families are encoded. Analysis of congenic strains demonstrated that the FcgammaR and SLAM intervals independently controlled the severity of autoantibody production and renal disease, yet are both required for lupus susceptibility. Deregulated homeostasis of terminally differentiated B cells was found to be controlled by the FcgammaR interval where FcgammaRIIb-mediated apoptosis of germinal center B cells and plasma cells was impaired. Increased numbers of activated plasmacytoid dendritic cells that were distinctly CD19+ and promoted plasma cell differentiation via the proinflammatory cytokines IL-10 and IFNalpha were linked to the SLAM interval. These findings suggest that SLAM and FcgammaR intervals act cooperatively to influence the clinical course of disease through supporting the differentiation and survival of autoantibody-producing cells.


Downregulation of uncoupling protein 2 mRNA in white adipose tissue and uncoupling protein 3 mRNA in skeletal muscle during the early stages of leptin treatment.
The mechanisms underlying the increase in energy expenditure during leptin treatment are not clear. We recently showed that a 5-h intravenous or intracerebroventricular infusion of leptin elevated basal glucose uptake in skeletal muscle (SM) and brown adipose tissue and increased whole-body glucose turnover in C57Bl/6J mice (Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ: Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389:374-377, 1997). We extended the previous study by measuring steady-state levels of uncoupling protein (UCP)-2 mRNA and UCP-3 mRNA in white adipose tissue (WAT) and SM. Leptin by intravenous or intracerebroventricular infusion for 5 h was associated with a decrease in UCP-2 mRNA in WAT (47-52%) and UCP-3 mRNA in SM (33-37%). Because overexpression of UCP-2 or UCP-3 can depolarize the inner mitochondrial membrane, suppression of UCP-2 mRNA and UCP-3 mRNA may in fact lower respiratory demands in WAT and SM. This is consistent with the parallel suppression of cytochrome oxidase subunit IV (COX-IV) mRNA in WAT (35-39%) after leptin infusion. COX-IV mRNA in SM did not respond to acute leptin treatment. Mitochondrial inorganic phosphate carrier (P1C) mRNA was also suppressed in WAT (33-35%) by either method of leptin infusion, but only intravenous infusion of leptin reduced P1C mRNA in SM (40%). Denervation suppressed mRNA levels for UCP-2 (49%), UCP-3 (36%), and COX-IV (59%) and eliminated the acute response to leptin in SM. The comparable response to leptin under intravenous or intracerebroventricular infusion and the loss of responsiveness after denervation strongly suggest that the acute effects of leptin involve central signaling pathways.


Estimating anatomical trajectories with Bayesian mixed-effects modeling.
We introduce a mass-univariate framework for the analysis of whole-brain structural trajectories using longitudinal Voxel-Based Morphometry data and Bayesian inference. Our approach to developmental and aging longitudinal studies characterizes heterogeneous structural growth/decline between and within groups. In particular, we propose a probabilistic generative model that parameterizes individual and ensemble average changes in brain structure using linear mixed-effects models of age and subject-specific covariates. Model inversion uses Expectation Maximization (EM), while voxelwise (empirical) priors on the size of individual differences are estimated from the data. Bayesian inference on individual and group trajectories is realized using Posterior Probability Maps (PPM). In addition to parameter inference, the framework affords comparisons of models with varying combinations of model order for fixed and random effects using model evidence. We validate the model in simulations and real MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project. We further demonstrate how subject specific characteristics contribute to individual differences in longitudinal volume changes in healthy subjects, Mild Cognitive Impairment (MCI), and Alzheimer's Disease (AD).


