Method for evaluating bow tie filter angle-dependent attenuation in CT: theory and simulation results.
Dosimetry in computed tomography (CT) is increasingly based on Monte Carlo studies that define the dose in the patient (in mGy) as a function of air kerma (free in air) at isocenter (mGy). The accuracy of Monte Carlo studies depends in part on the accuracy of the characterization of the bow tie filter for a given CT scanner model. A simple method for characterizing the bow tie filter attenuation profile in CT scanners would therefore be very useful. The theory behind such a method is proposed. A measurement protocol is discussed mathematically and demonstrated using computer simulation. The proposed method requires the placement of a radiation monitor at the periphery of the CT field, and the time domain signal (kerma rate versus time) is measured with good temporal resolution (-200 Hz or better) and with all other objects (e.g., patient couch) retracted from the field of view. Knowledge of the source to isocenter distance (or alternately, the isocenter to probe distance) is required. The stationary detector records the kerma rate versus time signal as the gantry rotates through several revolutions. From this temporal data, signal processing techniques are used to extract in-phase peaks, as well as out-of-phase kerma rate levels. From these data, the distance from isocenter to the probe can be determined (or, alternatively, the source to isocenter distance), and the angle-dependent bow tie filter attenuation can be computed. By measuring the angle-dependent bow tie filter attenuation at several kVp settings, the bow tie composition versus fan angle can be computed using basis decomposition techniques. The simulations illustrated that with 2% added noise in the kerma rate versus time signal, the attenuation properties of a hypothetical two component (aluminum and polymethyl methacrylate) bow tie filter could be determined (r2 > 0.99). Although the computed basis material thicknesses were not exactly equal to the actual thicknesses, their combined attenuation factors matched that of the actual filter across kVp's to within an average of 0.057%. It is concluded that the proposed method may provide a simple noninvasive approach to characterizing the performance of bow tie filters in CT systems; however, experimental validation is necessary.


Development of a minimal KASP marker panel for distinguishing genotypes in apple collections.
Accurate identification of named accessions in germplasm collections is extremely important, especially for vegetatively propagated crops which are expensive to maintain. Thus, an inexpensive, reliable, and rapid genotyping method is essential because it avoids the need for laborious and time-consuming morphological comparisons. Single Nucleotide Polymorphism (SNP) marker panels containing large numbers of SNPs have been developed for many crop species, but such panels are much too large for basic cultivar identification. Here, we have identified a minimum set of SNP markers sufficient to distinguish apple cultivars held in the English and Welsh national collections providing a cheaper and automatable alternative to the markers currently used by the community. We show that SNP genotyping with a small set of well selected markers is equally efficient as microsatellites for the identification of apple cultivars and has the added advantage of automation and reduced cost when screening large numbers of samples.


Functional screening and in vitro analysis reveal thioesterases with enhanced substrate specificity profiles that improve short-chain fatty acid production in Escherichia coli.
Short-chain fatty acid (SCFA) biosynthesis is pertinent to production of biofuels, industrial compounds, and pharmaceuticals from renewable resources. To expand on Escherichia coli SCFA products, we previously implemented a coenzyme A (CoA)-dependent pathway that condenses acetyl-CoA to a diverse group of short-chain fatty acyl-CoAs. To increase product titers and reduce premature pathway termination products, we conducted in vivo and in vitro analyses to understand and improve the specificity of the acyl-CoA thioesterase enzyme, which releases fatty acids from CoA. A total of 62 putative bacterial thioesterases, including 23 from the cow rumen microbiome, were inserted into a pathway that condenses acetyl-CoA to an acyl-CoA molecule derived from exogenously provided propionic or isobutyric acid. Functional screening revealed thioesterases that increase production of saturated (valerate), unsaturated (trans-2-pentenoate), and branched (4-methylvalerate) SCFAs compared to overexpression of E. coli thioesterase tesB or native expression of endogenous thioesterases. To determine if altered thioesterase acyl-CoA substrate specificity caused the increase in product titers, six of the most promising enzymes were analyzed in vitro. Biochemical assays revealed that the most productive thioesterases rely on promiscuous activity but have greater specificity for product-associated acyl-CoAs than for precursor acyl-CoAs. In this study, we introduce novel thioesterases with improved specificity for saturated, branched, and unsaturated short-chain acyl-CoAs, thereby expanding the diversity of potential fatty acid products while increasing titers of current products. The growing uncertainty associated with protein database annotations denotes this study as a model for isolating functional biochemical pathway enzymes in situations where experimental evidence of enzyme function is absent.


Determinants of eGFR at start of renal replacement therapy in paediatric patients.
Few studies have investigated the determinants of glomerular filtration rate (GFR) in paediatric patients starting on dialysis or with a transplant. Data were collected as part of the European Society of Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association registry from 14 European countries and referred to incident paediatric patients starting on renal replacement therapy (RRT) between 2002 and 2007 under the age of 18 years. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula. Data were adjusted for age, gender, treatment modality at start, primary cause of renal failure (PRD) and regions in Europe (eGFR(adj)). Median eGFR in the 938 patients starting RRT was 10.4 mL/min/1.73 m(2) (5th and 95th percentile: 4.0-26.9). Twenty-six patients (2.8%), mainly infants with Finnish-type nephropathy, started with eGFR levels >50 mL/min/1.73 m(2). Younger age, female gender, starting on dialysis and having a short time between the first visit to a paediatric nephrologist (PN) and start of RRT were associated with lower eGFR at start of RRT. Gender differences were only present during adolescent age and disappeared when using the same K value for both genders. The various PRDs showed large differences in the rate of decline in eGFR between the first visit to a PN and start of RRT; however, this did not result in differences in eGFR(adj) at start of RRT. The main determinants of eGFR at start of RRT were age, gender, treatment modality at start, and the time between the first visit to a PN and start of RRT. Research is needed to determine the consequences of these differences.


Basic empathy in older adults: conceptualization, measurement, and application.
Older adults comprise the most rapidly increasing age group in America. In addition, an increasing number of older adults are involved in helping behaviors or volunteering. Although empathy has been identified as a critical component of a helping relationship, few studies concerning empathy have been conducted with older adults and few instruments have been developed that can be used with this population. The purpose of this study was to explore the relationship between two measures of empathy in older adults. The Hogan Empathy Scale and an Adjective Check List Empathy Scale were used to assess basic empathy in 43 older adults between the ages of 63 and 96. Results indicated that the mean scores of older adults were lower than mean scores in younger populations. Scores on both measures were comparable suggesting that both instruments could be used to measure basic empathy in older adults.


Ethnic disparities in accessing treatment for depression and substance use disorders in an integrated health plan.
This study examined ethnic differences in accessing treatment for depression and substance use disorders (SUDs) among men and women in a large integrated health plan, and explored factors potentially contributing to health care disparities. Participants were 22,543 members ages 20 to 65 who responded to health surveys in 2002 and 2005. Survey questions were linked to provider-assigned diagnoses, electronic medication, psychiatry, and chemical dependency program records. Among women diagnosed with depression, Latinas (p < .01) and Asian-Americans (p < .001) were less likely than Whites to fill an antidepressant prescription. Among men diagnosed with depression, African Americans (p < .01) were less likely than Whites to do so. Among women diagnosed with an SUD, African Americans (p < .05) were less likely than Whites to have one or more chemical dependency program visits. Results demonstrated ethnic differences in accessing depression and SUD treatment among patients diagnosed with these disorders, which persisted after controlling for education, income, having a regular health care provider and length of health plan enrollment. Findings highlight potential gender differences in ethnic disparities, lower antidepressant utilization among Asian Americans, and the effects of co-occurring disorders in accessing behavioral health care.


Effects of milk production capacity and metabolic status on HPA function in early postpartum dairy cows.
Increasing milk yields in modern dairy cows cause concern that high yield may impair the cows' health and welfare, for example, via negative effects on metabolic status and hypothalamo-pituitary-adrenocortical (HPA) function. This study aims to investigate whether a high level of milk production, and the associated metabolic status, affects HPA function in dairy cows and changes their adaptive capacity. Additionally, it aims to establish whether possible effects of milk production level only show under challenging conditions. Holstein-Friesian cows, which produced on average 11,443 and 7727 kg of fat and protein-corrected milk (FPCM)/305 d in their previous lactation, were compared. During the dry period, the cows were fed to requirements or overfed. High milk yield and the concomitant large energy deficit were associated with 1) increased pituitary (re)activity, i.e., increased ACTH baseline concentrations and higher ACTH concentrations after corticotropin-releasing hormone (CRH) administration, and 2) decreased adrenocortical reactivity, i.e., lower cortisol responses after ACTH administration. Although significant, the effects of milk production level on HPA function were relatively small. Animals showed seemingly normal hormonal responses to CRH and ACTH administration. Also, cortisol baseline concentrations were unaffected. It seems, therefore, unlikely that the adaptive capacity of the high-producing cows was significantly impaired compared with their low-producing herdmates.


