The Significance of Emotions and Professional Relations for Accommodating a Web-Based Ulcer Record and Improving Home-Based Care.
Evidence of technological performance, medical improvements and economic effectiveness is generally considered sufficient for judging advances in healthcare. In this paper, I aim to add knowledge about the ways human emotions and professional relations play roles in the processes of accommodating new technologies for quality improvements. A newly-implemented, web-based ulcer record service for patients with chronic skin ulcers constitutes the case. After one year, only a few home care nurses were using the service, interacting with a specialist team. The result was disappointing, but the few users were enthusiastic. An explorative, qualitative study was initiated to understand the users, the processes that accounted for use and how improvements were enacted. In the paper, I expose the emotional aspects of the record accommodation by analyzing the ways emotions were translated in the process and how they influenced the improvements. I contend that use came about through a heterogeneous assemblage of ethical engagement and compassionate emotions stemming from frustration, combined with technological affordances and relations between different professionals. Certain aspects of the improvements are exposed. These are discussed as: (1) reconciliations between the medical facts and rational judgments, on one side, and the emotional and subjective values for judging quality, on the other; and (2) mediation between standardized and personalized care. The healing of ulcers was combined with a sense of purpose and wellbeing to validate improvements. Emotions were strongly involved, and the power of evaluative emotions and professional relations should be further explored to add to the understanding of innovation processes and to validate quality improvements.


Value-based provider payment: towards a theoretically preferred design.
Worldwide, policymakers and purchasers are exploring innovative provider payment strategies promoting value in health care, known as value-based payments (VBP). What is meant by 'value', however, is often unclear and the relationship between value and the payment design is not explicated. This paper aims at: (1) identifying value dimensions that are ideally stimulated by VBP and (2) constructing a framework of a theoretically preferred VBP design. Based on a synthesis of both theoretical and empirical studies on payment incentives, we conclude that VBP should consist of two components: a relatively large base payment that implicitly stimulates value and a relatively small payment that explicitly rewards measurable aspects of value (pay-for-performance). Being the largest component, the base payment design is essential, but often neglected when it comes to VBP reform. We explain that this base payment ideally (1) is paid to a multidisciplinary provider group (2) for a cohesive set of care activities for a predefined population, (3) is fixed, (4) is adjusted for the population's risk profile and (5) includes risk-mitigating measures. Finally, some important trade-offs in the practical operationalisation of VBP are discussed.


Tryptophan metabolites and incident cardiovascular disease: The EPIC-Norfolk prospective population study.
Cardiovascular disease (CVD) remains the largest cause of death globally due to various risk factors. One novel potential contributor to CVD might be the metabolism of the essential amino acid tryptophan (Trp), which through many pathways can produce immunomodulatory metabolites such as kynurenine, indole-3-propionate and serotonin. We aim to identify the metabolites with the strongest association with cardiovascular disease, utilizing a substantial and diverse cohort of individuals. In our pursuit of this aim, our primary focus is to validate and reinforce the findings from previous cross-sectional studies. We used the community-based EPIC-Norfolk cohort (46.3 % men, age 59.8 ± 9.0) with a median follow-up of 22.1 (17.6-23.3) years to study associations between the relative levels of Trp metabolites measured with untargeted metabolomics and incident development of CVD. Serum from n = 11,972 apparently healthy subjects was analysed, of which 6982 individuals had developed CVD at the end of follow-up. Cox proportional hazard models were used to study associations, adjusted for sex, age, conventional cardiovascular risk factors and CRP. All metabolites were Ln-normalised prior to analysis. Higher levels of Trp were inversely associated with mortality (HR 0.73; CI 0.64-0.83) and fatal CVD (HR 0.76; CI 0.59-0.99). Higher levels of kynurenine (HR 1.33; CI 1.19-1.49) and the [Kynurenine]/[Tryptophan]-ratio (HR 1.24; CI 1.14-1.35) were associated with a higher incident development of CVD. Serotonin was not associated with overall CVD, but we did find associations for myocardial infarction and stroke. Adjustment for CRP did not yield any discernible differences in effect size. Tryptophan levels were inversely correlated with CVD, while several of its major metabolites (especially kynurenine and serotonin) were positively correlated. These findings indicate that mechanistic studies are required to understand the role of Trp metabolism in CVD with the goal to identify new therapeutic targets.


Computed tomography bronchial lumen to pulmonary artery diameter ratio in dogs without clinical pulmonary disease.
Bronchiectasis is diagnosed in humans using multiple computed tomography (CT) criteria, the most important being dilatation of the bronchi. The most widely used criterion for detection of bronchial dilatation is a bronchial lumen to pulmonary artery diameter (bronchoarterial [BA]) ratio >1.0. No studies have been performed to determine the BA ratio in normal dogs. Thoracic CT images of 24 dogs without clinical pulmonary disease were reviewed. The BA ratio of the lobar bronchi of the left cranial (cranial and caudal parts), right cranial, right middle, left caudal, and right caudal lung lobes was measured. The mean of the mean BA ratio for all dogs was 1.45 +/- 0.21 (99% confidence interval [CI] = 1.34-1.56). The mean of the mean BA ratio as determined by lung lobe was 1.45 +/- 0.04 (99% CI = 1.41-1.49). The range of individual BA ratios was 0.8-2.0. There was no significant difference in mean BA ratios as a function of lung lobe (P = 0.60). The BA ratio in these clinically normal dogs was consistent and may be a useful tool in evaluating for bronchiectasis on CT images. BA ratios >2.0 were not identified in this population, suggesting a threshold to differentiate normal from abnormal bronchi.


[Aging and cancer: coincidence or etiologic relationship?].
In Belgium and in other countries, the Cancer Registry data show an increased incidence of cancers related to age, the majority of tumors being diagnosed beyond 60 years. However, the mechanisms responsible for this increase are not clear. Cancer could be chronologically associated with aging because of the long latency period between the exposition to carcinogenic agents and the appearance of clinical signs. Aging could also predispose directly to cancer by different mechanisms (impaired immune response, increased oxidative stress, shortening of telomeres, accumulation of senescent cells). In this review, we propose to describe different hypotheses which could explain the increased incidence of cancers in the elderly.


Bone marrow injection: A novel treatment for tennis elbow.
The objective of this prospective study was assessment of efficacy of bone marrow aspirate (BMA) (containing plasma rich in growth factors and mesenchymal stem cells) injection in treatment of tennis elbow. A total of 30 adult patients of previously untreated tennis elbow were administered single injection of BMA. This concentrate was made by centrifugation of iliac BMA at 2000 rpm for 20-30 min and only upper layer containing platelet rich plasma and mononuclear cells was injected. Assessment was performed at baseline, 2 weeks, 6 weeks and 12 weeks using Patient-rated Tennis Elbow Evaluation (PRTEE) score. Baseline pre-injection mean PRTEE score was 72.8 ± 6.97 which decreased to a mean PRTEE score of 40.93 ± 5.94 after 2 weeks of injection which was highly significant (P < 0.0001). The mean PRTEE score at 6 week and 12 week follow-up was 24.46 ± 4.58 and 14.86 ± 3.48 respectively showing a highly significant decrease from baseline scores (P < 0.0001). Treatment of tennis elbow patients with single injection of BMA showed a significant improvement in short to medium term follow-up. In future, such growth factors and/or stem cells based injection therapy can be developed as an alternative conservative treatment for patients of tennis elbow, especially who have failed non-operative treatment before surgical intervention is taken.


Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome.
Tenascin-X is an extracellular matrix protein initially identified because the gene encoding it overlaps with the human CYP21B gene. Because studies of gene and protein function of other tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating tenascin-X mutations and novel recessive and dominant forms of Ehlers-Danlos syndrome (EDS). Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes EDS. Tenascin-X null mice recapitulate the skin findings of the human disease, confirming a causative role for this gene in EDS. Further evaluation of these mice showed that tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of EDS. Further studies suggest that tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human "experiments of nature" can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins.


Thermal conductivity of electrospun polyethylene nanofibers.
We report on the structure-thermal transport property relation of individual polyethylene nanofibers fabricated by electrospinning with different deposition parameters. Measurement results show that the nanofiber thermal conductivity depends on the electric field used in the electrospinning process, with a general trend of higher thermal conductivity for fibers prepared with stronger electric field. Nanofibers produced at a 45 kV electrospinning voltage and a 150 mm needle-collector distance could have a thermal conductivity of up to 9.3 W m(-1) K(-1), over 20 times higher than the typical bulk value. Micro-Raman characterization suggests that the enhanced thermal conductivity is due to the highly oriented polymer chains and enhanced crystallinity in the electrospun nanofibers.


Molecular mapping of the new blast resistance genes Pi47 and Pi48 in the durably resistant local rice cultivar Xiangzi 3150.
The indica rice cultivar Xiangzi 3150 (XZ3150) confers a high level of resistance to 95% of the isolates of Magnaporthe oryzae (the agent of rice blast disease) collected in Hunan Province, China. To identify the resistance (R) gene(s) controlling the high level of resistance in this cultivar, we developed 286 F(9) recombinant inbred lines (RILs) from a cross between XZ3150 and the highly susceptible cultivar CO39. Inoculation of the RILs and an F(2) population from a cross between the two cultivars with the avirulent isolate 193-1-1 in the growth chamber indicated the presence of two dominant R genes in XZ3150. A linkage map with 134 polymorphic simple sequence repeat and single feature polymorphism markers was constructed with the genotype data of the 286 RILs. Composite interval mapping (CIM) using the results of 193-1-1 inoculation showed that two major R genes, designated Pi47 and Pi48, were located between RM206 and RM224 on chromosome 11, and between RM5364 and RM7102 on chromosome 12, respectively. Interestingly, the CIM analysis of the four resistant components of the RILs to the field blast population revealed that Pi47 and Pi48 were also the major genetic factors responsible for the field resistance in XZ3150. The DNA markers linked to the new R genes identified in this study should be useful for further fine mapping, gene cloning, and marker-aided breeding of blast-resistant rice cultivars.