Association of nuclear membrane protein lamin B1 with necrosis and apoptosis in cell death induced by 5-fluoro-2'-deoxyuridine.
We report that anticancer 5-fluoro-2 '-deoxyuridine (FUdR) shows cytotoxicity against mouse cancer cell line FM3A, using a progeny clone F28-7 and its variant F28-7-A. In this process, the cell-death morphology is different between F28-7 and F28-7-A cells, that is, necrosis in F28-7 but apoptosis in F28-7-A cells. In the proteomic analysis of these cells before their exposure to FUdR, the nuclear inner-membrane protein lamin B1 is up-regulated in F28-7 but not in F28-7-A, suggesting that lamin B1 may possess a function to regulate the morphology of cell-death. A knockdown of lamin B1 expression in F28-7 cells was performed by use of the small interfering RNA technique, resulting in a decrease of the lamin B1-expression level down to the level in F28-7-A. Remarkably, the FUdR-induced death morphology of this knocked-down F28-7 was apoptosis, definitely different from the necrosis that occurs in the FUdR-treated original F28-7. Thus, the swelling feature for the necrosis was no longer observable, and instead cell shrinkage typical of apoptosis took place in almost all the cells examined. This finding suggests a new role for lamin B1 as a regulator in cell death.


Elevated expression of DNA ligase I in human cancers.
Human DNA ligase I plays an essential role in DNA replication, recombination, and repair by catalyzing the formation of phosphodiester bonds between adjacent 5'-phosphoryl and 3'-hydroxyl termini at single breaks in duplex DNA molecules. DNA ligase I is responsible for the majority of DNA ligase activity present in proliferating cells among four different forms of DNA ligases, designated DNA ligase I, II, III, and IV. In this study, we were interested in comparing DNA ligase I level in human tumors versus normal tissues and in studying whether the inhibition of DNA ligase I could lead to tumor cell death. DNA ligase I level was measured by Western immunoblot assay in various human malignant tumor specimens and benign tissues obtained from patients, in peripheral blood lymphocytes obtained from healthy donors, and in human tumors grown in nude mice. We also have designed antisense oligonucleotides (ODNs) targeting the mRNA of DNA ligase I and tested whether DNA ligase I antisense ODNs could control tumor cell growth. The amount of DNA ligase I enzyme in malignant tumors was considerably higher than that in benign normal tissues and peripheral blood lymphocytes. The level of DNA ligase I in human tumors grown in nude mice was also very high, and the expression of DNA ligase I appears to be constitutive during in vivo tumor development. We have observed that DNA ligase I antisense ODN inhibited tumor cell growth in a dose-response manner, but nonspecific control ODNs had little effect on the growth of the same cell lines. The presence of DNA ligase I at higher levels in human tumors than in benign normal tissues and normal peripheral lymphocytes suggests DNA ligase I plays more of a role in proliferating cells than in resting cells. These results, together with our finding that DNA ligase I antisense ODNs can suppress tumor cell proliferation, warrant the design and testing of human DNA ligase I inhibitors as new anticancer agents.


Psychiatric gene discoveries shape evidence on ADHD's biology.
A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.


Countrywide multi-serotype outbreak of Salmonella Bovismorbificans ST142 and monophasic Salmonella Typhimurium ST34 associated with dried pork sausages in France, September 2020* to January 2021.
The French National Reference Centre for Escherichia coli, Shigella and Salmonella (FNRC-ESS) detected two human clusters of 33 cases (median age: 10 years; 17 females) infected by Salmonella enterica serotype Bovismorbificans, ST142, HC5_243255 (EnteroBase HierCC‑cgMLST scheme) in September-November 2020 and of 11 cases (median age: 11 years; seven males) infected by S. enterica serotype 4,12:i:-, ST34, HC5_198125 in October-December 2020. Epidemiological investigations conducted by Santé publique France linked these outbreaks to the consumption of dried pork sausages from the same manufacturer. S. Bovismorbificans and S. 4,12:i:- were isolated by the National Reference Laboratory from different food samples, but both strains were identified in a single food sample only by qPCR. Three recalls and withdrawals of dried pork products were issued by the French general directorate of food of the French ministry for agriculture and food in November 2020, affecting eight supermarket chains. A notification on the European Rapid Alert System for Food and Feed and a European urgent enquiry on the Epidemic Intelligence Information System for Food and Waterborne Diseases and Zoonoses (EPIS-FWD) were launched. No cases were reported outside France. Outbreaks caused by multiple serotypes of Salmonella may go undetected by protocols in standard procedures in microbiology laboratories.