European Association for Osseointegration Delphi study on the trends in Implant Dentistry in Europe for the year 2030.
To assess the potential trends for the year 2030 in dental implant dentistry in Europe using the Delphi methodology. A steering committee and a management team of experts in implant dentistry were created and validated a questionnaire including 60 questions, divided in eight topics. The survey was conducted in two rounds using an anonymous questionnaire, which provided the participants in the second round with the results of the first. Each question had three possible answers, and the results were expressed as percentages. A total of 138 experts were invited to participate in the survey. From all the invited experts, 52 answered in both the first and second rounds. Three different consensus categories were established based on the percentage of agreement: no consensus (<65%); moderate consensus (65%-85%); and high consensus (≥86%). Within the topic categories, a consensus was reached (mainly moderate consensus) for the majority of questions discussed among experts during a face to face consensus meeting. However, consensus was not reached for a small number of questions/topics. About 82% of the questions reached consensus. The consensus points towards a lower number of implants to replace chewing units, with implants surfaces made of bioactive materials with reduced micro-roughness using mainly customized abutments with polished surfaces and an internal implant-abutment connection (85%). CBCT-3D technologies will be the main tool for pre-surgical implant placement diagnosis together with direct digital restorative workflows. There will be an increase in the incidence of peri-implantitis, although there will be more efficient interventions its treatment and prevention.


Reprogramming and carcinogenesis--parallels and distinctions.
Rapid progress made in various areas of regenerative medicine in recent years occurred both at the cellular level, with the Nobel prize-winning discovery of reprogramming (generation of induced pluripotent stem (iPS) cells) and also at the biomaterial level. The use of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 (called commonly "Yamanaka factors") for the conversion of differentiated cells, back to the pluripotent/embryonic stage, has opened virtually endless and ethically acceptable source of stem cells for medical use. Various types of stem cells are becoming increasingly popular as starting components for the development of replacement tissues, or artificial organs. Interestingly, many of the transcription factors, key to the maintenance of stemness phenotype in various cells, are also overexpressed in cancer (stem) cells, and some of them may find the use as prognostic factors. In this review, we describe various methods of iPS creation, followed by overview of factors known to interfere with the efficiency of reprogramming. Next, we discuss similarities between cancer stem cells and various stem cell types. Final paragraphs are dedicated to interaction of biomaterials with tissues, various adverse reactions generated as a result of such interactions, and measures available, that allow for mitigation of such negative effects.


Validation of 213Bi-alpha radioimmunotherapy for multiple myeloma.
The efficacy of radioimmunotherapy (RIT) with beta emitters has been clinically demonstrated in the treatment of refractory forms of lymphoma. Alpha-emitting radionuclides with a short half-life are also good potential candidates for RIT directed at tumor targets easily accessible to radioimmunoconjugate molecules and small enough to benefit from the short range of alpha particles (<100 microm). The purpose of this study was to demonstrate the feasibility of ex vivo purging of multiple myeloma-invaded bone marrow. Tumor cells were targeted by a specific monoclonal antibody (B-B4) coupled to 213Bi by a chelating agent (pentaacetic triamine diethylene p-aminobenzyl acid). The efficacy of alpha-RIT was assessed in vitro by analysis of thymidine incorporation, cell mortality, apoptosis of myeloma cells, and the study of nonspecific irradiation of hematopoietic cell lines not recognized by B-B4-pentaacetic triamine diethylene p-aminobenzyl acid immunoconjugate. High dose-dependent cell mortality of myeloma cells was found with radiolabeled B-B4, and this mortality was total at 30 kBq/10(5) cells. Cells were found in apoptotic state at rates of up to 40% for a dose of 7.4 kBq/10(5) cells. Nonspecific mortality was low compared with specific mortality (up to 1%).


Seleniranium ion-triggered reactions: new aspects of Friedel-Crafts and N-detosylative cyclizations.
Seleniranium ions at low temperatures (-90 to -78 degrees C) will initiate effective Friedel-Crafts cyclization if a suitably placed arene is allowed to react even when the arene is unactivated. These intermediates generated from N-aryl-N-tosylamides undergo a novel, surprisingly efficient, detosylative cyclization to form 5- or 6-membered nitrogen heterocycles. A debenzylation route is preferred if both benzyl and tosyl groups are present in the substrate.


Conjugal transfer of multiple antibiotic resistance from hospital isolates of Klebsiella to Escherichia coli.
Six independent isolates of Klebsiella from hospital environmental sources in Malaysia were found to be resistant to at least ampicillin, carbenicillin, cefoperazone, chloramphenicol, gentamicin and tetracycline. On the basis of their antibiograms, they were divided into four antibiogroups. They transferred all or part of their multiple antibiotic resistance traits to E. coli by conjugation. The results suggest that these Klebsiella strains harbour self-transmissible R plasmids. The significance of these findings are discussed.


A method for neighborhood-level surveillance of food purchasing.
Added sugar, particularly in carbonated soft drinks (CSDs), represents a considerable proportion of caloric intake in North America. Interventions to decrease the intake of added sugar have been proposed, but monitoring their effectiveness can be difficult due to the costs and limitations of dietary surveys. We developed, assessed the accuracy of, and took an initial step toward validating an indicator of neighborhood-level purchases of CSDs using automatically captured store scanner data in Montreal, Canada, between 2008 and 2010 and census data describing neighborhood socioeconomic characteristics. Our indicator predicted total monthly neighborhood sales based on historical sales and promotions and characteristics of the stores and neighborhoods. The prediction error for monthly sales in sampled stores was low (2.2%), and we demonstrated a negative association between predicted total sales and median personal income. For each $10,000 decrease in median personal income, we observed a fivefold increase in predicted monthly sales of CSDs. This indicator can be used by public health agencies to implement automated systems for neighborhood-level monitoring of an important upstream determinant of health. Future refinement of this indicator is possible to account for factors such as store catchment areas and to incorporate nutritional information about products.


Adverse Pathologic Findings for Men Electing Immediate Radical Prostatectomy: Defining a Favorable Intermediate-Risk Group.
Active surveillance is recommended for patients with very low-risk (VLR) and low-risk (LR) prostate cancer. Despite controversy, recent clinical guidelines state surveillance may be considered for men with low-volume intermediate-risk (LVIR) disease. To compare rates of adverse pathologic findings among VLR, LR, and LVIR men electing immediate radical prostatectomy and evaluate criteria to define if a favorable intermediate-risk group minimizing risk exists. This was a cohort study of men (2005-July 2016) with clinically localized VLR (1264 patients), LR (4849 patients), and LVIR (608 patients) (1-2 cores, Gleason 3 + 4 = 7, prostate-specific antigen [PSA] level <20 ng/mL) prostate cancer undergoing radical prostatectomy evaluated retrospectively at Johns Hopkins Hospital. Radical prostatectomy. The proportions of men found to have at least Gleason 4 + 3 = 7 disease and other adverse pathologic features were compared by risk group. Log-binomial regression calculated relative risk (RR) of adverse pathologic findings in the LVIR cohort compared with VLR and LR cohorts. Analyses were repeated in subgroups of the LVIR population who otherwise met criteria for VLR (T1c, PSA density [PSAD] <0.15 ng/mL/cm3, ≤50% cancer in any core) and LR (≤T2a, PSA level <10 ng/mL) disease. Rates of adverse pathologic findings within the LVIR group were calculated based on various clinical thresholds, and univariable and multivariable logistic regression analyses were performed to identify predictors of adverse pathologic findings. The rate of adverse pathologic findings was significantly higher for LVIR disease (150 of 608 patients [24.7%]; RR, 4.50; 95% CI, 3.73-5.43; P < .001) compared with LR disease (280 of 4849 [5.8%]), and LVIR disease (RR, 5.14; 95% CI, 3.84-6.89; P < .001) compared with men with VLR disease (60 of 1264 [4.7%]). Restriction of LVIR men to additional criteria did not significantly affect results. There were no preoperative clinical or pathologic criteria that could identify a subgroup of the LVIR population with rates of adverse pathologic findings comparable with those of the VLR and LR cohorts. PSAD was a significant predictor of adverse pathologic findings, but Gleason score had the largest effect (odds ratio, 4.30 (95% CI, 3.40-5.44; P < .001). Nearly 25% of men (150 of 608) electing immediate radical prostatectomy with low-volume, Gleason 3 + 4 prostate cancer on biopsy are found to harbor adverse surgical pathologic findings. These data do not support the presence of a "favorable" subgroup among included patients and could have important implications for active surveillance in similar patients with Gleason 3 + 4 = 7 prostate cancer.