Src and ADAM-17-mediated shedding of transforming growth factor-alpha is a mechanism of acute resistance to TRAIL.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) has emerged as a promising anticancer agent. However, resistance to TRAIL is likely to be a major problem, and sensitization of cancer cells to TRAIL may therefore be an important anticancer strategy. In this study, we examined the effect of the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib and a human epidermal receptor 2 (HER2)-TKI (M578440) on the sensitivity of human colorectal cancer (CRC) cell lines to recombinant human TRAIL (rhTRAIL). A synergistic interaction between rhTRAIL and gefitinib and rhTRAIL and M578440 was observed in both rhTRAIL-sensitive and resistant CRC cells. This synergy correlated with an increase in EGFR and HER2 activation after rhTRAIL treatment. Furthermore, treatment of CRC cells with rhTRAIL resulted in activation of the Src family kinases (SFK). Importantly, we found that rhTRAIL treatment induced shedding of transforming growth factor-alpha (TGF-alpha) that was dependent on SFK activity and the protease ADAM-17. Moreover, this shedding of TGF-alpha was critical for rhTRAIL-induced activation of EGFR. In support of this, SFK inhibitors and small interfering RNAs targeting ADAM-17 and TGF-alpha also sensitized CRC cells to rhTRAIL-mediated apoptosis. Taken together, our findings indicate that both rhTRAIL-sensitive and resistant CRC cells respond to rhTRAIL treatment by activating an EGFR/HER2-mediated survival response and that these cells can be sensitized to rhTRAIL using EGFR/HER2-targeted therapies. Furthermore, this acute response to rhTRAIL is regulated by SFK-mediated and ADAM-17-mediated shedding of TGF-alpha, such that targeting SFKs or inhibiting ADAM-17, in combination with rhTRAIL, may enhance the response of CRC tumors to rhTRAIL.


Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment.
Chronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported. Thirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome. Naproxen treatment was highly effective in general, inducing a symptom-free status in 43% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67% of them were clinically silent. Most children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics.


Molecular inference, multivariate morphometrics and ecological assessment are applied in concert to delimit species in the Russula clavipes complex.
Species of Russula subsect. Xerampelinae are notoriously difficult to identify and name and have not been subject to molecular study. A group of species, referred to here as the R. clavipes complex, growing in association with Salix, Betula and Populus as well as coniferous tree species from temperate to arctic and alpine habitats, were examined. Analyses of the nuc rDNA internal transcribed spacer (ITS) region and a numerical analysis of morphological characters were used. The R. clavipes complex is a monophyletic group within Russula subsect. Xerampelinae, according to molecular results. The complex includes three species: R. nuoljae is a phylogenetically and morphologically well-supported species while the other two, R. clavipes and R. pascua, are similar based on ITS data and morphology but separate based on their ecology. Russula pseudoolivascens is conspecific with R. clavipes Several combinations of characters traditionally used in the taxonomy of R. subsect. Xerampelinae are inappropriate for species delimitation in this group and the adequacy of the ITS for species identification in this group is discussed. Detailed microscopic observations on the type collection of R. nuoljae are presented and illustrated, along with a key to the European members of R. subsect. Xerampelinae.


Staging of primary mediastinal tumors.
Primary mediastinal tumors, with the exception of lymphoma, are generally rare neoplasms. The diagnosis, classification, and treatment of these tumors still cause some degree of difficulty due to their low incidence and morphologic heterogeneity. This is particularly true for thymic epithelial neoplasms, that is, thymoma and thymic carcinoma, and also applies to primary neuroendocrine carcinomas of the thymus and primary mediastinal germ cell tumors. The appropriate staging of these tumors, likewise, has been a matter of debate over the years and numerous proposals for the staging of thymic epithelial neoplasms have been put forward in the last few decades. Unfortunately, variations of such proposals have been used in some instances to stage other tumors such as thymic neuroendocrine carcinomas and germ cell tumors, which has led to the often inappropriate use of a single staging system for different types of tumors with different biological behavior. This review will provide an overview of the staging of primary mediastinal tumors with special emphasis on more recent assessments in this particular area.


Visual and optical performance of the Akreos Adapt Advanced Optics and Tecnis Z9000 intraocular lenses: Swedish multicenter study.
To compare the subjective visual and objective optical performance of 2 aspherical intraocular lenses (IOLs), the Akreos Adapt Advanced Optics (AO) (Bausch & Lomb, Inc.) and the Tecnis Z9000 (Advanced Medical Optics, Inc.). Four university hospitals in Sweden. This study comprised 80 patients, 20 each from 4 university hospital centers in Sweden. All patients had bilateral clear corneal phacoemulsification with implantation of an Akreos Adapt AO IOL in 1 eye and Tecnis Z9000 IOL in the other eye according to a randomization protocol. Preoperatively, 90% contrast Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity was measured and the mesopic pupil sizes were determined. Ten to 12 weeks postoperatively, 12.5% and 90% contrast ETDRS visual acuities and photopic and mesopic Functional Acuity Contrast Test chart contrast sensitivities were determined. Wavefront analysis was performed with the Zywave II aberrometer (Bausch & Lomb, Inc.), and a questionnaire on the subjective quality of vision was completed by each patient. The Akreos AO IOL and Tecnis Z9000 IOL produced similar high- and low-contrast visual acuities as well as photopic and mesopic contrast sensitivities. The Tecnis Z9000 IOL resulted in lower spherical aberrations of the eye (mean 0.05 +/- 0.13 microm versus 0.35 +/- 0.13 microm root mean square, 6.0 mm pupil) (P<.001); however, the Akreos AO IOL provided a larger depth of field (mean 1.22 diopter [D] +/- 0.48 [SD] versus 0.86 +/- 0.50 D, 6.0 mm pupil) (P<.001). Patient satisfaction was generally high, although 68.8% of the patients reported some type of visual disturbance postoperatively. Twenty-eight percent of patients reported better subjective visual quality in the Akreos AO eye and 14%, in the Tecnis Z9000 eye (P<.0001). Accordingly, 33% perceived more visual disturbances in the Tecnis Z9000 eye and 11%, in the Akreos AO eye (P<.0001). Maximum reduction of spherical aberration did not maximize subjective visual quality. The higher perceived quality of vision with the Akreos AO IOL could be because of differences in depth of field, IOL material, or IOL design.


Parental investment and the optimization of human family size.
Human reproductive behaviour is marked by exceptional variation at the population and individual level. Human behavioural ecologists propose adaptive hypotheses to explain this variation as shifting phenotypic optima in relation to local socioecological niches. Here we review evidence that variation in fertility (offspring number), in both traditional and modern industrialized populations, represents optimization of the life-history trade-off between reproductive rate and parental investment. While a reliance on correlational methods suggests the true costs of sibling resource competition are often poorly estimated, a range of anthropological and demographic studies confirm that parents balance family size against offspring success. Evidence of optimization is less forthcoming. Declines in fertility associated with modernization are particularly difficult to reconcile with adaptive models, because fertility limitation fails to enhance offspring reproductive success. Yet, considering alternative measures, we show that modern low fertility confers many advantages on offspring, which are probably transmitted to future generations. Evidence from populations that have undergone or initiated demographic transition indicate that these rewards to fertility limitation fall selectively on relatively wealthy individuals. The adaptive significance of modern reproductive behaviour remains difficult to evaluate, but may be best understood in response to rising investment costs of rearing socially and economically competitive offspring.


GARS axonopathy: not every neuron's cup of tRNA.
Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work.


Lycopene supplementation prevents the development of spontaneous smooth muscle tumors of the oviduct in Japanese quail.
Leiomyomas (fibroids) are benign tumors of the uterus affecting millions of women. Spontaneous leiomyomas of the oviduct are common tumors of the Japanese quail (Coturnix coturnix japonica), which makes it a good animal model for screening potential agents for testing in the prevention and treatment of human myoma uteri. Because dietary intake of lycopene has been associated with a reduced risk of a variety of human cancers, we investigated the effects of lycopene supplementation on the development of leiomyomas in the oviduct of Japanese quail. We also measured serum levels of oxidative stress markers [malondialdehyde (MDA) and homocysteine], lycopene, vitamins C, E, and A, and tissue biomarkers Bcl-2 and Bax expression. One hundred twenty quails (6 mo old) were assigned to 3 treatment groups consisting of 4 replicates of 10 birds in each group. Birds were fed either a basal diet (group C) or the basal diet supplemented with 100 mg (group L1) or 200 mg (group L2) of lycopene per kilogram of diet. The animals were sacrificed after 285 days and the tumors were identified. Lycopene supplementation decreased the number of leiomyomas compared with control subjects (P=0.056). The tumors in lycopene-fed birds were smaller than those found in control birds (P=0.01). There were no significant differences in the expression of tissue Bcl-2 and Bax among the study groups. Serum vitamins C, E, and A increased (P=0.01), whereas MDA and homocysteine concentrations decreased (P=0.01) with lycopene supplementation. No measurable lycopene could be detected in the serum of control birds, whereas a dose-dependent increase was observed in the serum of lycopene-supplemented birds. The results indicate that dietary supplementation with lycopene reduces the incidence and size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of lycopene supplementation in the prevention and treatment of uterine leiomyoma in humans.