Comparing age effects in normally and extremely highly educated and intellectually engaged 65 - 80 year-olds: potential protection from deficit through educational and intellectual activities across the lifespan.
Education and cognitive activity have been suggested to protect against cognitive decline in old age. However, little is known about the long-term effects of extremely high levels of education and intellectual activity across the lifespan. The present study investigated the extent to which these two variables may moderate the age-related differences in cognitive performance in old adults. Therefore, story recall, paired-associates learning, reading span and letter digit performance of 62 university professors (mean age = 72.47) were compared with those of a representative sample of 196 participants of the Zurich Longitudinal Study of Cognitive Aging (mean age = 73.04). The results demonstrate that the highly educated sample performed significantly better than the normally educated sample in the paired-associates learning and reading span test. Furthermore, age effects were found in the letter digit as well as in the paired-associates learning test. While the normally educated sample demonstrated an age-related decrease in the paired-associates learning test, the performance of the highly educated sample actually increased with increasing age. These findings suggest that extremely high levels of education and intellectual activity may postpone age-related deficits in paired-associates learning tasks, but not in speed of processing tasks.


No moderating influence of education on the association between changes in hippocampus volume and memory performance in aging.
Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.


Heavy Metal-Induced Expression of PcaA Provides Cadmium Tolerance to Aspergillus fumigatus and Supports Its Virulence in the Galleria mellonella Model.
Most of the metal transporters in Aspergillus fumigatus are yet uncharacterized. Their role in fungal metabolism and virulence remains unclear. This paper describes the novel PIB-type cation ATPase PcaA, which links metal homeostasis and heavy metal tolerance in the opportunistic human pathogen A. fumigatus. The protein possesses conserved ATPase motif and shares 51% amino acid sequence identity with the Saccharomyces cerevisiae cadmium exporter Pca1p. A pcaA deletion, an overexpression and a gfp-pcaA complementation strain of A. fumigatus were constructed and their heavy metal susceptibilities were studied. The pcaA knock out strain showed drastically decreased cadmium tolerance, however, its growth was not affected by the exposure to high concentrations of copper, iron, zinc, or silver ions. Although the lack of PcaA had no effect on copper adaption, we demonstrated that not only cadmium but also copper ions are able to induce the transcription of pcaA in A. fumigatus wild type Af293. Similarly, cadmium and copper ions could induce the copper exporting ATPase crpA. These data imply a general response on the transcriptomic level to heavy metals in A. fumigatus through the induction of detoxification systems. Confocal microscopy of the gfp-pcaA complementation strain expressing functional GFP-PcaA supports the predicted membrane localization of PcaA. The GFP-PcaA fusion protein is located in the plasma membrane of A. fumigatus in the presence of cadmium ions. Virulence assays support a function of PcaA for virulence of A. fumigatus in the Galleria mellonella wax moth larvae model, which might be linked to the elimination of reactive oxygen species.


Transcriptional repressor functions of Drosophila E2F1 and E2F2 cooperate to inhibit genomic DNA synthesis in ovarian follicle cells.
Individual members of the E2F/DP protein family control cell cycle progression by acting predominantly as an activator or repressor of transcription. In Drosophila melanogaster the E2f1, E2f2, Dp, and Rbf1 genes all contribute to replication control in ovarian follicle cells, which become 16C polyploid and subsequently undergo chorion gene amplification late in oogenesis. Mutation of E2f2, Dp, or Rbf1 causes ectopic DNA replication throughout the follicle cell genome during gene amplification cycles. Here we show by both reverse transcription-PCR and DNA microarray analysis that the transcripts of prereplication complex (pre-RC) genes are elevated compared to the wild type in E2f2, Dp, and Rbf1 mutant follicle cells. For some genes the magnitude of this transcriptional derepression is greater in Rbf1 than in E2f2 mutants. These differences correlate with differences in the magnitude of the replication defects in follicle cells, which attain an inappropriate 32C DNA content in both Rbf1 and Dp mutants but not in E2f2 mutants. The ectopic genomic replication of E2f2 mutant follicle cells can be suppressed by reducing the Orc2, Orc5, or Mcm2 gene dose by half, indicating that small changes in pre-RC gene expression can affect DNA synthesis in these cells. We conclude that RBF1 forms complexes with both E2F1/DP and E2F2/DP that cooperate to repress the expression of pre-RC genes, which helps confine DNA synthesis to sites of gene amplification. In contrast, E2F1 and E2F2 repressors function redundantly for some genes in the embryo. Thus, the relative functional contributions of E2F1 and E2F2 to gene expression and cell cycle control depends on the developmental context.