[Analysis of factors associated with non-acceptance of hepatitis B vaccine among low income adolescent students].
To evaluate the predictor factors for non-acceptance of hepatitis B vaccine among low-income adolescent students in the Goiânia Metropolitan Region, Goiás State, Brazil. In this study, 304 HBV-susceptible individuals enrolled in two schools were interviewed, and the HBV vaccine was offered. Only 195 (64%) of adolescents accepted the first dose of vaccine. On the other hand, 182/195 (93.3%) received the full HBV vaccine scheme. School factors played a role in vaccine acceptance, as School B and night classes were independently associated with non-acceptance of hepatitis B vaccination. The findings of this study ratify the low acceptance of hepatitis B vaccine among adolescents, highlighting the need for health education programs aiming at this group for hepatitis B vaccinations, while buttressing the importance of school-based vaccination strategies for attaining full HBV immunization of this target population.


The Epidemiology of Cholera in Zanzibar: Implications for the Zanzibar Comprehensive Cholera Elimination Plan.
Cholera poses a public health and economic threat to Zanzibar. Detailed epidemiologic analyses are needed to inform a multisectoral cholera elimination plan currently under development. We collated passive surveillance data from 1997 to 2017 and calculated the outbreak-specific and cumulative incidence of suspected cholera per shehia (neighborhood). We explored the variability in shehia-specific relative cholera risk and explored the predictive power of targeting intervention at shehias based on historical incidence. Using flexible regression models, we estimated cholera's seasonality and the relationship between rainfall and cholera transmission. From 1997 and 2017, 11921 suspected cholera cases were reported across 87% of Zanzibar's shehias, representing an average incidence rate of 4.4 per 10000/year. The geographic distribution of cases across outbreaks was variable, although a number of high-burden areas were identified. Outbreaks were highly seasonal with 2 high-risk periods corresponding to the annual rainy seasons. Shehia-targeted interventions should be complemented with island-wide cholera prevention activities given the spatial variability in cholera risk from outbreak to outbreak. In-depth risk factor analyses should be conducted in the high-burden shehias. The seasonal nature of cholera provides annual windows of opportunity for cholera preparedness activities.


Adenovirus enhancement of transferrin-polylysine-mediated gene delivery.
Gene transfer may be accomplished by the receptor-mediated endocytosis pathway using transferrin-polylysine conjugates. For some target cells, however, gene transfer by this vector is extremely limited, despite the presence of the appropriate surface receptors, a phenomenon attributed to lysosomal degradation of endosome-internalized conjugate-DNA complexes. To enhance DNA escape from the cell vesicle system and thus augment gene transfer by this route, we have used the capacity of adenoviruses to disrupt endosomes as part of their entry mechanism. Adenoviral infection augmented levels of gene transfer by transferrin-polylysine conjugates in a dose-dependent manner: levels of gene transfer of greater than 2000-fold above baseline were achieved. Use of the adenovirus in this context allowed enhanced levels of gene transfer in a variety of target cells, including cell lines otherwise refractory to gene transfer by transferrin-polylysine conjugates. This augmentation was based on adenoviral-mediated vesicle disruption, a process independent of viral gene expression. Thus, the development of specific mechanisms to effect release from the endosome in combination with gene transfer by the receptor-mediated endocytosis pathway will increase the utility of this delivery system by allowing high levels of gene expression in target cells.


Caffeine-reinforced conditioned flavor preferences in rats.
In 4 experiments, rats were trained to associate 1 of 2 differently flavored solutions with caffeine. During later 2-bottle extinction tests, they consistently preferred flavors that had been previously mixed with 2 lower (0.25 and 0.125 mg/ml), but not 2 higher (0.5 and 0.75 mg/ml), caffeine concentrations. Hunger during conditioning increased the size of these preferences, but neither preexposure to unflavored caffeine nor hunger during the choice test had any effect on them. Because caffeine is noncaloric, this last finding strengthens the hypothesis that hunger enhances the expression of only calorie-based conditioned flavor preferences. More fundamentally, the present results represent the first clear evidence that, through Pavlovian conditioning, rats can develop preferences for flavors associated with caffeine.


DNA metabarcoding adds valuable information for management of biodiversity in roadside stormwater ponds.
Stormwater ponds are used to compensate for the adverse effects that road runoff might have on the natural environment. Depending on their design and placement, stormwater ponds can act as both refugia and traps for local biodiversity. To evaluate the impact of stormwater ponds on biodiversity, it is critical to use effective and precise methods for identification of life associated with the water body. DNA metabarcoding has recently become a promising tool for identification and assessment of freshwater biodiversity.Using both morphology and DNA metabarcoding, we analyze species richness and biological composition of samples from 12 stormwater ponds and investigate the impact of pond size and pollution levels in the sediments and water column on the macroinvertebrate community structure.DNA metabarcoding captured and identified more than twice the number of taxa compared to morphological identification. The (dis)similarity of macroinvertebrate community composition in different ponds showed that the ponds appear better separated in the results obtained by DNA metabarcoding, but that the explained variation is higher for the results obtained by morphologically identification, since it provides abundance data.The reliance on morphological methods has limited our perception of the aquatic biodiversity in response to anthropogenic stressors, thereby providing inaccurate information for appropriate design and management of stormwater ponds; these drawbacks can be overcome by DNA metabarcoding. Synthesis and applications. The results indicate that DNA metabarcoding is a useful tool in identifying species, especially Diptera, which are difficult to determine. Application of DNA metabarcoding greatly increases the number of species identified at each sampling site, thereby providing a more accurate information regarding the way the ponds function and how they are affected by management. This article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at https://www.ebi.ac.uk/ena/data/view/PRJEB30841.


Correction: Elaborating the interplay between the detecting unit and emitting unit in infrared quantum dot up-conversion photodetectors.
Correction for 'Elaborating the interplay between the detecting unit and emitting unit in infrared quantum dot up-conversion photodetectors' by Qiulei Xu et al., Nanoscale, 2023, 15, 8197-8203, https://doi.org/10.1039/D3NR01237A.


Endothelin-1 promotes cell survival in renal cell carcinoma through the ET(A) receptor.
Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to significantly impact many benign and malignant tissues by signaling through its two cognate receptors: ET(A) and ET(B). As ET-1 has a role in both normal and diseased kidney, we initiated studies to investigate endothelin axis expression and function in renal cell carcinoma (RCC). In this study, relatively high levels of ET-1 were detected in all six human RCC cell lines investigated. RT-PCR and Southern analyses revealed that all six RCC cell lines expressed ET(A) receptor mRNA, while 3/6 cell lines also expressed ET(B) mRNA. High affinity ET-1 binding occurred in all but one RCC cell line and quantitative RT-PCR demonstrated ET(A) mRNA expression in all six cell lines. Methylation of the ET(B) promoter (EDNRB) in 4/6 RCC cell lines was observed, suggesting a mechanism for repressed ET(B) expression. Moreover, methylation occurred in 32/48 of renal tumors and in 27/55 of histologically normal adjacent tissue samples studied, while no methylation was evident in any normal tissue isolated from nephrectomy or at autopsy. Functionally, ET-1 significantly inhibited paclitaxel-induced apoptosis in RCC cells through binding ET(A) with the ET-1 signaling mediated via the PI3-kinase/Akt pathway. Collectively, these data support the therapeutic targeting of the ET(A) receptor as a novel treatment strategy for RCC.


What Policies Address Both the Coronavirus Crisis and the Climate Crisis?
The coronavirus pandemic has led many countries to initiate unprecedented economic recovery packages. Policymakers tackling the coronavirus crisis have also been encouraged to prioritize policies which help mitigate a second, looming crisis: climate change. We identify and analyze policies that combat both the coronavirus crisis and the climate crisis. We analyze both the long-run climate impacts from coronavirus-related economic recovery policies, and the impacts of long-run climate policies on economic recovery and public health post-recession. We base our analysis on data on emissions, employment and corona-related layoffs across sectors, and on previous research. We show that, among climate policies, labor-intensive green infrastructure projects, planting trees, and in particular pricing carbon coupled with reduced labor taxation boost economic recovery. Among coronavirus policies, aiding services sectors (leisure services such as restaurants and culture, or professional services such as technology), education and the healthcare sector appear most promising, being labor intensive yet low-emission-if such sectoral aid is conditioned on being directed towards employment and on low-carbon supply chains. Large-scale green infrastructure projects and green R&D investment, while good for the climate, are unlikely to generate enough employment to effectively alleviate the coronavirus crisis.