Contemporary ethical issues in human milk-banking in the United States.
Donor human milk has been used in the United States for >90 years, but recent advances in human milk science and laboratory techniques have led to increasing use of this resource. Pediatricians began using donor human milk in the 1900s in response to anecdotal observation that premature infants had better health outcomes when receiving their own mothers' milk. Since then, a formalized human milk-banking system developed in the mid-1980s and distributed >1 million ounces of pasteurized donor human milk in 2008. Despite growth in the use of pasteurized donor human milk, there is little discussion in the medical literature regarding the ethical considerations of collection and use of this resource. Key ethical considerations include issues surrounding medical decision-making and informed consent, increasing the limited supply of human milk, how ethically to allocate this scarce resource, and concerns linked to the marketing of a human milk.


Binaural auditory beats affect vigilance performance and mood.
When two tones of slightly different frequency are presented separately to the left and right ears the listener perceives a single tone that varies in amplitude at a frequency equal to the frequency difference between the two tones, a perceptual phenomenon known as the binaural auditory beat. Anecdotal reports suggest that binaural auditory beats within the electroencephalograph frequency range can entrain EEG activity and may affect states of consciousness, although few scientific studies have been published. This study compared the effects of binaural auditory beats in the EEG beta and EEG theta/delta frequency ranges on mood and on performance of a vigilance task to investigate their effects on subjective and objective measures of arousal. Participants (n = 29) performed a 30-min visual vigilance task on three different days while listening to pink noise containing simple tones or binaural beats either in the beta range (16 and 24 Hz) or the theta/delta range (1.5 and 4 Hz). However, participants were kept blind to the presence of binaural beats to control expectation effects. Presentation of beta-frequency binaural beats yielded more correct target detections and fewer false alarms than presentation of theta/delta frequency binaural beats. In addition, the beta-frequency beats were associated with less negative mood. Results suggest that the presentation of binaural auditory beats can affect psychomotor performance and mood. This technology may have applications for the control of attention and arousal and the enhancement of human performance.


Coordinate nuclear targeting of the FANCD2 and FANCI proteins via a FANCD2 nuclear localization signal.
Fanconi anemia (FA) is a rare recessive disease, characterized by congenital defects, bone marrow failure, and increased cancer susceptibility. FA is caused by biallelic mutation of any one of sixteen genes. The protein products of these genes function cooperatively in the FA-BRCA pathway to repair DNA interstrand crosslinks (ICLs). A central step in the activation of this pathway is the monoubiquitination of the FANCD2 and FANCI proteins. Monoubiquitinated FANCD2 and FANCI localize to discrete chromatin regions where they function in ICL repair. Despite their critical role in ICL repair, very little is known about the structure, function, and regulation of the FANCD2 and FANCI proteins, or how they are targeted to the nucleus and chromatin. In this study, we describe the functional characterization of an amino-terminal FANCD2 nuclear localization signal (NLS). We demonstrate that the amino terminal 58 amino acids of FANCD2 can promote the nuclear expression of GFP and is necessary for the nuclear localization of FANCD2. Importantly, mutation of this FANCD2 NLS reveals that intact FANCD2 is required for the nuclear localization of a subset of FANCI. In addition, the NLS is necessary for the efficient monoubiquitination of FANCD2 and FANCI and, consequently, for their localization to chromatin. As a result, FANCD2 NLS mutants fail to rescue the ICL sensitivity of FA-D2 patient cells. Our studies yield important insight into the domain structure of the poorly characterized FANCD2 protein, and reveal a previously unknown mechanism for the coordinate nuclear import of a subset of FANCD2 and FANCI, a key early step in the cellular ICL response.


Nonconventional interventions for chronic post-traumatic stress disorder: Ketamine, repetitive trans-cranial magnetic stimulation (rTMS), and alternative approaches.
It is alarming that only 59% of those who have post-traumatic stress disorder (PTSD) respond to selective serotonin reuptake inhibitors. Many existing treatments, both pharmacological and nonpharmacological, do not directly target trauma memories that lay at the core of the PTSD pathogenesis. Notable exceptions are medications like ketamine and propranolol and trauma-focused psychotherapies like eye-movement desensitization and reprocessing therapy (developed by Shapiro) and Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) for trauma memories (developed by Pradhan). Although the antidepressant effects of ketamine are no longer news, ketamine's effects on treatment refractory PTSD (TR-PTSD) is a recent concept. As TR-PTSD has a marked public health burden and significant limitations in terms of treatment interventions, a thorough assessment of current strategies is required. Research to bring clarity to the underlying pathophysiology and neurobiology of TR-PTSD delineating the chemical, structural, and circuitry abnormalities will take time. In the interim, in the absence of a 1-size-fits-all therapeutic approach, pragmatically parallel lines of research can be pursued using the pharmacological and nonpharmacological treatments that have a strong theoretical rationale for efficacy. This article aims to review the current literature on interventions for PTSD, most notably ketamine, trans-cranial magnetic stimulation treatment, yoga and mindfulness interventions, and TIMBER. We present an outline for their future use, alone as well as in combination, with a hope of providing additional insights as well as advocating for developing more effective therapeutic intervention for this treatment-resistant and debilitating condition.


Caseinate-Stabilized Emulsions of Black Cumin and Tamanu Oils: Preparation, Characterization and Antibacterial Activity.
Caseinate-stabilized emulsions of black cumin (Nigella sativa) and tamanu (Calophyllum inophyllum) oils were studied in terms of preparation, characterization, and antibacterial properties. The oils were described while using their basic characteristics, including fatty acid composition and scavenging activity. The oil-in-water (o/w) emulsions containing the studied oils were formulated, and the influence of protein stabilizer (sodium caseinate (CAS), 1-12 wt%), oil contents (5-30 wt%), and emulsification methods (high-shear homogenization vs sonication) on the emulsion properties were investigated. It was observed that, under both preparation methods, emulsions of small, initial droplet sizes were predominantly formed with CAS content that was higher than 7.5 wt%. Sonication was a more efficient emulsification procedure and was afforded emulsions with smaller droplet size throughout the entire used concentration ranges of oils and CAS when compared to high-shear homogenization. At native pH of ~ 6.5, all of the emulsions exhibited negative zeta potential that originated from the presence of caseinate. The antibacterial activities of both oils and their emulsions were investigated with respect to the growth suppression of common spoilage bacteria while using the disk diffusion method. The oils and selected emulsions were proven to act against gram positive strains, mainly against Staphylococcus aureus (S. aureus) and Bacillus cereus (B. cereus); regrettably, the gram negative species were fully resistant against their action.


Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992.
To describe trends in systemic lupus erythematosus (SLE) incidence and mortality over the past 4 decades. Using the Rochester Epidemiology Project resources, medical records were screened to identify all Rochester, Minnesota residents with any SLE-associated diagnoses, discoid lupus, positivity for antinuclear antibodies, and/or false-positive syphilis test results determined between January 1, 1980 and December 31, 1992. Medical records were then reviewed using a pretested data collection form in order to identify cases of SLE according to the American College of Rheumatology 1982 revised criteria for SLE. Drug-induced cases were excluded. All identified SLE patients were followed up until death, migration from the county, or October 1, 1997. These data were combined with similar data from the same community obtained between 1950 and 1979, and trends in the SLE incidence and mortality over time were calculated. Of the 430 medical records reviewed, 48 newly diagnosed cases of SLE (42 women and 6 men) were identified between 1980 and 1992. The average incidence rate (age- and sex-adjusted to the 1970 US white population) was 5.56 per 100,000 (95% confidence interval [95% CI] 3.93-7.19), compared with an incidence of 1.51 (95% CI 0.85-2.17) in the 1950-1979 cohort. The age- and sex-adjusted prevalence rate as of January 1, 1993 was approximately 1.22 per 1,000 (95% CI 0.97-1.47). Survival among SLE patients was significantly worse than in the general population (P = 0.017 compared with the 1980-1992 cohort, and P < 0.0001 compared with the 1950-1979 cohort, by log-rank test). Cox proportional hazards modeling demonstrated a statistically significant improvement in the survival rate over time (P = 0.035). Over the past 4 decades, the incidence of SLE has nearly tripled, and there has been a statistically significant improvement in survival. These findings are likely due to a combination of improved recognition of mild disease and better approaches to therapy.


proGenomes: a resource for consistent functional and taxonomic annotations of prokaryotic genomes.
The availability of microbial genomes has opened many new avenues of research within microbiology. This has been driven primarily by comparative genomics approaches, which rely on accurate and consistent characterization of genomic sequences. It is nevertheless difficult to obtain consistent taxonomic and integrated functional annotations for defined prokaryotic clades. Thus, we developed proGenomes, a resource that provides user-friendly access to currently 25 038 high-quality genomes whose sequences and consistent annotations can be retrieved individually or by taxonomic clade. These genomes are assigned to 5306 consistent and accurate taxonomic species clusters based on previously established methodology. proGenomes also contains functional information for almost 80 million protein-coding genes, including a comprehensive set of general annotations and more focused annotations for carbohydrate-active enzymes and antibiotic resistance genes. Additionally, broad habitat information is provided for many genomes. All genomes and associated information can be downloaded by user-selected clade or multiple habitat-specific sets of representative genomes. We expect that the availability of high-quality genomes with comprehensive functional annotations will promote advances in clinical microbial genomics, functional evolution and other subfields of microbiology. proGenomes is available at http://progenomes.embl.de.