Effect of location and stage of development of dominant follicle on ovulation and embryo survival rate in alpacas.
This study was designed to determine the effect of location of the preovulatory dominant follicle and stage of ovarian follicle development on ovulation rate and embryo survival in alpacas. In Experiment 1, mature lactating alpacas were randomly assigned to one of two groups according to the location of the dominant follicle detected by ultrasonography: (a) Right ovary (RO, n=96) or (b) Left ovary (LO, n=108). All females were mated once by an intact adult male. Ovulation rate, CL diameter and embryo survival rate (heartbeat) were assessed by ultrasonography on Days 2 (Day 0=mating), 8 and 30, respectively. Ovulation rate (96.5 and 96.3% for RO and LO group, respectively), corpus luteum (CL) diameter (10.2 and 10.6 mm for RO and LO group, respectively) and pregnancy rate (60.2 and 56.7% for RO and LO group, respectively) did not differ among groups. In Experiment 2, lactating alpacas (n=116) were submitted to ultrasonic-guided follicle ablation to synchronize follicular wave emergence. Afterwards, daily ultrasonography examinations were performed and females were randomly assigned to the following groups according to the growth phase and diameter of the dominant follicle: (a) early growing (5-6 mm, n=27), (b) growing (7-12 mm, n=30); (c) static (7-12 mm, n=30), or (d) regressing phase (12-7 mm, n=29). All alpacas were mated with a proven intact male, except five alpacas from early growing group that rejected the male. Females were examined by ultrasonography on Day 2 (ovulation rate), Day 8 (CL diameter), and Days 15, 20, 25, 30 and 35 (embryo survival by the presence of embryo proper and heartbeat). No differences were detected in ovulation rate among groups (96%, 97%, 100%, and 97%) or in CL size (10.3, 11.7, 11.1, and 11.1 mm, for early growing, growing, early static and regressing, respectively). Although, embryo survival rate at Day 35 after mating was numerically greatest in growing (65.5%), intermediate in early growing (52.4%) and static (53.3%), and least in regressing phase (42.9%), there were no differences among groups. Results suggest that neither location nor stage of development of the dominant follicle has an influence on ovulation and embryo survival rate in alpacas.


Idiopathic Inflammatory Myopathies: an Update on Classification and Treatment with Special Focus on Juvenile Forms.
Juvenile inflammatory myopathies represent a heterogeneous group of rare and potentially fatal disorders of unknown aetiology, characterised by inflammation and proximal and symmetric muscle weakness. Beyond many similarities, specific clinical, laboratoristic and histopathologic features underlie different subsets with distinguishing demographic, prognostic and therapeutic peculiarities. Over time, several forms of inflammatory idiopathic myopathies have been described, including macrophagic myofascitis, immune-mediated necrozing myopathy and the spectrum of amyopathic dermatomyositis that include hypomyopathic dermatomyositis, inclusion body myositis and cancer-associated myositis occurring almost exclusively in adults. However, juvenile dermatomyositis is the most frequent in childhood, whereas polymyositis is relatively more frequent in adults. The aetiology is nowadays widely unclear; however, current theories contemplate a combination of environmental triggers, immune dysfunction and specific tissue responses involving muscle, skin and small vessels endothelium in genetically susceptible individuals. Myositis-specific autoantibodies, found almost exclusively in patients with myositis and myositis-associated autoantibodies, detectable both among patients with myositis and in subjects suffering from other autoimmune diseases, have an important clinical role because of their relation to specific clinical features, response to therapy and prognosis. The gold standard treatment for juvenile dermatomyositis is represented by corticosteroids, along with adjunctive steroid-sparing immunosuppressive therapies, which are used to counteract disease activity, prevent mortality, and reduce long-term disability. Further treatment approach such as biologic agents and autologous stem cell transplantation are emerging during the last years, in particular in patients difficult to treat and with poor prognosis. Therefore, a highly medical specialised approach is required for diagnosis and management of these conditions. This review comprehensively examines juvenile inflammatory myopathies focusing on clinical and laboratory classifications as well as on the current treatment approaches, referring in particular on biologic agents and latest therapeutic opportunities.