From Continuous Observations to Symbolic Concepts: A Discrimination-Based Strategy for Grounded Concept Learning.
Autonomous agents perceive the world through streams of continuous sensori-motor data. Yet, in order to reason and communicate about their environment, agents need to be able to distill meaningful concepts from their raw observations. Most current approaches that bridge between the continuous and symbolic domain are using deep learning techniques. While these approaches often achieve high levels of accuracy, they rely on large amounts of training data, and the resulting models lack transparency, generality, and adaptivity. In this paper, we introduce a novel methodology for grounded concept learning. In a tutor-learner scenario, the method allows an agent to construct a conceptual system in which meaningful concepts are formed by discriminative combinations of prototypical values on human-interpretable feature channels. We evaluate our approach on the CLEVR dataset, using features that are either simulated or extracted using computer vision techniques. Through a range of experiments, we show that our method allows for incremental learning, needs few data points, and that the resulting concepts are general enough to be applied to previously unseen objects and can be combined compositionally. These properties make the approach well-suited to be used in robotic agents as the module that maps from continuous sensory input to grounded, symbolic concepts that can then be used for higher-level reasoning tasks.


Essential role of RAB27A in determining constitutive human skin color.
Human skin color is predominantly determined by melanin produced in melanosomes within melanocytes and subsequently distributed to keratinocytes. There are many studies that have proposed mechanisms underlying ethnic skin color variations, whereas the processes involved from melanin synthesis in melanocytes to the transfer of melanosomes to keratinocytes are common among humans. Apart from the activities in the melanogenic rate-limiting enzyme, tyrosinase, in melanocytes and the amounts and distribution patterns of melanosomes in keratinocytes, the abilities of the actin-associated factors in charge of melanosome transport within melanocytes also regulate pigmentation. Mutations in genes encoding melanosome transport-related molecules, such as MYO5A, RAB27A and SLAC-2A, have been reported to cause a human pigmentary disease known as Griscelli syndrome, which is associated with diluted skin and hair color. Thus we hypothesized that process might play a role in modulating skin color variations. To address that hypothesis, the correlations of expression of RAB27A and its specific effector, SLAC2-A, to melanogenic ability were evaluated in comparison with tyrosinase, using human melanocytes derived from 19 individuals of varying skin types. Following the finding of the highest correlation in RAB27A expression to the melanogenic ability, darkly-pigmented melanocytes with significantly higher RAB27A expression were found to transfer significantly more melanosomes to keratinocytes than lightly-pigmented melanocytes in co-culture and in human skin substitutes (HSSs) in vivo, resulting in darker skin color in concert with the difference observed in African-descent and Caucasian skins. Additionally, RAB27A knockdown by a lentivirus-derived shRNA in melanocytes concomitantly demonstrated a significantly reduced number of transferred melanosomes to keratinocytes in co-culture and a significantly diminished epidermal melanin content skin color intensity (ΔL* = 4.4) in the HSSs. These data reveal the intrinsically essential role of RAB27A in human ethnic skin color determination and provide new insights for the fundamental understanding of regulatory mechanisms underlying skin pigmentation.


Influence of resveratrol on liver fibrosis induced by dimethylnitrosamine in male rats.
Liver fibrosis is a significant health problem which represents the liver's scarring process and response to injury through deposition of collagen and extracellular matrix, and ultimately leads to cirrhosis. Resveratrol is a naturally occurring phytoalexin found predominantly in grapes. This study aimed to investigate the antifibrotic role of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were divided into four groups and treated for three weeks; control, resveratrol administered orally (20 mg/kg daily), DMN intraperitoneally injected (10 mg/kg 3 days/week), and the last group was pre-treated daily with resveratrol then injected with DMN, 3 days/week. DMN administration induced severe liver pathological alterations. However, oral administration of resveratrol before DMN significantly prevented the induced loss in body weight, as well as the increase in liver weight which arise from DMN administration. Resveratrol has also inhibited the elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin levels. Furthermore, resveratrol significantly increased hepatic reduced glutathione (GSH) levels and reduced the levels of malondialdehyde (MDA) due to its antioxidants effect as well as increased serum protein levels. In addition, DMN induced elevation in hydroxyproline content. On the other hand, hydroxyproline level was significantly reduced in the resveratrol pretreated rats. Resveratrol has also remarkably maintained the normal liver lobular architecture. Moreover, resveratrol had displayed potent potentials to prevent collagen deposition, lymphocytic infiltration, necrosis, steatosis, vascular damage, blood hypertention, cholangiocyte proliferation. It can be concluded that resveratrol has a marked protective role on DMN-induced liver fibrosis in rats, and can be considered as antiproliferative, antihypertensive, as well as antifibrotic agent and may be used to block the development of liver fibrosis.


Infrastructure for reaching disadvantaged consumers: telecommunications in rural and remote nursing in Australia.
Both consumers and health service providers need access to up-to-date information, including patient and practice guidelines, that allows them to make decisions in partnership about individual and public health in line with the primary health care model of health service delivery. Only then is it possible for patient preferences to be considered while the health of the general population is improved. The Commonwealth Government of Australia has allocated $250 million over five years, starting July 1, 1997, to support activities and projects designed to meet a range of telecommunication needs in regional, rural, and remote Australia. This paper defines rural and remote communities, then reviews rural and remote health services, information, and telecommunication technology infrastructures and their use in Australia to establish the current state of access to information tools by rural and remote communities and rural health workers in Australia today. It is argued that a suitable telecommunication infrastructure is needed to reach disadvantaged persons in extremely remote areas and that intersectoral support is essential to build this infrastructure. In addition, education will make its utilization possible.


Serotonin and cyclic GMP both induce an increase of the calcium current in the same identified molluscan neurons.
Serotonin (5-HT) has previously been shown to evoke an increase in the duration of the Ca2+-dependent spike of molluscan neurons by decreasing the S current (Klein et al., 1982), a K+ current controlled by cAMP. However, in a group of identified ventral neurons of the snail Helix aspersa in which 5-HT (1-10 microM) also prolonged the duration of the Ca2+-dependent action potential, no 5-HT-induced depression of S current or of any other outward current was observed. Instead, 5-HT was found to evoke the prolongation of the somatic spike by inducing an increase in Ca2+ membrane conductance. This 5-HT-induced increase of Ca2+-current was mimicked neither by the intracellular injection of cAMP nor by the extracellular application of forskolin (20 microM). In contrast, it was mimicked by the intracellular injection of cGMP and by the extracellular application of 100 nM zaprinast, a cGMP-phosphodiesterase inhibitor. The extracellular application of phorbol ester TPA (100 nM), an activator of protein kinase C, was also found to increase the Ca2+ current in the identified snail ventral neurons, but this enhancing effect had a different time course from that induced by 5-HT. These results indicate that there is a second mechanism for prolonging the Ca2+ spike of molluscan neurons, consisting of an increase in Ca2+ current, in which cGMP may play a role as second messenger.


Isolation and genetic characterization of Toxoplasma gondii from striped dolphin (Stenella coeruleoalba) from Costa Rica.
Toxoplasma gondii infection in marine mammals is of interest because of mortality and mode of transmission. It has been suggested that marine mammals become infected with T. gondii oocysts washed from land to the sea. We report the isolation and genetic characterization of viable T. gondii from a striped dolphin (Stenella coeruleoalba), the first time from this host. An adult female dolphin was found stranded on the Pacific Coast of Costa Rica, and the animal died the next day. The dolphin had a high (1:6400) antibody titer to T. gondii in the modified agglutination test. Severe nonsuppurative meningoencephalomyelitis was found in its brain and spinal cord, but T. gondii was not found in histological sections of the dolphin. Portions of its brain and the heart were bioassayed in mice for the isolation of T. gondii. Viable T. gondii was isolated from the brain, but not from the heart, of the dolphin. A cat fed mice infected with the dolphin isolate (designated TgSdCol) shed oocysts. Genomic DNA from tachyzoites of this isolate was used for genotyping at 10 genetic loci, including SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico, and this TgSdCo1 isolate was found to be Type II.


Leptin: Less Is More.
The successful use of leptin for the treatment of individuals with lipodystrophy and leptin deficiency is well established. However, pharmacological approaches of leptin therapy for the treatment of diet-induced obesity have been ineffective. There is ample room for a better understanding of the much famed "leptin resistance" phenomenon. Our recent data in this area prompt us to call for a conceptual shift. This shift entails a model in which a reduction of bioactive leptin levels in the context of obesity triggers a high degree of leptin sensitization and improved leptin action, both centrally and peripherally. Put another way, hyperleptinemia per se causes leptin resistance and associated metabolic disorders. In this perspective, we briefly discuss the underlying conceptual steps that led us to explore partial leptin reduction as a viable therapeutic avenue. We hope this discussion will contribute to potential future applications of partial leptin reduction therapy for the treatment of obesity and type 2 diabetes.