Nutritional support for acute kidney injury.
Treatment for acute kidney Injury (AKI) primarily relies on treating the underlying cause and maintaining the patient until kidney function has recovered. Enteral and parenteral nutrition are commonly used to treat nutritional disorders in AKI patients, however their efficacy in treating AKI are still debated. To evaluate the effectiveness and safety of nutritional support for patients with AKI. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese Biomedical Disc, VIP and China National Knowledge Infrastructure (CNKI). All randomised controlled trials (RCTs) reported for AKI and nutrition were included. Review authors independently assessed study quality and extracted data. Results were expressed as risk ratio (RR) with 95% confidence intervals (CI) or mean difference (MD). Eight studies (257 participants) were included. An overall pooled analysis was not performed due to the different interventions used and different outcomes measured. There was a significant increase in recovery rate for AKI (RR 1.70, 95% CI 1.70 to 2.79) and survival in dialysed patients (RR 3.56, 95% CI 0.97 to 13.08) for intravenous essential L-amino acids (EAA) compared to hypertonic glucose alone. Compared to lower calorie-total parenteral nutrition (TPN), higher calorie-TPN did not improve estimated nitrogen balance, protein catabolic rate, or urea generation rate, but increased serum triglycerides, glucose, insulin need and nutritional fluid administration. There was no difference between groups in estimated nitrogen balance, but there were differences between urea nitrogen appearance (MD 0.98, 95% CI 0.25 to 1.71) and net protein utilisation (MD 21.50%, 95% CI 0.39 to 42.61). Urea nitrogen appearance was lower in the low nitrogen intake group than in the high nitrogen intake group. There was no significant difference in death between EAA and general amino acids (GAA) (RR 1.52, 95% CI 0.63 to 3.68). High dose amino acids did not improve cumulative water excretion, furosemide requirement, nitrogen balance or death compared to normal dose amino acids. Glucose+EAA+histidin had better nitrogen balance than glucose+GAA; glucose+nitrogen+fat significantly increased serum creatinine compared with glucose+GAA; glucose+EAA+histidin significantly improved nitrogen balance, U/P urea and serum creatinine, but increased plasma urea compared to glucose+nitrogen+fat. There is not enough evidence to support the effectiveness of nutritional support for AKI. Further high quality studies are required to provide reliable evidence of the effect and safety of nutritional support.


Asymptomatic carriers of toxigenic C. difficile in long-term care facilities: a meta-analysis of prevalence and risk factors.
The impact of Clostridium difficile colonization in C. difficile infection (CDI) is inadequately explored. As a result, asymptomatic carriage is not considered in the development of infection control policies and the burden of carrier state in long-term care facilities (LTCFs) is unknown. To explore the epidemiology of C. difficile colonization in LTCFs, identify predisposing factors and describe its impact on healthcare management. PubMed, Embase and Web of Science (up to June 2014) without language restriction, complemented by reference lists of eligible studies. All studies providing extractable data on the prevalence of toxigenic C. difficile colonization among asymptomatic residents in LTCFs. Two authors extracted data independently. The pooled colonization estimates were calculated using the double arcsine methodology and reported along with their 95% random-effects confidence intervals (CIs), using DerSimonian-Laird weights. We assessed the impact of patient-level covariates on the risk of colonization and effects were reported as odds ratios (OR, 95% CI). We used the colonization estimates to simulate the effective reproduction number R through a Monte Carlo technique. Based on data from 9 eligible studies that met the specified criteria and included 1,371 subjects, we found that 14.8% (95%CI 7.6%-24.0%) of LTCF residents are asymptomatic carriers of toxigenic C. difficile. Colonization estimates were significantly higher in facilities with prior CDI outbreak (30.1% vs. 6.5%, p = 0.01). Patient history of CDI (OR 6.07; 95% CI 2.06-17.88; effect derived from 3 studies), prior hospitalization (OR 2.11; 95% CI 1.08-4.13; derived from 3 studies) and antimicrobial use within previous 3 months (OR 3.68; 95% CI 2.04-6.62; derived from 4 studies) were associated with colonization. The predicted colonization rate at admission was 8.9%. Asymptomatic carriage of toxigenic C. difficile represents a significant burden in LTCFs and is associated with prior CDI outbreaks in the facility, a history of CDI, prior hospitalization and antimicrobial use. These findings can impact infection control measures at LTCFs.


Advancing Crop Transformation in the Era of Genome Editing.
Plant transformation has enabled fundamental insights into plant biology and revolutionized commercial agriculture. Unfortunately, for most crops, transformation and regeneration remain arduous even after more than 30 years of technological advances. Genome editing provides novel opportunities to enhance crop productivity but relies on genetic transformation and plant regeneration, which are bottlenecks in the process. Here, we review the state of plant transformation and point to innovations needed to enable genome editing in crops. Plant tissue culture methods need optimization and simplification for efficiency and minimization of time in culture. Currently, specialized facilities exist for crop transformation. Single-cell and robotic techniques should be developed for high-throughput genomic screens. Plant genes involved in developmental reprogramming, wound response, and/or homologous recombination should be used to boost the recovery of transformed plants. Engineering universal Agrobacterium tumefaciens strains and recruiting other microbes, such as Ensifer or Rhizobium, could facilitate delivery of DNA and proteins into plant cells. Synthetic biology should be employed for de novo design of transformation systems. Genome editing is a potential game-changer in crop genetics when plant transformation systems are optimized.


Gender-transformative interventions to reduce HIV risks and violence with heterosexually-active men: a review of the global evidence.
Emerging out of increased attention to gender equality within HIV and violence prevention programming has been an intensified focus on masculinities. A new generation of health interventions has attempted to shift norms of masculinity to be more gender equitable and has been termed "gender-transformative." We carried out a systematic review of gender-transformative HIV and violence prevention programs with heterosexually-active men in order to assess the efficacy of this programming. After reviewing over 2,500 abstracts in a systematic search, a total of 15 articles matched review criteria. The evidence suggests that gender-transformative interventions can increase protective sexual behaviors, prevent partner violence, modify inequitable attitudes, and reduce STI/HIV, though further trials are warranted, particularly in establishing STI/HIV impacts. In the conclusion, we discuss the promises and limitations of gender-transformative work with men and make suggestions for future research focused on HIV and/or violence prevention.


Patient registries for substance use disorders.
This commentary discusses the need for developing patient registries of substance use disorders (SUD) in general medical settings. A patient registry is a tool that documents the natural history of target diseases. Clinicians and researchers use registries to monitor patient comorbidities, care procedures and processes, and treatment effectiveness for the purpose of improving care quality. Enactments of the Affordable Care Act 2010 and the Mental Health Parity and Addiction Equity Act 2008 open opportunities for many substance users to receive treatment services in general medical settings. An increased number of patients with a wide spectrum of SUD will initially receive services with a chronic disease management approach in primary care. The establishment of computer-based SUD patient registries can be assisted by wide adoption of electronic health record systems. The linkage of SUD patient registries with electronic health record systems can facilitate the advancement of SUD treatment research efforts and improve patient care.


Type 2 diabetes mellitus is becoming the most common type of diabetes in school children.
Obesity, now an epidemic in the USA, northern Europe, and Italy, is associated with several co-morbidities that shorten life expectancy, in particular type 2 diabetes mellitus (T2DM), arterial hypertension, and hyperlipidemia. The impact of obesity on mortality is evident in all ages, and is especially strong in young persons. Obesity, especially visceral obesity, associated with a sedentary lifestyle, is among the strongest risk factors for T2DM, and a diagnosis of T2DM seems to increase linearly as a function of duration of obesity. The pathogenesis of T2DM is based on a dual defect, i.e. increased insulin resistance coupled with defective insulin release. The main abnormality in obesity is increased insulin resistance, while insulin release, even though defective compared with body needs, is usually abundant. The incidence of obesity among children aged 6-16 years is now even greater than that among adults: in Italy, figures up to 30% have been reported. As in adults, obesity is a cause, among children, of arterial hypertension, left ventricular hypertrophy, hyperlipidemia, non-alcoholic-steato hepatitis, sleep apnea syndrome (SAS), and orthopedic, psychological, and social problems. Together with an increase in body weight, there is an increase of visceral fat. Obesity in children has also led to a tremendous increase in the prevalence of impaired glucose tolerance (IGT); the percentages span from 25% in a multiethnic cohort in the USA, to 4% in Italian Caucasians. Management of obesity and of T2DM in children has to face the issue of poor compliance; there is consensus that dietary treatment of obese T2DM children is a failure, so that drugs are required; the only drug evaluated in a formal trial is metformin, that behaves in terms of efficacy and of minor side effects as in adults. In conclusion, obesity in children is not pure obesity, but is accompanied by co-morbidities that cluster to form the "metabolic syndrome" just like in the adults. If this epidemics continues and is not properly challenged, in the next decades we will face an epidemic of early cardiovascular morbidity and mortality.


Human immunodeficiency virus type 1 Tat-dependent activation of an arrested RNA polymerase II elongation complex.
The human immunodeficiency virus type 1 (HIV-1) Tat protein is a transcriptional activator that is essential for efficient viral gene expression and replication. Tat increases the level of full-length transcripts from the HIV-1 promoter by dramatically enhancing the elongation efficiency of the RNA polymerase II complexes assembled on this promoter. Tat could potentially activate the transcription machinery during initiation, elongation, or both. We used an immobilized HIV-1 promoter template with a reversible lac repressor (LacR) elongation block inserted downstream to dissect the stages in transcription affected by Tat. Transcription complexes assembled in the absence of Tat and blocked by LacR cannot be activated by incubation with Tat alone. These complexes can, however, be activated if Tat is added in combination with cellular factors. In this system, Tat also promoted the assembly of preinitiation complexes capable of elongating efficiently, suggesting that Tat can associate with transcription complex at an early stage. These data indicate that Tat can activate elongation of RNA polymerase by modifying an already elongating transcription complex. The data also suggest the possibility that Tat can interact with initiation complexes.