Preventing infections during cancer treatment: development of an interactive patient education website.
Despite advances in oncology care, infections from both community and healthcare settings remain a major cause of hospitalization and death among patients with cancer receiving chemotherapy. Neutropenia (low white blood cell count) is a common and potentially dangerous side effect in patients receiving chemotherapy treatments and may lead to higher risk of infection. Preventing infection during treatment can result in significant decreases in morbidity and mortality for patients with cancer. As part of the Centers for Disease Control and Prevention's (CDC's) Preventing Infections in Cancer Patients public health campaign, a public-private partnership was formed between the CDC Foundation and Amgen, Inc. The CDC's Division of Cancer Prevention and Control developed and launched an interactive website, www.PreventCancerInfections.org, designed for patients with cancer undergoing chemotherapy. The site encourages patients to complete a risk assessment for developing neutropenia during their treatment. After completing the assessment, patients receive information about how to lower the risk for infection and keep themselves healthy while receiving chemotherapy.


Pathophysiology, diagnosis and management of exercise-induced anaphylaxis.
The aim of this review is to challenge the current opinions of the pathophysiological mechanisms that give rise to food dependent exercise-induced anaphylaxis (FDEIA) and to consider these mechanisms within the wider context of exercise physiology to further inform our understanding and treatment of this condition. Exercise-induced anaphylaxis (food dependent and nonfood dependent) is a clinical syndrome in which anaphylaxis occurs in conjunction with exercise. Given the rarity of the condition, our current understanding relies on the many case studies and reviews of the topic. The pathophysiology of FDEIA remains to be fully elucidated with well constructed trials but current working hypotheses to date involve alterations in plasma osmolaltiy and pH, tissue enzyme activity, blood flow redistribution, altered gastrointestinal permeability and facilitated epitope recognition/allergen binding. Implications for future research are the physiological changes that occur during exercise need deeper consideration to ensure that proposed mechanisms are realistic and actually occur within the time frame and exercise-intensity domain during which the reported FDEIA occurred. These theories must be tested rigorously with sufficiently powered studies if progress is to be made in determining the perplexing pathophysiology of FDEIA.


Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct.
Two histopathological subtypes of Meniere's disease (MD) were recently described in a human post-mortem pathology study. The first subtype demonstrated a degenerating distal endolymphatic sac (ES) in the affected inner ear (subtype MD-dg); the second subtype (MD-hp) demonstrated an ES that was developmentally hypoplastic. The two subtypes were associated with different clinical disease features (phenotypes), suggesting that distinct endotype-phenotype patterns exist among MD patients. Therefore, clinical endotyping based on ES pathology may reveal clinically meaningful MD patient subgroups. Here, we retrospectively determined the ES pathologies of clinical MD patients (n = 72) who underwent intravenous delayed gadolinium-enhanced inner ear magnetic resonance imaging using previously established indirect radiographic markers for both ES pathologies. Phenotypic subgroup differences were evidenced; for example, the MD-dg group presented a higher average of vertigo attacks (ratio of vertigo patterns daily/weekly/other vs. monthly, MD-dg: 6.87: 1; MD-hp: 1.43: 1; p = 0.048) and more severely reduced vestibular function upon caloric testing (average caloric asymmetry ratio, MD-dg: 30.2% ± 30.4%; MD-hp: 13.5% ± 15.2%; p = 0.009), while the MD-hp group presented a predominantly male sex ratio (MD-hp: 0.06:1 [f/m]; MD-dg: 1.2:1 [f/m]; p = 0.0004), higher frequencies of bilateral clinical affection (MD-hp: 29.4%; MD-dg: 5.5%; p = 0.015), a positive family history for hearing loss/vertigo/MD (MD-hp: 41.2%; MD-dg: 15.7%; p = 0.028), and radiographic signs of concomitant temporal bone abnormalities, i.e., semicircular canal dehiscence (MD-hp: 29.4%; MD-dg: 3.6%; p = 0.007). In conclusion, this new endotyping approach may potentially improve the diagnosis, prognosis and clinical decision-making for individual MD patients.