Pediatric cardiology national education series: A remote education response to COVID-19.
Medical education experienced widespread disruption during the first peak of the COVID-19 pandemic. In response, members of the Society of Pediatric Cardiology Training Program Directors (SPCTPD) created a series of live, Zoom-based lectures for pediatric cardiology fellows. The goals were to support fellow didactic education and connect fellows and faculty during the pandemic. We sought to determine the impact of the lecture series on pediatric cardiology fellows around the country. Pediatric cardiology experts from across the country volunteered to give lectures in the Pediatric Cardiology National Education Series (PC-NES). Lectures were held online once or twice weekly for 3 months during Spring 2020, while many fellows had modified clinical responsibilities. Fellows voluntarily completed an online survey before and after the lecture series. On the initial survey, a majority of fellows responded they would benefit from more didactic education while their training was impacted by COVID-19. After the series concluded, almost all (95%) fellows responded that PC-NES lectures were valuable supplements to their training during COVID-19. They included quality of lectures, board-relevance, and a way to connect to the pediatric cardiology community as key reasons for participating in PC-NES, and 100% responded they felt PC-NES should continue in some capacity. The PC-NES was a low-cost, simple way to deliver high-quality supplemental education to pediatric cardiology fellows, help trainees build a network of peers and learn from experts outside their home institution. Similar models could connect other pediatric trainees at local, regional, or national levels, and provide valuable supplemental education opportunities.


Ovine fetal testis stage-specific sensitivity to environmental chemical mixtures.
Exposure of the fetal testis to numerous individual environmental chemicals (ECs) is frequently associated with dysregulated development, leading to impaired adult reproductive competence. However, 'real-life' exposure involves complex mixtures of ECs. Here we test the consequences, for the male fetus, of exposing pregnant ewes to EC mixtures derived from pastures treated with biosolids fertiliser (processed human sewage). Fetal testes from continuously exposed ewes were either unaffected at day 80 or exhibited a reduced area of testis immunostained for CYP17A1 protein at day 140. Fetal testes from day 140 pregnant ewes that were exposed transiently for 80-day periods during early (0-80 days), mid (30-110 days), or late (60-140 days) pregnancy had fewer Sertoli cells and reduced testicular area stained for CYP17A1. Male fetuses from ewes exposed during late pregnancy also exhibited reduced fetal body, adrenal and testis mass, anogenital distance, and lowered testosterone; collectively indicative of an anti-androgenic effect. Exposure limited to early gestation induced more testis transcriptome changes than observed for continuously exposed day 140 fetuses. These data suggest that a short period of EC exposure does not allow sufficient time for the testis to adapt. Consequently, testicular transcriptomic changes induced during the first 80 days of gestation may equate with phenotypic effects observed at day 140. In contrast, relatively fewer changes in the testis transcriptome in fetuses exposed continuously to ECs throughout gestation are associated with less severe consequences. Unless corrected by or during puberty, these differential effects would predictably have adverse outcomes for adult testicular function and fertility.


Prevention of mental disorder among Hmong refugees in the U.S.: lessons from the period 1976-1986.
Scientifically valid, well controlled studies on the prevention of mental disorders are sparse. Nonetheless, much quasi-experimental and descriptive work does exist. Published findings permit an evaluation of the mental health effects of policies, procedures and programs designed for refugees. The federal government assigns legal status to refugees and is paramount in matters of refugee relocation and readjustment within its borders. In matters of social adjustment and prevention of mental disorder, agents of the federal government must consider the accumulation and distribution of knowledge, skill and expertise on refugee social and mental health issues; policies and procedures for relocation; premigration education, training, assessment, and orientation; postmigration support and acculturation; and the development of treatment resources to meet the mental health needs. Once refugees arrive in the United States of America, much of the actual implementation of policy and procedures has been left to state governments. At this level there have been neither the resources nor the expertise to develop programs for the mental health of refugees. Limited resources have been wasted and the mental health of refugees has been neglected or made worse by some state initiated programs.


The role of ionotropic glutamate receptors in nociception with special regard to the AMPA binding sites.
The recent literature on the antinociceptive action of ionotropic glutamate receptor antagonists is reviewed with special emphasis on their clinical potential. Actually the glutamatergic pathways descending from the brain stem into the spinal cord may generate analgesia. However, physiologically more important is that glutamate and aspartate are apparently the main neurotransmitters along the ascending nociceptive pathways in the spinal cord. Glutamate, aspartate and their receptors can be detected in particularly high concentrations in the dorsal root ganglia and the superficial laminae (I, II) of the spinal cord. In low doses glutamate receptor antagonists only slightly elevate the threshold of the physiological pain sensation. However, they suppress the process of pathological sensitisation i.e. lowering of the pain threshold seen upon excessive or lasting stimulation of C-fibre afferents, a process that takes place during inflammation or other kinds of tissue injury. At electrophysiological level antagonists of both the NMDA- and AMPA/kainate receptors inhibit wind up i.e. lasting activation of the polymodal, second-order sensory neurones in the deeper layers of the dorsal horn. During sensitisation the resting Mg(++) blockade of transmembrane Ca(++) channels is abolished, certain second messenger pathways are activated, the transcription of many genes is enhanced leading to overproduction of glutamate and other excitatory neurotransmitters and expression of Na(+) channels in the primary sensory neurones activated at lower level of depolarisation. This cascade of events leads to increased excitability of the pain pathways. NMDA antagonists are apparently more potent in experimental models of neuropathic pain, whereas AMPA antagonists are more effective in abolition of hyperalgesia seen during experimental inflammation. Clinically, of the previously known NMDA antagonists amantadine, dextromethorphan and ketamine have been tested, the latter extensively. Ketamine has been found quite active in certain cases of neuropathic pain and it reduced the opiate demand when used for postoperative analgesia. However, in other types of clinical pain their efficacy is less convincing. Not being registered there are no clinical data on the AMPA antagonists. There are, however, some investigational new drugs and some novel compounds in the stage of preclinical development which antagonise the AMPA receptors in competitive fashion or allosterically. Of the latter molecules 2,3-benzodiazepines are particularly promising.


Taking a break: The effect of taking a vacation from Facebook and Instagram on subjective well-being.
Social Networking Sites (SNS) such as Facebook and Instagram have relocated a large portion of people's social lives online, but can be intrusive and create social disturbances. Many people therefore consider taking an "SNS vacation." We investigated the effects of a one-week vacation from both Facebook and Instagram on subjective well-being, and whether this would vary for passive or active SNS users. Usage amount was measured objectively, using RescueTime software, to circumvent issues of self-report. Usage style was identified at pre-test, and SNS users with a more active or more passive usage style were assigned in equal numbers to the conditions of one-week SNS vacation (n = 40) or no SNS vacation (n = 38). Subjective well-being (life satisfaction, positive affect, and negative affect) was measured before and after the vacation period. At pre-test, more active SNS use was found to correlate positively with life satisfaction and positive affect, whereas more passive SNS use correlated positively with life satisfaction, but not positive affect. Surprisingly, at post-test the SNS vacation resulted in lower positive affect for active users and had no significant effects for passive users. This result is contrary to popular expectation, and indicates that SNS usage can be beneficial for active users. We suggest that SNS users should be educated in the benefits of an active usage style and that future research should consider the possibility of SNS addiction among more active users.


Fuzzy color histogram and its use in color image retrieval.
A conventional color histogram (CCH) considers neither the color similarity across different bins nor the color dissimilarity in the same bin. Therefore, it is sensitive to noisy interference such as illumination changes and quantization errors. Furthermore, CCHs large dimension or histogram bins requires large computation on histogram comparison. To address these concerns, this paper presents a new color histogram representation, called fuzzy color histogram (FCH), by considering the color similarity of each pixel's color associated to all the histogram bins through fuzzy-set membership function. A novel and fast approach for computing the membership values based on fuzzy c-means algorithm is introduced. The proposed FCH is further exploited in the application of image indexing and retrieval. Experimental results clearly show that FCH yields better retrieval results than CCH. Such computing methodology is fairly desirable for image retrieval over large image databases.


Campaigns with oral polio vaccine may lower mortality and create unexpected results.
Three studies from Guinea-Bissau found conflicting effects of OPV-at-birth (OPV0) on child survival. One study from 2004 suggested excess male mortality among children receiving OPV0 compared with children receiving NoOPV0 during a period of shortage of OPV. However, two subsequent studies showed beneficial effects of OPV0. In 2004, two national OPV-campaigns had been conducted in Guinea-Bissau. In a reanalysis of the 2004-study, in a survival analysis the age-adjusted mortality rate of study participants was 67% (95% CI=42-81%) lower after the OPV-campaigns than before the campaigns. In the OPV0 group only 22% (655/3031 person-years (pyrs)) of follow-up time was "after" the OPV-campaigns whereas 55% (473/859 pyrs) of the time in the NoOPV0 group was post-campaign (p<0.0001, Chi2). Censoring for OPV-campaigns in the original study removed excess male mortality and made the three studies more homogeneous. Overall, there is now considerable evidence that OPV, like other live vaccines, has important beneficial non-specific effects.