The Genetic Landscape of Diamond-Blackfan Anemia.
Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.


A rocky planet transiting a nearby low-mass star.
M-dwarf stars--hydrogen-burning stars that are smaller than 60 per cent of the size of the Sun--are the most common class of star in our Galaxy and outnumber Sun-like stars by a ratio of 12:1. Recent results have shown that M dwarfs host Earth-sized planets in great numbers: the average number of M-dwarf planets that are between 0.5 to 1.5 times the size of Earth is at least 1.4 per star. The nearest such planets known to transit their star are 39 parsecs away, too distant for detailed follow-up observations to measure the planetary masses or to study their atmospheres. Here we report observations of GJ 1132b, a planet with a size of 1.2 Earth radii that is transiting a small star 12 parsecs away. Our Doppler mass measurement of GJ 1132b yields a density consistent with an Earth-like bulk composition, similar to the compositions of the six known exoplanets with masses less than six times that of the Earth and precisely measured densities. Receiving 19 times more stellar radiation than the Earth, the planet is too hot to be habitable but is cool enough to support a substantial atmosphere, one that has probably been considerably depleted of hydrogen. Because the host star is nearby and only 21 per cent the radius of the Sun, existing and upcoming telescopes will be able to observe the composition and dynamics of the planetary atmosphere.


Posterior foraminotomy versus anterior decompression and fusion in patients with cervical degenerative disc disease with radiculopathy: up to 5 years of outcome from the national Swedish Spine Register.
The long-term efficacy of posterior foraminotomy compared with anterior cervical decompression and fusion (ACDF) for the treatment of degenerative disc disease with radiculopathy has not been previously investigated in a population-based cohort. All patients in the national Swedish Spine Register (Swespine) from January 1, 2006, until November 15, 2017, with cervical degenerative disc disease and radiculopathy were assessed. Using propensity score matching, patients treated with posterior foraminotomy were compared with those undergoing ACDF. The primary outcome measure was the Neck Disability Index (NDI), a patient-reported outcome score ranging from 0% to 100%, with higher scores indicating greater disability. A minimal clinically important difference was defined as > 15%. Secondary outcomes were assessed with additional patient-reported outcome measures (PROMs). A total of 4368 patients (2136/2232 women/men) met the inclusion criteria. Posterior foraminotomy was performed in 647 patients, and 3721 patients underwent ACDF. After meticulous propensity score matching, 570 patients with a mean age of 54 years remained in each group. Both groups had substantial decreases in their NDI scores; however, after 5 years, the difference was not significant (2.3%, 95% CI -4.1% to 8.4%; p = 0.48) between the groups. There were no significant differences between the groups in EQ-5D or visual analog scale (VAS) for neck and arm scores. The secondary surgeries on the index level due to restenosis were more frequent in the foraminotomy group (6/100 patients vs 1/100), but on the adjacent segments there was no difference between groups (2/100). In patients with cervical degenerative disc disease and radiculopathy, both groups demonstrated clinical improvements at the 5-year follow-up that were comparable and did not achieve a clinically important difference from one another, even though the reoperation rate favored the ACDF group. This study design obtains population-based results, which are generalizable.


Antibodies to chondroitin sulfate A-binding infected erythrocytes: dynamics and protection during pregnancy in women receiving intermittent preventive treatment.
Plasmodium falciparum parasites that cause malaria in pregnancy express unique variant surface antigens (VSAs). Levels of immunoglobulin G (IgG) antibody to pregnancy-associated VSAs measured at delivery are gravidity dependent, and they have been associated with protection from disease. It is not known how these IgG responses develop in pregnant women receiving intermittent preventive treatment during pregnancy (IPTp) or whether IgG levels in early pregnancy predict pregnancy outcomes. We performed longitudinal measurements of IgG antibody to VSAs by flow cytometric analysis of serum samples obtained from 549 Malawian women receiving IPTp. We examined fluctuations in IgG levels over time and associated the IgG levels noted at study enrollment with clinical outcomes. Levels of IgG antibody to pregnancy-associated VSAs were gravidity dependent. Overall, levels decreased while women were receiving IPTp, but the levels of the individuals were highly dynamic. Primigravidae developed low levels of pregnancy-specific IgG, which were often boosted during second pregnancies. The prevalence of parasites was low (8.4% at enrollment and 2.4% in late pregnancy). Antibody levels at enrollment did not predict birth weight, duration of gestation at delivery, or the maternal hemoglobin level in late pregnancy. Levels of IgG antibody to pregnancy-specific VSAs decrease during receipt of IPTp. Antibody levels in early pregnancy did not predict clinical outcome. IPTp and decreasing malaria prevalence pose challenges for the evaluation of novel interventions for malaria during pregnancy.


The Toll and Imd pathways are the major regulators of the immune response in Drosophila.
Microarray studies have shown recently that microbial infection leads to extensive changes in the Drosophila gene expression programme. However, little is known about the control of most of the fly immune-responsive genes, except for the antimicrobial peptide (AMP)-encoding genes, which are regulated by the Toll and Imd pathways. Here, we used oligonucleotide microarrays to monitor the effect of mutations affecting the Toll and Imd pathways on the expression programme induced by septic injury in Drosophila adults. We found that the Toll and Imd cascades control the majority of the genes regulated by microbial infection in addition to AMP genes and are involved in nearly all known Drosophila innate immune reactions. However, we identified some genes controlled by septic injury that are not affected in double mutant flies where both Toll and Imd pathways are defective, suggesting that other unidentified signalling cascades are activated by infection. Interestingly, we observed that some Drosophila immune-responsive genes are located in gene clusters, which often are transcriptionally co-regulated.


Transcriptional profile of GTP-mediated differentiation of C2C12 skeletal muscle cells.
Several purine receptors have been localised on skeletal muscle membranes. Previous data support the hypothesis that extracellular guanosine 5'-triphosphate (GTP) is an important regulatory factor in the development and function of muscle tissue. We have previously described specific extracellular binding sites for GTP on the plasma membrane of mouse skeletal muscle (C2C12) cells. Extracellular GTP induces an increase in intracellular Ca(2+) concentrations that results in membrane hyperpolarisation through Ca(2+)-activated K(+) channels, as has been demonstrated by patch-clamp experiments. This GTP-evoked increase in intracellular Ca(2+) is due to release of Ca(2+) from intracellular inositol-1,4,5-trisphosphate-sensitive stores. This enhances the expression of the myosin heavy chain in these C2C12 myoblasts and commits them to fuse into multinucleated myotubes, probably via a phosphoinositide-3-kinase-dependent signal-transduction mechanism. To define the signalling of extracellular GTP as an enhancer or modulator of myogenesis, we investigated whether the gene-expression profile of differentiated C2C12 cells (4 and 24 h in culture) is affected by extracellular GTP. To investigate the nuclear activity and target genes modulated by GTP, transcriptional profile analysis and real-time PCR were used. We demonstrate that in the early stages of differentiation, GTP up-regulates genes involved in different pathways associated with myogenic processes, including cytoskeleton structure, the respiratory chain, myogenesis, chromatin reorganisation, cell adhesion, and the Jak/Stat pathway, and down-regulates the mitogen-activated protein kinase pathway. GTP also increases the expression of three genes involved in myogenesis, Pp3ca, Gsk3b, and Pax7. Our data suggests that in the myogenic C2C12 cell line, extracellular GTP acts as a differentiative factor in the induction and sustaining of myogenesis.


Partial two-dimensional gel electrophoresis (2-DE) maps of Streptococcus iniae ATCC29178 and Lactococcus garvieae KG9408.
To examine the proteomes of 2 important causative agents of fish streptococcosis, Streptococcus iniae ATCC29178 and Lactococcus garvieae KG9408, we used 2-dimensional gel electrophoresis (2-DE) followed by mass spectrometry to generate 2-DE maps of these type strains. Silver-stained 2-DE gels of S. iniae ATCC29178 and L. garvieae KG9408 revealed approximately 320 and 300 spots, respectively, and immobilized pH gradient strips (13 cm, pH 4 to 7) revealed that the majority of the detected spots were concentrated in the pH range of 4.5 to 5.5. The spots were randomly selected from the 2-DE profiles and identified by peptide mass fingerprinting using matrix-assisted laser desorption/ionization time of flight mass spectrometry. The majority of the identified proteins were functionally related to energy and carbohydrate metabolism (e.g. enolase ATPase, glyceraldehyde-3-phosphate dehydrogenase) or translation and translocation (e.g. elongation factor G, elongation factor Tu, DNA-directed RNA polymerase alpha chain). These data, along with our partial 2-DE maps of S. iniae ATCC29178 and L. garvieae KG9408, may help suggest antigenic proteins for the development of effective diagnostic tools and vaccines against S. iniae and L. garvieae.