Nephronophthisis-associated ciliopathies.
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. Contrary to polycystic kidney disease, NPHP shows normal or diminished kidney size, cysts are concentrated at the corticomedullary junction, and tubulointerstitial fibrosis is dominant. NPHP can be associated with retinitis pigmentosa (Senior-Løken syndrome), liver fibrosis, and cerebellar vermis aplasia (Joubert syndrome) in approximately 10% of patients. Positional cloning of six novel genes (NPHP1 through 6) as mutated in NPHP and functional characterization of their encoded proteins have contributed to the concept of "ciliopathies." It has helped advance a new unifying theory of cystic kidney diseases. This theory states that the products of all genes that are mutated in cystic kidney diseases in humans, mice, or zebrafish are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, osmotic, and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary theory explains the multiple organ involvement in NPHP regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation. Mutations in NPHP genes cause defects in signaling mechanisms, including the noncanonical Wnt signaling pathway. The "ciliopathy" NPHP thereby is caused by defects in tissue differentiation and maintenance as a result of impaired processing of extracellular cues. Nephrocystins, the proteins that are encoded by NPHP genes, are highly conserved in evolution. Positional cloning of additional causative genes of NPHP will elucidate further signaling mechanisms that are involved, thereby establishing therapeutic approaches using animal models in mouse, zebrafish, and Caenorhabditis elegans.


Effect of Autumn Planting Date and Stand Age on Severity of Stem Rust in Seed Crops of Perennial Ryegrass.
Perennial ryegrass (Lolium perenne) grown for seed is planted in autumn for July harvest (first-year seed crop), then kept in production for subsequent yearly harvests. Plots of first-year perennial ryegrass planted in early November had only 3% as much stem rust in June as plots planted in mid-September. In other plots where fungicides were used to prevent rust development, seed yield from the November-planted plots was reduced by 23% compared with September-planted plots. In the second-year seed crop, stem rust severity in June was intermediate between severities in early- and late-planted first-year plots. The association of reduced stem rust severity with late planting for first-year crops was observed for five of six perennial ryegrass cultivars tested. Degree of reduction in disease severity due to planting date was greatest for the cultivars that had the highest disease severity in early-planted stands. Delay of autumn planting date may provide a useful cultural control method for first-year stands of perennial ryegrass seed crops.


Total antioxidant capacity and the severity of the pain in patients with fibromyalgia.
The purpose of the study was to determine the oxidative and antioxidative status of plasma in patients with fibromyalgia. Total antioxidant capacity (TAC) of plasma was significantly lower in patients with fibromyalgia (n = 20) than in healthy controls (n = 20) [1.5 (SD 0.3) and 1.9 (SD 0.3) mmol Trolox equiv./l, P = 0.001]. In contrast, the total peroxide level of plasma was significantly higher in patients than in healthy controls [37.4 (SD 6.7) and 33.0 (SD 2.7) micromol H2O2/l; P = 0.01]. The oxidative stress index (OSI) level was significantly higher in patients with fibromyalgia than in healthy controls [2.5 (SD 1.0) and 1.8 (SD 0.4); P = 0.007]. A significant negative correlation between visual analogue scale (VAS) and TAC level was determined (r = -0.79, P < 0.001). The present results indicate that patients with fibromyalgia are exposed to oxidative stress and this increased oxidative stress may play a role in the etiopathogenesis of the disease. Supplementation of antioxidant vitamins such as vitamins C and E to the therapy may be indicated.


A Lipidomics Approach in the Characterization of Zika-Infected Mosquito Cells: Potential Targets for Breaking the Transmission Cycle.
Recent outbreaks of Zika virus in Oceania and Latin America, accompanied by unexpected clinical complications, made this infection a global public health concern. This virus has tropism to neural tissue, leading to microcephaly in newborns in a significant proportion of infected mothers. The clinical relevance of this infection, the difficulty to perform accurate diagnosis and the small amount of data in literature indicate the necessity of studies on Zika infection in order to characterize new biomarkers of this infection and to establish new targets for viral control in vertebrates and invertebrate vectors. Thus, this study aims at establishing a lipidomics profile of infected mosquito cells compared to a control group to define potential targets for viral control in mosquitoes. Thirteen lipids were elected as specific markers for Zika virus infection (Brazilian strain), which were identified as putatively linked to the intracellular mechanism of viral replication and/or cell recognition. Our findings bring biochemical information that may translate into useful targets for breaking the transmission cycle.