Exposure prediction approaches used in air pollution epidemiology studies: key findings and future recommendations.
Many epidemiologic studies of the health effects of exposure to ambient air pollution use measurements from central-site monitors as their exposure estimate. However, measurements from central-site monitors may lack the spatial and temporal resolution required to capture exposure variability in a study population, thus resulting in exposure error and biased estimates. Articles in this dedicated issue examine various approaches to predict or assign exposures to ambient pollutants. These methods include combining existing central-site pollution measurements with local- and/or regional-scale air quality models to create new or "hybrid" models for pollutant exposure estimates and using exposure models to account for factors such as infiltration of pollutants indoors and human activity patterns. Key findings from these articles are summarized to provide lessons learned and recommendations for additional research on improving exposure estimation approaches for future epidemiological studies. In summary, when compared with use of central-site monitoring data, the enhanced spatial resolution of air quality or exposure models can have an impact on resultant health effect estimates, especially for pollutants derived from local sources such as traffic (e.g., EC, CO, and NO(x)). In addition, the optimal exposure estimation approach also depends upon the epidemiological study design. We recommend that future research develops pollutant-specific infiltration data (including for PM species) and improves existing data on human time-activity patterns and exposure to local source (e.g., traffic), in order to enhance human exposure modeling estimates. We also recommend comparing how various approaches to exposure estimation characterize relationships between multiple pollutants in time and space and investigating the impact of improved exposure estimates in chronic health studies.


Distribution and sources of polyfluoroalkyl substances (PFAS) in the River Rhine watershed.
The concentration profile of 40 polyfluoroalkyl substances (PFAS) in surface water along the River Rhine watershed from the Lake Constance to the North Sea was investigated. The aim of the study was to investigate the influence of point as well as diffuse sources, to estimate fluxes of PFAS into the North Sea and to identify replacement compounds of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). In addition, an interlaboratory comparison of the method performance was conducted. The PFAS pattern was dominated by perfluorobutane sulfonate (PFBS) and perfluorobutanoic acid (PFBA) with concentrations up to 181 ng/L and 335 ng/L, respectively, which originated from industrial point sources. Fluxes of SigmaPFAS were estimated to be approximately 6 tonnes/year which is much higher than previous estimations. Both, the River Rhine and the River Scheldt, seem to act as important sources of PFAS into the North Sea.


Long-term sensitization of a defensive withdrawal reflex in Aplysia.
When a weak tactile stimulus is applied to the siphon of Aplysia californica, the animal withdraws the siphon between the parapodia. This defensive withdrawal reflex can be facilitated (sensitized) if the animal is previously given 4 days of training, consisting of four brief noxious stimuli each day. The sensitization of this reflex can last for up to 3 weeks after training and is mediated by the abdominal ganglion which also mediates long-term habituation. This preparation may provide a system for analyzing the neural mechanism of long-term behavioral modifications of complexity which is intermediate between habituation and associative learning.


Intensive therapy for small-cell lung cancer using carboplatin alternating with cisplatin, ifosfamide, etoposide, mid-cycle vincristine, and radiotherapy.
Forty patients with small-cell lung cancer (31 patients with limited-stage [LS] disease, and nine patients with extensive-stage [ES] disease but of good performance status) have been treated with an intensive therapy composed of carboplatin alternating with cisplatin, ifosfamide, and etoposide with vincristine on day 14 of each carboplatin cycle. A maximum of six cycles were administered at 3 weekly intervals after the cisplatin combination and 4 weekly after the carboplatin combination. Prophylactic cranial irradiation was given with the first cycle of chemotherapy and thoracic irradiation with the third cycle. The median nadir for neutrophils was 0.47 x 10(9)/L and for platelets, 40 x 10(9)/L. Chemotherapy dosages were not reduced in response to myelosuppression, but treatment was delayed to allow blood count recovery. Sixty-eight percent of patients received all six cycles of chemotherapy, and there were four deaths associated with treatment-related neutropenia. Twenty-eight patients (70%) achieved a complete response (CR) when assessed 1 month after the end of treatment, and a further five patients (12.5%) had a partial response (PR). Median duration of CR was 16 months and of PR, 8 months. Cerebral metastases occurred in 20% of all patients and was the apparent sole site of relapse in 11% of the CR patients. The median survival of the total group was 14 months with an actual 2-year survival of 30% and a minimum follow-up of 28 months.


Possible Association of Pulmonary Atresia with In-Utero Coxsackievirus B Exposure.
Gestational viral infection has been associated with congenital heart disease (CHD). Few studies, however, have studied the potential role of gestational Coxsackievirus B (CVB) exposure in the pathogenesis of CHD. We prospectively enrolled women with pregnancies affected by CHD to explore possible associations with in utero CVB exposure. Serum samples were obtained from 122 women referred for fetal echocardiography between 2006 and 2018. We quantified CVB IgG and IgM levels, with titers ≥ 15.0 U/mL considered positive and measured neutralizing antibodies for three CVB serotypes: CVB1, CVB3, and CVB4. Using data from the national enterovirus surveillance system, we compared the annual exposure rates for each serotype in our cohort to infections reported across the United States. 98 pregnancies with no genetic defects were included. Overall, 29.6% (29/98) had positive IgG and 4.1% (4/98) of women had positive CVB IgM titers. To explore first-trimester CVB exposure, we focused exclusively on the 26 women with positive IgG and negative IgM titers. 61.5% (16/26) had neutralizing antibodies against a single serotype and 38.5% (10/26) against multiple CVB serotypes. CVB4 neutralizing antibodies were the most common (65.4%, 17/26), followed by CVB3 (53.9%, 14/26) and CVB1 (30.8%, 8/26). Among these, 30.8% of babies presented pulmonary valve anomalies: 19.2% (5/26) pulmonary atresia, and 11.5% (3/26) pulmonary stenosis. 23.1% (6/26) of babies had coronary sinusoids. CVB exposure in our cohort mirrored that of reported infections in the United States. Our results suggest a possible association between gestational CVB exposure and specific CHD, particularly pulmonary valve anomalies and coronary sinusoids.


Construction of an Enterococcus faecalis Tn917-mediated-gene-disruption library offers insight into Tn917 insertion patterns.
Sequencing the insertion sites of 8,865 Tn917 insertions in Enterococcus faecalis strain OG1RF identified a hot spot in the replication terminus region corresponding to 6% of the genome where 65% of the transposons had inserted. In E. faecalis, Tn917 preferentially inserted at a 29-bp consensus sequence centered on TATAA, a 5-bp sequence that is duplicated during insertion. The regional insertion site preference at the chromosome terminus was not observed in another low-G+C gram-positive bacterium, Listeria monocytogenes, although the consensus insertion sequence was the same. The 8,865 Tn917 insertion sites sequenced in E. faecalis corresponded to only approximately 610 different open reading frames, far fewer than the predicted number of 2,400, assuming random insertion. There was no significant preference in orientation of the Tn917 insertions with either transcription or replication. Even though OG1RF has a smaller genome than strain V583 (2.8 Mb versus 3.2 Mb), the only E. faecalis strain whose sequence is in the public domain, over 10% of the Tn917 insertions appear to be in a OG1RF-specific sequence, suggesting that there are significant genomic differences among E. faecalis strains.


A systematic review and meta-analysis of growth mindset interventions: For whom, how, and why might such interventions work?
As growth mindset interventions increase in scope and popularity, scientists and policymakers are asking: Are these interventions effective? To answer this question properly, the field needs to understand the meaningful heterogeneity in effects. In the present systematic review and meta-analysis, we focused on two key moderators with adequate data to test: Subsamples expected to benefit most and implementation fidelity. We also specified a process model that can be generative for theory. We included articles published between 2002 (first mindset intervention) through the end of 2020 that reported an effect for a growth mindset intervention, used a randomized design, and featured at least one of the qualifying outcomes. Our search yielded 53 independent samples testing distinct interventions. We reported cumulative effect sizes for multiple outcomes (i.e., mindsets, motivation, behavior, end results), with a focus on three primary end results (i.e., improved academic achievement, mental health, or social functioning). Multilevel metaregression analyses with targeted subsamples and high fidelity for academic achievement yielded, d = 0.14, 95% CI [.06, .22]; for mental health, d = 0.32, 95% CI [.10, .54]. Results highlighted the extensive variation in effects to be expected from future interventions. Namely, 95% prediction intervals for focal effects ranged from -0.08 to 0.35 for academic achievement and from 0.07 to 0.57 for mental health. The literature is too nascent for moderators for social functioning, but average effects are d = 0.36, 95% CI [.03, .68], 95% PI [-.50, 1.22]. We conclude with a discussion of heterogeneity and the limitations of meta-analyses. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Corticobasal degeneration as a cognitive disorder.
The presence of cognitive impairment in corticobasal degeneration (CBD) is now widely recognised. Our review of the literature reveals that, although the pattern and severity of neuropsychological impairments can be highly variable across patients, several general trends can be identified. The most characteristic impairments are limb apraxia (usually ideomotor), constructional and visuospatial difficulties, acalculia, frontal dysfunction, and nonfluent aphasia. The limb apraxia is associated with deficits in drawing, copying, and handwriting, but there is emerging evidence that the problems with handwriting are not due exclusively to the apraxia. The findings with respect to episodic memory are more variable, but when there is impairment in this area, it tends to be milder than that seen in Alzheimer's disease. Semantic memory functioning appears relatively preserved but has been poorly studied. Problems with speech are common, and may be due to dysarthria or buccofacial apraxia. Aphasia, although initially considered rare, is in fact a common accompaniment of CBD, may be the presenting feature, and is typically nonfluent in type. More systematic investigation of the clinical and neuropathological overlap between progressive nonfluent aphasia (generally considered to be a form of frontotemporal dementia) and CBD is needed.