Implications of a new definition of vitamin D deficiency in a multiracial us adolescent population: the National Health and Nutrition Examination Survey III.
In children, vitamin D deficiency can interfere with bone mineralization, leading to rickets. In adults, it is linked to cardiovascular disease, insulin resistance, and hypertension. Accurate estimates of the prevalence of vitamin D deficiency are complicated by the lack of consensus as to optimal vitamin D status. Currently, individuals with serum 25-hydroxyvitamin D levels of <11 ng/mL are classified as vitamin D deficient. Experts collectively have proposed that minimum levels be at least 20 ng/mL. Our objectives were to (1) determine the national prevalence of vitamin D deficiency in adolescents by using both the current and recommended cutoffs and (2) examine the implications of the new recommendation after adjustment for various factors. Data were obtained from National Health and Nutrition Examination Survey III, a cross-sectional survey administered to a nationally representative sample of noninstitutionalized civilians aged 2 months and older. Analyses were restricted to 2955 participants aged 12 to 19 with serum 25-hydroxyvitamin D levels. Relationships between serum 25-hydroxyvitamin D levels and sociodemographic variables were evaluated by using logistic regression. Changing the definition of vitamin D deficiency from <11 to <20 ng/mL increased the prevalence from 2% to 14%. After adjustment for all covariates, non-Hispanic black adolescents had 20 times the risk of serum 25-hydroxyvitamin D <20 ng/mL compared with non-Hispanic white adolescents. The risk of deficiency was more than double for females compared with males. An inverse relationship between weight and serum 25-hydroxyvitamin D levels was found. Overweight adolescents had increased risk of deficiency compared with normal-weight adolescents. There was a disproportionate burden of vitamin D deficiency in the non-Hispanic black adolescent population. Routine supplementation and monitoring of serum levels should be considered. Females and overweight adolescents are at increased risk. The consequences of chronic vitamin D deficiency in adolescents should be prospectively investigated.


Viral persistence in vivo through selection of neutralizing antibody-escape variants.
Despite initial virus control by CD8(+) cytotoxic T lymphocytes (CTLs), noncytopathic or variably cytopathic viruses (e.g., hepatitis B and C viruses, HIV) are able to establish persistent infections. The role of neutralizing antibodies (nAbs) in controlling disease progression is unclear. Therefore, the phenomenon of viral evasion from the nAb response and its implications for virus persistence remain controversial. Here we demonstrate nAb-mediated viral clearance in CTL-deficient mice infected with the prototypic noncytopathic lymphocytic choriomeningitis virus (strain WE). During prolonged CTL absence, neutralization-resistant virus mutants were selected in individual mice within 70-90 days. In naive animals infected with these virus variants only low nAb responses were induced, resulting in an increased tendency of virus to persist.


Educating Physicians for Rural America: Validating Successes and Identifying Remaining Challenges With the Rural Medical Scholars Program.
To evaluate the Rural Medical Scholars (RMS) Program's effectiveness to produce rural physicians for Alabama. A nonrandomized intervention study compared RMS (1997-2002) with control groups in usual medical education (1991-2002) at the University of Alabama School of Medicine's main and regional campuses. Participants were RMS and others admitted to regular medical education, and the intervention was the RMS Program. Measures assessed the percentage of graduates practicing in rural areas. Odds ratios compared effectiveness of producing rural Alabama physicians. The RMS Program (N = 54), regional campuses (N = 182), and main campus (N = 649) produced 48.1% (odds ratio 6.4, P < .001), 23.8% (odds ratio 2.5, P < .001), and 11.2% (odds ratio 1.0) rural physicians, respectively. The RMS Program, contrasted to other local programs of medical education, was effective in producing rural physicians. These results were comparable to benchmark programs in the Northeast and Midwest USA on which the RMS Program was modeled, justifying the assumption that model programs can be replicated in different regions. However, this positive effect was not shared by a disparate rural minority population, suggesting that models for rural medical education must be adjusted to meet the challenge of such communities for physicians.


Hysterical again: the gastrointestinal woman in medical discourse.
This article suggests increased attention to how medical discourses of gastrointestinal (GI) disorder and distress are fraught with social assumptions and consequences by examining nineteenth-century and contemporary medical texts focused on chronic constipation and Irritable Bowel Syndrome (IBS). I suggest that these medical discourses present what I call the "gastrointestinal woman," who is characterized as having unjustified anxiety and is to blame for her condition. My approach to understanding, and ultimately revising, the representation of the gastrointestinal woman is shaped by disability studies scholarship, which encourages intervention in problematic medical discourses and more active shaping of discourses of chronic pain and illness by those who have these conditions.


Why the COI barcode should be the community DNA metabarcode for the metazoa.
Metabarcoding of complex metazoan communities is increasingly being used to measure biodiversity in terrestrial, freshwater and marine ecosystems, revolutionizing our ability to observe patterns and infer processes regarding the origin and conservation of biodiversity. A fundamentally important question is which genetic marker to amplify, and although the mitochondrial cytochrome oxidase subunit I (COI) gene is one of the more widely used markers in metabarcoding for the Metazoa, doubts have recently been raised about its suitability. We argue that (a) the extensive coverage of reference sequence databases for COI; (b) the variation it presents; (c) the comparative advantages for denoising protein-coding genes; and (d) recent advances in DNA sequencing protocols argue in favour of standardizing for the use of COI for metazoan community samples. We also highlight where research efforts should focus to maximize the utility of metabarcoding.


Two-dimensional auditory p300 speller with predictive text system.
P300-based Brain Computer Interfaces offer communication pathways which are independent of muscle activity. Mostly visual stimuli, e.g. blinking of different letters are used as a paradigm of interaction. Neural degenerative diseases like amyotrophic lateral sclerosis (ALS) also cause a decrease in sight, but the ability of hearing is usually unaffected. Therefore, the use of the auditory modality might be preferable. This work presents a multiclass BCI paradigm using two-dimensional auditory stimuli: cues are varying in pitch (high/medium/low) and location (left/middle/right). The resulting nine different classes are embedded in a predictive text system, enabling to spell a letter with a 9-class decision. Moreover, an unbalanced subtrial selection is investigated and compared to the well-established sequence-wise paradigm. Twelve healthy subjects participated in an online study to investigate these approaches.


How Salmonella oxidises H(2) under aerobic conditions.
Salmonella enterica serovar Typhimurium is a Gram negative bacterial pathogen and a common cause of food-borne illness. Molecular hydrogen has been shown to be a key respiratory electron donor during infection and H(2) oxidation can be catalysed by three genetically-distinct [NiFe] hydrogenases. Of these, hydrogenases-1 (Hyd-1) and Hyd-2 have well-characterised homologues in Escherichia coli. The third, designated Hyd-5 here, is peculiar to Salmonella and is expressed under aerobic conditions. In this work, Salmonella was genetically modified to enable the isolation and characterisation of Hyd-5. Electrochemical analysis established that Hyd-5 is a H(2)-oxidising enzyme that functions in very low levels of H(2) and sustains this activity in high levels of O(2). In addition, electron paramagnetic resonance spectroscopy of the Hyd-5 isoenzyme reveals a complex paramagnetic FeS signal at high potentials which is comparable to that observed for other O(2)-tolerant respiratory [NiFe] hydrogenases. Taken altogether, Hyd-5 can be classified as an O(2)-tolerant hydrogenase that confers upon Salmonella the ability to use H(2) as an electron donor in aerobic respiration.


Characteristics and outcome of prostate cancer with PSA <4 ng/ml at diagnosis: a population-based study.
This population-based study aims to assess prognosis of prostate cancer diagnosed with prostate-specific antigen (PSA) levels <4 ng/ml in routine care. Materials and methods We compared prostate cancer patients with low PSA values (n=59) with other prostate cancer patients (n=1330) by logistic regression and the Cox model using data from the Geneva Cancer Registry. Results Patients with low PSA values more frequently had early-stage and well differentiated tumours. Nevertheless, 35% presented with aggressive tumour characteristics or metastases. After adjustment for other prognostic factors, prostate cancer-specific mortality was similar for both groups (hazard ratio: 1.1; 95%CI: 0.6-2.2). Conclusion We conclude that cancer with low PSA values at diagnosis is not indolent.


Development of a shear stress-free microfluidic gradient generator capable of quantitatively analyzing single-cell morphology.
Microfluidics, the science of engineering fluid streams at the micrometer scale, offers unique tools for creating and controlling gradients of soluble compounds. Gradient generation can be used to recreate complex physiological microenvironments, but is also useful for screening purposes. For example, in a single experiment, adherent cells can be exposed to a range of concentrations of the compound of interest, enabling high-content analysis of cell behaviour and enhancing throughput. In this study, we present the development of a microfluidic screening platform where, by means of diffusion, gradients of soluble compounds can be generated and sustained. This platform enables the culture of adherent cells under shear stress-free conditions, and their exposure to a soluble compound in a concentration gradient-wise manner. The platform consists of five serial cell culture chambers, all coupled to two lateral fluid supply channels that are used for gradient generation through a source-sink mechanism. Furthermore, an additional inlet and outlet are used for cell seeding inside the chambers. Finite element modeling was used for the optimization of the design of the platform and for validation of the dynamics of gradient generation. Then, as a proof-of-concept, human osteosarcoma MG-63 cells were cultured inside the platform and exposed to a gradient of Cytochalasin D, an actin polymerization inhibitor. This set-up allowed us to analyze cell morphological changes over time, including cell area and eccentricity measurements, as a function of Cytochalasin D concentration by using fluorescence image-based cytometry.


Waterborne fluoride exposure changed the structure and the expressions of steroidogenic-related genes in gonads of adult zebrafish (Danio rerio).
Excessive fluoride in natural water ecosystem has been demonstrated to have adverse effects on reproductive system in humans and mammals, while the most vulnerable aquatic organisms were ignored. In this study, the effects of waterborne fluoride on growth performance, sex steroid hormone, histological structure, and the transcriptional profiles of sex steroid related genes were examined in both female and male zebrafish exposed to different concentrations of 0.79, 18.60, 36.83 mg L(-1) of fluoride for 30 and 60 d to investigate the effects of fluoride on reproductive system and the underlying toxic mechanisms caused by fluoride. The results showed that the body weight was remarkably decreased, the structure of ovary and testis were serious injured, and the T and E2 levels were significantly reduced in male zebrafish. The transcriptional profiles of steroidogenic related genes displayed phenomenal alterations, the expressions of pgr and cyp19a1a were significantly up-regulated, while the transcriptional levels of er, ar and hsd3β were decreased both in the ovary and testis, and hsd17β8 were down-regulated just in males. Taken together, these results demonstrated that fluoride could significantly inhibit the growth of zebrafish, and notably affect the reproductive system in both sex zebrafish by impairing the structure of ovary and testis, altering steroid hormone levels and steroidogenic genes expression related to the synthesis of sex hormones in zebrafish.