A deep learning approach for pose estimation from volumetric OCT data.
Tracking the pose of instruments is a central problem in image-guided surgery. For microscopic scenarios, optical coherence tomography (OCT) is increasingly used as an imaging modality. OCT is suitable for accurate pose estimation due to its micrometer range resolution and volumetric field of view. However, OCT image processing is challenging due to speckle noise and reflection artifacts in addition to the images' 3D nature. We address pose estimation from OCT volume data with a new deep learning-based tracking framework. For this purpose, we design a new 3D convolutional neural network (CNN) architecture to directly predict the 6D pose of a small marker geometry from OCT volumes. We use a hexapod robot to automatically acquire labeled data points which we use to train 3D CNN architectures for multi-output regression. We use this setup to provide an in-depth analysis on deep learning-based pose estimation from volumes. Specifically, we demonstrate that exploiting volume information for pose estimation yields higher accuracy than relying on 2D representations with depth information. Supporting this observation, we provide quantitative and qualitative results that 3D CNNs effectively exploit the depth structure of marker objects. Regarding the deep learning aspect, we present efficient design principles for 3D CNNs, making use of insights from the 2D deep learning community. In particular, we present Inception3D as a new architecture which performs best for our application. We show that our deep learning approach reaches errors at our ground-truth label's resolution. We achieve a mean average error of 14.89 ± 9.3 µm and 0.096 ± 0.072° for position and orientation learning, respectively.


Solar-driven carbon dioxide fixation using photosynthetic semiconductor bio-hybrids.
Solar-driven conversion of carbon dioxide to value-added carbon products is an ambitious objective of ongoing research efforts. However, high overpotential, low selectivity and poor CO2 mass transfer plague purely inorganic electrocatalysts. In this instance, we can consider a class of biological organisms that have evolved to achieve CO2 fixation. We can harness and combine the streamlined CO2 fixation pathways of these whole organisms with the exceptional ability of semiconducting nanomaterials to harvest solar energy. A novel nanomaterial-biological interface has been pioneered in which light-capturing cadmium sulfide nanoparticles reside within individual organisms essentially powering biological CO2 fixation by solar energy. In order to further develop the photosensitized organism platform, more biocompatible photosensitizers and cytoprotective strategies are required as well as elucidation of charge transfer mechanisms. Here, we discuss the ability of gold nanoclusters to photosensitize a model acetogen effectively and biocompatibly. Additionally, we present innovative materials including two-dimensional metal organic framework sheets and alginate hydrogels to shield photosensitized cells. Finally, we delve into original work using transient absorption spectroscopy to inform on charge transfer mechanisms.


Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain.
The transient receptor potential channel subfamily member 5 (TRPC5) is a calcium permeable cation channel widely expressed in the brain. Accumulating evidence indicates that it plays a crucial role in psychiatric disorders including depression and anxiety. Positron emission tomography (PET) combined with a TRPC5 specific radioligand may provide a unique tool to investigate the functions of TRPC5 in animal disease models to guide drug development targeting TRPC5. To develop a TRPC5 PET radiotracer, the potent TRPC5 inhibitor HC608 was chosen for C-11 radiosynthesis through the N-demethyl amide precursor 7 reacting with [11C]methyl iodide. Under optimized conditions, [11C]HC608 was achieved with good radiochemical yield (25 ± 5%), high chemical and radiochemical purity (>99%), and high specific activity (204-377 GBq μmol-1, decay corrected to the end of bombardment, EOB). The in vitro autoradiography study revealed that [11C]HC608 specifically binds to TRPC5. Moreover, initial in vivo evaluation of [11C]HC608 performed in rodents and the microPET study in the brain of non-human primates further demonstrated that [11C]HC608 was able to penetrate the blood brain barrier and sufficiently accumulate in the brain. These results suggest that [11C]HC608 has the potential to be a PET tracer for imaging TRPC5 in vivo.