Synthesis and In Vitro Characterization of Fe3+-Doped Layered Double Hydroxide Nanorings as a Potential Imageable Drug Delivery System.
Highly dispersed Fe3+-doped layered double hydroxide (LDH-Fe) nanorings were obtained by a simple coprecipitation-acid etching approach. The morphology, structure, magnetic resonance imaging (MRI) performance in vitro, drug loading and releasing, Fe3+ leakage, and cytotoxicity of the as-prepared LDH-Fe nanorings were characterized. The LDH-Fe nanorings showed good water dispersity and a well-crystallized structure. The DLS average size of nanoparticles was measured to be 94.5 nm. Moreover, the MRI tests showed a favourable T₁-weighted MRI performance of the LDH-Fe nanoring with r₁ values of 0.54 and 1.68, and low r₂/r₁ ratios of 10.1 and 6.3, pre- and after calcination, respectively. The nanoparticles also showed high model drug (ibuprofen) loading capacities, low Fe3+ leakage, and negligible cytotoxicity. All these results demonstrate the potential of LDH-Fe nanorings as an imageable drug delivery system.


Increased expression of estrogen receptor beta in pachytene spermatocytes after short-term methoxyacetic acid administration.
Degeneration of primary spermatocytes by apoptosis occurs during normal spermatogenesis, as well as in several pathological conditions, including exposure to specific testicular toxicants. The mechanisms that regulate the death and survival of primary spermatocytes, however, are still not well understood. The recent localization of estrogen receptor beta (ERbeta) and P450 aromatase in pachytene spermatocytes suggests a role for estrogens in this step of spermatogenesis. Using a well-known model of pachytene spermatocyte apoptosis in adult rats consisting of the administration of methoxyacetic acid (MAA), we investigated the participation of ERbeta during the initial phase of apoptosis, prior to germ cell loss. Adult rats were treated with a single intraperitoneal dose of MAA, and DNA laddering analysis confirmed apoptotic cell death in the testis. In enriched germ cell fractions and testis from MAA-treated animals, ERbeta mRNA increased significantly at 3 and 6 hours, respectively. Next, stage-specific induction of ERbeta mRNA was demonstrated by use of laser capture microdissection of seminiferous tubules in combination with semiquantitative reverse transcription-polymerase chain reaction. The ERbeta protein also increased significantly after 6 hours and was mainly immunolocalized in the cytoplasm of pachytene spermatocytes of afflicted tubules. The cytoplasmic localization was confirmed by Western blot analysis of isolated cytoplasmic and nuclear fractions of testicular extracts. Finally, the MAA activation of ERbeta was tested in vitro in HepG2 cells cotransfected with ERbeta and a reporter construct that contained a consensus estrogen responsive element. Addition of MAA at similar doses used in vivo elicited a similar estrogenic activation as did estradiol at 1 nmol/L concentration. The present results raise the possibility that cytoplasmic ERbeta participates in the apoptotic process of pachytene spermatocytes induced by MAA. Whether MAA interacts with ERbeta in the cytoplasm of primary spermatocytes, preventing the progression of the first meiotic division, however, remains to be determined.


Resources and resilience in the transition to adulthood: continuity and change.
Patterns of continuity and change in competence and resilience over the transition to adulthood were examined in relation to adversity and psychosocial resources, with a focus on adaptive resources that may be particularly important for this transition. Variable-focused and person-focused analyses drew on data from the Project Competence longitudinal study of a school cohort followed over 20 years from childhood through emerging adulthood (EA) into the young adulthood (YA) years with excellent retention (90%). Success in age-salient and emerging developmental tasks from EA to YA was examined in a sample of 173 of the original participants with complete data on adversity, competence, and key resources. Regressions and extreme-group analyses indicated striking continuity in competence and resilience, yet also predictable change. Success in developmental tasks in EA and YA was related to core resources originating in childhood (IQ, parenting quality, socioeconomic status) and also to a set of EA adaptive resources that included planfulness/future motivation, autonomy, adult support, and coping skills. EA adaptive resources had unique predictive significance for successful transitions to adulthood, both overall and for the small group of individuals whose pattern of adaptation changed dramatically from maladaptive to resilient over the transition. Results are discussed in relation to the possibility that the transition to adulthood is a window of opportunity for changing the life course.


Modelling of organic field effect transistors with inkjet printed poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) electrodes: study of the annealing effects.
In the present work, the transport mechanism of organic transistors with bottom-gate/top-contact structure, manufactured by employing traditional and inkjet printing techniques, was studied. Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) conductive polymer was used for realizing printed source, drain and gate electrodes. The influence of the printing parameters (substrate temperature, drop overlapping degree, drop emission frequency) on the uniformity and morphology of the PEDOT:PSS layer was investigated. Polymethyl methacrylate (PMMA) was used as organic dielectric and pentacene, deposited by thermal evaporation, was employed as p-type semiconductor. Organic field effect transistors (OFETs) were fabricated and electrically characterized before and after the thermal annealing process at 120 degrees C for 1 h in nitrogen ambient. The effect of the annealing on the performances of the OFETs was investigated by modelling the measured electrical characteristics and analyzing them in terms of mobility, characteristic temperature and energy distribution of the density of localized states (DOS). In addition, the OFET working under electrical stress in ambient conditions was observed and discussed.


Host specialization differentiates cryptic species of feather-feeding lice.
Parasite species with differentiated host-specific populations provide a natural opportunity to explore factors involved in parasite diversification. Columbicola macrourae is a species of ectoparasitic feather louse currently recognized from 15 species of New World pigeons and doves. Mitochondrial sequences reveal five divergent haplotype clusters within C. macrourae, suggesting cryptic species. Each cluster is relatively host specific, with only one or a few hosts. We conducted a reciprocal transfer experiment with two of these lineages to test whether host use has an adaptive component. Our results demonstrate that the fitness of each lineage is considerably higher on its native host than on the novel host suggesting that one or more selective agents favor host specialization by the different lineages. In addition, we were able to morphologically separate individual lice from the two experimental lineages using discriminant function analysis. Furthermore, differences in the size of these louse lineages match differences in the size of their respective hosts, paralleling the strong correlation between parasite and host body size across the genus Columbicola. Together, these results suggest that selection in this cryptic species complex reflects selection across the whole genus, and that this selection, in part, contributes to the maintenance of host specialization.


[Therapeutic factors of lake Tagarskoye].
The results of comprehensive long-term investigations of therapeutic factors of Lake Tagarskoye, Krasnoyarsk krai (territory) are presented. It is shown that, in addition to favourable climatic conditions, the area of interest has a variety of therapeutic hydromineral resources the structure and quality of which are subject to marked seasonal and annual variations. The thorough analysis made it possible to elucidate dynamics of these changes and monitor qualitative characteristics of the resources; also, it promoted the search for methods of their more extensive exploitation and the development of the rationale for designation of Lake Tagarskoye and the surrounding locations as a strictly protected natural area.


EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma.
EphA2 overexpression is frequently observed in endometrial cancers and is predictive of poor clinical outcome. Here, we use an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor monomethylauristatin F. EphA2 expression was examined in endometrial cancer cell lines by Western blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models. EphA2 was expressed in the Hec-1A and Ishikawa cells but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2-positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays showed that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86% to 88% growth inhibition (P < 0.001) in the orthotopic Hec-1A and Ishikawa models compared with controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The antitumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells. The preclinical data for endometrial cancer treatment using MEDI-547 show substantial antitumor activity.