Drug treatment of delirium: past, present and future.
The aim of this review was to summarize and critically evaluate the current literature regarding the safety and efficacy of drug therapy in delirium. We also identified recent research developments and highlighted some ongoing clinical trials to explore future directions in drug treatment and prevention of delirium. We conducted a literature search of Medline, Embase, PsychInfo, and Cochrane Review databases, which included both prospective and retrospective clinical trials and case studies on delirium and drug therapy in adult patients up to March 2008. Abstracts from recent topical conferences were also reviewed. Ongoing delirium drug studies were identified via the WHO International Clinical Trials Registry Platform Search Portal, accessed March 12, 2008. The evidence base for effective drug treatment of delirium is restricted by limitations in many of the studies conducted to date. However, there has been an increase in the quantity and quality of delirium drug studies in recent years; preliminary reports and ongoing studies add to this trend. Although efficacy rates between typical and atypical antipsychotic agents are similar, the latter are associated with fewer extrapyramidal side effects. Prophylactic interventions with antipsychotic and cholinesterase inhibitors in high-risk patients provide an opportunity to improve postoperative patient care. Alternative techniques and medication opportunities could be explored in attempts to minimize drug induced delirium potential. Appropriate drug therapy should be considered part of systematic approaches to delirium treatment and prevention. There is a need for well-designed randomized, double-blind placebo-controlled trials investigating the drug management of various aspects of delirium, including delineating treatment by delirium subtype, dose ranging studies, and optimal duration of therapy.


3D nanofabrication inside rapid prototyped microfluidic channels showcased by wet-spinning of single micrometre fibres.
Microfluidics is an established multidisciplinary research domain with widespread applications in the fields of medicine, biotechnology and engineering. Conventional production methods of microfluidic chips have been limited to planar structures, preventing the exploitation of truly three-dimensional architectures for applications such as multi-phase droplet preparation or wet-phase fibre spinning. Here the challenge of nanofabrication inside a microfluidic chip is tackled for the showcase of a spider-inspired spinneret. Multiphoton lithography, an additive manufacturing method, was used to produce free-form microfluidic masters, subsequently replicated by soft lithography. Into the resulting microfluidic device, a three-dimensional spider-inspired spinneret was directly fabricated in-chip via multiphoton lithography. Applying this unprecedented fabrication strategy, the to date smallest printed spinneret nozzle is produced. This spinneret resides tightly sealed, connecting it to the macroscopic world. Its functionality is demonstrated by wet-spinning of single-digit micron fibres through a polyacrylonitrile coagulation process induced by a water sheath layer. The methodology developed here demonstrates fabrication strategies to interface complex architectures into classical microfluidic platforms. Using multiphoton lithography for in-chip fabrication adopts a high spatial resolution technology for improving geometry and thus flow control inside microfluidic chips. The showcased fabrication methodology is generic and will be applicable to multiple challenges in fluid control and beyond.


Self-monitoring of blood glucose in Type 2 diabetes: cross-sectional analyses in 1993, 1999 and 2009.
To characterize the numbers of reagent strips dispensed for self-monitoring of blood glucose to patients with Type 2 diabetes in Tayside, Scotland, in 1993, 1999 and 2009. A diabetes clinical information system in Tayside, record-linked to electronic dispensed prescribing records, was used to collate all dispensed prescribing records for three cross-sectional samples of patients with Type 2 diabetes in 1993 (n = 5728), 1999 (n = 8109) and at 1 January 2009 (n = 16,450). The numbers of reagent strips dispensed during the relevant calendar year were calculated and patients stratified by treatment. We also explored whether age, sex or material and social deprivation were associated with whether a patient received strips. Proportions of people who received self-monitoring reagent strips increased from 15.5% in 1993, to 24.2% in 1999 to 29.8% in 2009, as did numbers of strips dispensed. While the proportion of diet-treated patients who received reagent strips was still very low in 2009 (5.6%), the proportion among those treated with oral agents tripled from 9.4 to 27.4% between 1993 and 2009. Over 90% of patients treated with insulin received reagent strips and, among non-insulin-treated patients, this was more common among women, younger people and less deprived groups. The numbers of reagent strips dispensed for self-monitoring of blood glucose has increased and almost all insulin-treated patients receive strips. While few diet-treated patients receive strips, they are more extensively dispensed to those treated with oral agents. Given that self-monitoring of blood glucose is no longer routinely recommended in non-insulin treated patients, strategies to reduce unnecessary dispensing of reagent strips are needed.


Conjugated and unconjugated bilirubins in bile of humans and rhesus monkeys. Structure of adult human and rhesus-monkey bilirubins compared with dog bilirubins.
1. Bilirubin-IXalpha, -IXalpha diglucuronide, -IXalpha monoglucuronide, -IXalpha monoglucoside -IXalpha monoxyloside, a bilirubin-IXalpha diconjugate containing glucose and another unknown compound, and bilirubin-IXbeta are present in gall-bladder bile of adult human, rhesus monkey and dog. Dog bile normally also contains other bilirubin-IXalpha diconjugates, i.e. compounds containing two conjugating sugars such as glucuronic acid and glucose, glucuronic acid and xylose and glucose xylose. 2. Azopigments alphaF, alphaO, alpha2, alpha3, betax and delta derived from human and rhesus-monkey bilirubins are identical in their chemical composition with those obtained from the dog. 3. Azopigments alphaF and betax found in diazotized biles of adult humans, rhesus monkeys and dogs are products of unconjugated bilirubin-IXbeta. 4. Technical modifications of previously published procedures [Heirwegh, Fevery, Michiels, Van Hees & Compernolle, (1975) Biochem. J. 145, 185-199] were introduced which make it possible to separate the bilirubins, diazotize the separated bilirubins, extract the azopigments and chromatograph them in one working day (6-8h).


Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion.
We recently designed a mouse model of chronic cerebral hypoperfusion, in which the cerebral white matter is damaged without significant gray matter lesions. The behavioral characteristics of these mice were studied using a test battery for neurological and cognitive functions. Adult C57Bl/6 male mice were subjected to either sham-operation or bilateral common carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm. At 30 days after BCAS, 70 animals were divided into 3 groups and subjected to behavioral test batteries. The first group underwent comprehensive behavioral test, including the neurological screen, prepulse inhibition, hot plate, open field, light/dark transition, Porsolt forced swim and contextual and cued fear conditioning (BCAS n=13; sham-operated n=11). The second group was for the working memory task of the 8-arm radial maze test (BCAS n=12; sham-operated n=10), and the third for the reference memory task of the 8-arm radial maze test (BCAS n=13; sham-operated n=11). Another batch of animals were examined for histological changes (BCAS n=11; sham-operated n=12). The white matter including the corpus callosum was consistently found to be rarefied without clear ischemic lesions in the hippocampus. No apparent differences were observed in the comprehensive test batteries between the control and BCAS mice. However, in the working memory tasks tested with the 8-arm radial maze, the BCAS mice made significantly more errors than the control mice (P<0.0001). Again, there were no detectable differences in the reference memory tasks between the groups. At 30 days after BCAS, working memory deficits as well as white matter changes were apparent in the mice. Working memory deficit was attributable to damage of the frontal-subcortical circuits, suggesting the BCAS model is useful to evaluate the substrates of subcortical vascular dementia.


Does a Free-Trial Approach Increase Purchase and Use of a Household Water Treatment and Safe Storage Product in Rural Haiti?
A cluster, randomized control trial was conducted to assess the effects of social marketing approach on purchase rates and water treatment behavior of Klorfasil, a chlorine-based household water treatment product among seven villages in Thomassique, Haiti, from May to December 2016. Villages were randomized to the free-trial (257 households) or cost-sharing (240 households) group. Households in the free-trial group were allowed 30 days of free Klorfasil use before purchase decision. Households who purchased Klorfasil were then followed up for 30, 60, and 180 days. At the last follow-up, respondents were asked if they would like to repurchase Klorfasil. Questionnaire survey and water quality assessment by residual-free chlorine were conducted in each survey. Chi-square test, t-test, and logistic regression were applied. The first purchase rate of the cost-sharing group was significantly higher than that of the free-trial group (79.2% versus 67.3%). By contrast, the repurchase rate of the free-trial group was higher (82.9% versus 66.3%). However, the overall repurchase rate was 71.6% and the proportion of long-term users was significantly higher in the cost-sharing group (56% versus 47%). Water treatment rates in the cost-sharing group were significantly higher than those in the free-trial group in the first and final surveys (odds ratio [OR] = 0.15, OR = 0.32). Households with high and medium economic status both had significantly higher purchase rates than low economic status households (OR = 4.40, OR = 1.94). Households with higher educated respondents had significantly better water treatment practices (OR = 2.15). The free-trial approach did not increase the first purchase rate but increased the repurchase rate later. The cost-sharing approach significantly encouraged long-term usage.


Operant conditioning of specific patterns of neural and muscular activity.
In awake monkeys we recorded activity of single "motor" cortex cells, four contralateral arm muscles, and elbow position, while operantly reinforcing several patterns of motor activity. With the monkey's arm held semiprone in a cast hinged at the elbow, we reinforced active elbow movements and tested cell responses to passive elbow movements. With the cast immobilized we reinforced isometric contraction of each of the four muscles in isolation, and bursts of cortical cell activity with and without simultaneous suppression of muscle activity. Correlations between a precentral cell and specific arm muscles consistently appeared under several behavioral conditions, but could be dissociated by reinforcing cell activity and muscle suppression.


Supply Constraint from Earthquakes in Japan in Input-Output Analysis.
Disasters often cause exogenous flow damage (i.e., the [hypothetical] difference in economic scale with and without a disaster in a certain period) to production ("supply constraint"). However, input-output (IO) analysis (IOA) cannot usually consider it, because the Leontief quantity model (LQM) assumes that production is endogenous; the Ghosh quantity model (GQM) is considered implausible; and the Leontief price model (LPM) and the Ghosh price model (GPM) assume that quantity is fixed. This study proposes to consider a supply constraint in the LPM, introducing the price elasticity of demand. This study uses the loss of social surplus (SS) as a damage estimation because production (sales) is less informative as a damage index than profit (margin); that is, production can be any amount if without considering profit, and it does not tell exactly how much profit is lost for each supplier (upstream sector) and buyer (downstream sector). As a model application, this study examines Japan's largest five earthquakes from 1995 to 2017 and the Great East Japan Earthquake (GEJE) in March 2011. The worst earthquake at the peak tends to increase price by 10-20% and decrease SS by 20-30%, when compared with the initial month's prices/production. The worst damage tends to last eight months at most, accumulating 0.5-month-production damage (i.e., the sum of [hypothetical] differences in SS with and without an earthquake [for eight months] is 50% of the initial month production). Meanwhile, the GEJE in the five prefectures had cumulatively, a 25-month-production damage until the temporal recovery at the 37th month.


Cryo-EM structure of alpha-synuclein fibrils.
Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.


Evaluation of the Johne's disease risk assessment and management plan on dairy farms in Ontario, Canada.
Johne's disease (JD) is a production-limiting gastrointestinal disease in cattle. To minimize the effects of JD, the Ontario dairy industry launched the Ontario Johne's Education and Management Assistance Program in 2010. As part of the program, trained veterinarians conducted a risk assessment and management plan (RAMP), an on-farm questionnaire where high RAMP scores are associated with high risk of JD transmission. Subsequently, veterinarians recommended farm-specific management practices for JD prevention. Milk or serum ELISA results from the milking herd were used to determine the herd ELISA status (HES) and within-herd prevalence. After 3.5 yr of implementation of the program, the aim of this study was to evaluate the associations among RAMP scores, HES, and recommendations. Data from 2,103 herds were available for the analyses. A zero-inflated negative binomial model for the prediction of the number of ELISA-positive animals per farm was built. The model included individual RAMP questions about purchasing animals in the logistic portion, indicating risks for between-herd transmission, and purchasing bulls, birth of calves outside the designated calving area, colostrum and milk feeding management, and adult cow environmental hygiene in the negative binomial portion, indicating risk factors for within-herd transmission. However, farms which fed low-risk milk compared with milk replacer had fewer seropositive animals. The model additionally included the JD herd history in the negative binomial and the logistic portion, indicating that herds with a JD herd history were more likely to have at least 1 positive animal and to have a higher number of positive animals. Generally, a positive association was noted between RAMP scores and the odds of receiving a recommendation for the respective risk area; however, the relationship was not always linear. For general JD risk and calving area risk, seropositive herds had higher odds of receiving recommendations compared with seronegative herds if the section scores were low. This study suggests that the RAMP is a valuable tool to assess the risk for JD transmission within and between herds and to determine farm-specific recommendations for JD prevention.


Grouping design of eight-mirror projection objective for high-numerical aperture EUV lithography.
A grouping design method for all-sphere initial design of an eight-mirror projection objective is proposed for extreme ultraviolet lithography (EUVL). By separating the eight-mirror objective into three mirror groups (the object side group, the image side group, the middle group), this method allows designers to calculate the parameters of an eight-mirror objective by the nonobstruction constraints and the conjugation relationships of object image and pupils. Exhaustive paraxial search for the middle group is implemented while a designer-chosen combination of object side group and image side group is considered. The grouping design process is visualized and steerable. The load of calculation is well controlled in a practical acceptable span. The final eight-mirror design optimized with aspheric parameters achieves an 0.4 numerical aperture on the image side, and the image resolution achieves a diffraction limit with almost no distortion.


Prevention of sensitization to house dust mite by allergen avoidance in school age children: a randomized controlled study.
Sensitization to dust mites predisposes to asthma and allergic rhinitis, and prevention of this sensitization might reduce the rising prevalence of these disorders. To test the effectiveness of dust mite avoidance measures on the development of sensitization to dust mites in children. As part of a multicentre study (Study of Prevention of Allergy in Children of Europe), 242 children, aged 5-7 years, in three European countries (United Kingdom, Greece and Lithuania), were randomized to prophylactic group (n = 127) and control group (n = 115). At randomization these children were required to have a family history of atopy and positive skin test to an aeroallergen but not to house dust mite. Children in the prophylactic group were provided with dust mite impermeable mattress covers and advice on environmental measures to reduce exposure to dust-mite allergen. Control group children were given non-specific advice. After 12 months a standardized questionnaire was completed and skin prick tests were performed. Ten children in the prophylactic group and 19 in the control group were lost to follow-up. Three of 117 (2.56%) children in the prophylactic group and nine of 96 (9.38%) in the control group developed sensitization to dust mites. Logistic regression analysis confirmed an independent effect of prophylactic measures (adjusted odds ratio (OR): 0.14, 95% confidence interval (CI): 0.03-0.79, P = 0.03). Fifteen children need to be treated to prevent sensitization in one child. Dust mite sensitization can be reduced in school age children with simple mite avoidance measures.


Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer.
Survivin is an oncogene that functions in cancer cell cytoprotection and mitosis. Here we report that differential expression in cancer cells of a C-terminal splice variant of survivin, termed survivin-ΔEx3, is tightly associated with aggressive disease and markers of unfavorable prognosis. In contrast to other survivin variants, survivin-ΔEx3 localized exclusively to nuclei in tumor cells and was phosphorylated at multiple residues by the checkpoint kinase Chk2 during DNA damage. Mutagenesis of the Chk2 phosphorylation sites enhanced the stability of survivin-ΔEx3 in tumor cells, inhibited the expression of phosphorylated H2AX (γH2AX) in response to double-strand DNA breaks, and impaired growth after DNA damage. DNA damage induced Chk2 phosphorylation, stabilization of p53, induction of the cyclin-dependent kinase inhibitor p21, and homologous recombination-induced repair were not affected. In vivo, active Chk2 was detected at the earliest stages of the colorectal adenoma-to-carcinoma transition, persisted in advanced tumors, and correlated with increased survivin expression. Together, our findings suggest that Chk2-mediated phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint that may affect cancer cell sensitivity to genotoxic therapies.


The Hidden Impact of the COVID-19 Pandemic on Routine Childhood Immunization Coverage in Cameroon.
Background: The third round of the global pulse survey demonstrated that the abrupt and rapid progression of the COVID-19 pandemic significantly disrupted childhood immunization in many countries. Although Cameroon has reported over 120,000 COVID-19 cases, the reported national childhood vaccination coverage during the pandemic seems to have increased compared to that during the pre-COVID-19 period. Indeed, the first dose of the diphtheria, tetanus, and pertussis-containing vaccine (DTP-1) coverage increased from 85.4% in 2019 to 87.7% in 2020, and DTP-3 coverage increased from 79.5% in 2019 to 81.2% in 2020. The paucity of literature on the impact of COVID-19 on childhood vaccination in COVID-19 hotspot regions poses a challenge in developing a context-specific immunization recovery plan, hence the need to conduct this study. Methodology: We conducted a cross-sectional study using 2019 (pre-pandemic period) and 2020 (pandemic period) district childhood immunization data from the DHIS-2 database, weighted using completeness for each data entry against regional data completeness in 2020. Based on COVID-19 incidence, two hotspot regions were selected, with all districts (56/56) included in the final analysis. The Chi-square test was used to compare DTP-1 and DTP-3 coverage during the pre-pandemic and pandemic periods. Results: In the two hotspot regions, 8247 children missed DTP-1, and 12,896 children did not receive DTP-3 vaccines in the pandemic period compared to the results from the pre-pandemic period. Indeed, there was a significant drop in DTP-1 and DTP-3 coverage of 0.8% (p = 0.0002) and 3.1% (p = 0.0003), respectively, in the Littoral Region. Moreover, the Centre Region reported a 5.7% (p < 0.0001) and 7.6% (p < 0.0001) drop in DTP-1 and DTP-3 coverage, respectively. Most districts in the hotspot regions reported a decline in childhood immunization access (62.5%) and utilization (71.4%). Indeed, in the Littoral Region, 46% (11/24) and 58% (14/24) of districts experienced decreased vaccination access and utilization, respectively. Meanwhile, 75% (24/32) and 81% (26/32) of districts in the Centre Region experienced a drop in vaccination access and utilization, respectively. Conclusion: This study reported a situation where the national immunization indicators mask the impact of COVID-19 on childhood immunization in heavily hit regions. Therefore, this study presents valuable information for ensuring continuous vaccination service delivery during public health emergencies. The findings could also contribute to developing an immunization recovery plan and informing policy on future pandemic preparedness and response.