Latent factor structure of DSM-5 posttraumatic stress disorder: Evaluation of method variance and construct validity of novel symptom clusters.
[Correction Notice: An Erratum for this article was reported online in Psychological Assessment on Nov 19 2018 (see record 2018-60122-001). In the article, the affiliations of multiple authors were incorrectly listed in the author byline and author note. For Daniel J. Lee, Michelle J. Bovin, Denise M. Sloan, Terence M. Keane, and Brian P. Marx, the affiliations should have read "National Center for PTSD, Boston, Massachusetts; VA Boston Healthcare System, Boston, Massachusetts; and Department of Psychiatry, Boston University School of Medicine." For author Paula P. Schnurr, the affiliations should have read "National Center for PTSD, White River Junction, Vermont; Department of Psychiatry, Geisel School of Medicine at Dartmouth." All versions of this article have been corrected.] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 4-factor model of posttraumatic stress disorder (PTSD) has demonstrated adequate fit in several confirmatory factor analysis (CFA) studies. Although several alternative measurement models have demonstrated better fit, there is no consensus yet on the best model, and newly proposed models lack sufficient construct validation. Notably, these studies have relied exclusively on questionnaire data, and thus their findings may be attributable to a method effect. This study examined the factor structure of DSM-5 PTSD symptoms using both questionnaire and interview data to determine the impact of assessment method on factor structure and construct validity of alternative model symptom clusters. Participants (N = 380) were veterans who completed the PTSD Checklist for DSM-5 (PCL-5; Weathers et al., 2013) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; Weathers et al., 2013). Fit was similar across models. However, the seven-factor Hybrid model (Armour et al., 2015) fit best. Limited evidence of a method effect was observed. Results of construct validity analyses were mixed; some of the newly proposed symptom clusters demonstrated hypothesized differential associations with external correlates, but others did not. These findings suggest that results of previous DSM-5 PTSD CFAs supporting the Hybrid model are not attributable to a method effect. However, observed limited difference in model fit and mixed construct validity evidence raise concerns regarding the value of parsing DSM-5 symptom clusters. Constructs implied by the new factors in the more complex measurement models of PTSD require greater explication and construct validation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Pectoral Nerve and Transverse Abdominis Plane Block in a Patient Undergoing Mastectomy With Transverse Rectus Abdominis Muscle Flap: A Case Report.
Postoperative nausea, vomiting, and pain present considerable concerns after reconstructive breast surgery. We present a case report of a 65-year-old woman with a history of severe postoperative nausea and vomiting, presenting for unilateral mastectomy with transverse rectus abdominis muscle flap. We performed unilateral pectoral nerve block and transverse abdominis plane block, which provided 24 hours of pain control and mitigated nausea and vomiting during the postoperative period.


Antimyelin antibodies as predictors of disability after clinically isolated syndrome.
There is controversy whether determination of antibodies against myelin, myelin oligodendrocyte glycoprotein, and myelin basic protein in serum from patients with a first episode suggestive of multiple sclerosis is of prognostic value. We evaluated whether detection of antimyelin antibodies in serum indicates a worse course with earlier time to a second relapse and increased progression of disability. We conducted a prospective study at the Department of Neurology, Inselspital Bern, Switzerland from 2004 to 2008 in patients presenting with a clinically isolated syndrome (CIS) and a follow-up of at least 4 months. Antimyelin antibodies were assessed by Western blot. Results were correlated with clinical course and sex. Among 93 consecutive patients with a CIS, 74 (80%) were positive for either one or both antimyelin antibodies. A relapse occurred in 49 (53%) and the median EDSS was 2 (range 1-3.5) after a mean observation period of 20 months. Presence of antimyelin antibodies at CIS neither increased the risk for a second relapse nor for progression of disability. Stratification for gender did not reveal differences for any of the clinical surrogates. The sole determination of antimyelin antibodies in serum is of limited prognostic value for the identification of patients with different short-term course.


On-line quality assurance of rotational radiotherapy treatment delivery by means of a 2D ion chamber array and the Octavius phantom.
For routine pretreatment verification of innovative treatment techniques such as (intensity modulated) dynamic arc therapy and helical TomoTherapy, an on-line and reliable method would be highly desirable. The present solution proposed by TomoTherapy, Inc. (Madison, WI) relies on film dosimetry in combination with up to two simultaneous ion chamber point dose measurements. A new method is proposed using a 2D ion chamber array (Seven29, PTW, Freiburg, Germany) inserted in a dedicated octagonal phantom, called Octavius. The octagonal shape allows easy positioning for measurements in multiple planes. The directional dependence of the response of the detector was primarily investigated on a dual energy (6 and 18 MV) Clinac 21EX (Varian Medical Systems, Palo Alto, CA) as no fixed angle incidences can be calculated in the Hi-Art TPS of TomoTherapy. The array was irradiated from different gantry angles and with different arc deliveries, and the dose distributions at the level of the detector were calculated with the AAA (Analytical Anisotropic Algorithm) photon dose calculation algorithm implemented in Eclipse (Varian). For validation on the 6 MV TomoTherapy unit, rotational treatments were generated, and dose distributions were calculated with the Hi-Art TPS. Multiple cylindrical ion chamber measurements were used to cross-check the dose calculation and dose delivery in Octavius in the absence of the 2D array. To compensate for the directional dependence of the 2D array, additional prototypes of Octavius were manufactured with built-in cylindrically symmetric compensation cavities. When using the Octavius phantom with a 2 cm compensation cavity, measurements with an accuracy comparable to that of single ion chambers can be achieved. The complete Octavius solution for quality assurance of rotational treatments consists of: The 2D array, two octagonal phantoms (with and without compensation layer), an insert for nine cylindrical ion chambers, and a set of inserts of various tissue equivalent materials of different densities. The combination of the 2D array with the Octavius phantom proved to be a fast and reliable method for pretreatment verification of rotational treatments. Quality control of TomoTherapy patients was reduced to a total of approximately 25 min per patient.


Improved survival prediction and comparison of prognostic models for patients with hepatocellular carcinoma treated with sorafenib.
The 'Prediction Of Survival in Advanced Sorafenib-treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9-4.6 months). A total of 920 patients (n = 615 in training set, n = 305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59). In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies.


A meta-analysis of the association of fracture risk and body mass index in women.
Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20-105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m(2) ) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m(2) , the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m(2) was 0.87 (95% confidence interval [CI], 0.85-0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09-1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored.


Atherosclerosis amelioration by allicin in raw garlic through gut microbiota and trimethylamine-N-oxide modulation.
Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE-/-) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.


[The use of personal computers for the mathematical processing of the results of chemical-toxicological studies].
Three programs in BASIC and SUPER BASIC language for personal computer are suggested. The first program makes it possible to calculate the degree of substance extraction and factor of its distribution between two liquid immiscible phases. The second program is designed to make calculations on distribution of substance in the organs of experimental animals. The third program is designed to determine specific and molar factors of light absorption. Results of calculations are presented as tables. Programs can be also used in mathematical processing of results obtained in the course of scientific research.


C-reactive protein and procalcitonin to discriminate between tuberculosis, Pneumocystis jirovecii pneumonia, and bacterial pneumonia in HIV-infected inpatients meeting WHO criteria for seriously ill: a prospective cohort study.
Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients. We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results. Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively). CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.


Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia.
Fms-like tyrosine kinase 3 (FLT3) has been validated as a therapeutic target for acute myeloid leukemia (AML). While a number of FLT3 kinase inhibitors have been approved for AML treatment, the clinical data revealed that they cannot achieve complete and sustained suppression of FLT3 signaling at the tolerated dose. Here we report a series of new, potent and selective FLT3 proteolysis targeting chimera degraders. The optimal compound LWY713 potently induced the degradation of FLT3 with a DC50 value of 0.64 nM and a Dmax value of 94.8% in AML MV4-11 cells with FLT3-internal tandem duplication (ITD) mutation. Mechanistic studies demonstrated that LWY713 selectively induced FLT3 degradation in a cereblon- and proteasome-dependent manner. LWY713 potently inhibited FLT3 signaling, suppressed cell proliferation, and induced cell G0/G1-phase arrest and apoptosis in MV4-11 cells. Importantly, LWY713 displayed potent in vivo antitumor activity in MV4-11 xenograft models.


[The IREPRO List of Indicators--a tool for systematic evaluation of the prognosis for reintegration and the need for rehabilitation in the course of psychiatric disability pension assessment].
There is little research on the process of decision making in sociomedical expert opinion especially on prognostic issues. Experts therefore have to rely upon experience and their own routines of judgement. The IREPRO List of Indicators offers a systematic scheme for the sociomedical exploration and evaluation of the prognosis for reintegration and the need for rehabilitation in claimants for disability pension due to mental illness. A set of ten indicators was defined and its practical use tested in an expert-based process of development. In a manual each indicator is thoroughly described in a standardized manner including a five-point rating scale. In a profile sheet the ratings of all ten indicators are visualized, appropriate therapeutical and rehabilitative means are assigned, and the final judgement of prognosis is deduced. At present the IREPRO List of Indicators offers a good tool to structure the process of decision making and contributes to enhancing transparency and uniformity of the process. It can also be used to discuss cases among colleagues. The basic principle can be transferred to other fields of sociomedical expert opinion-building. The article describes requirements and difficulties in psychiatric disability assessment, the list of indicators and experiences gained from the process of development.


[Interrelation of the epiphysis and parathyroid glands].
Synergism between parathyroidin and epithalamin (an extract from the cattle epiphyses) with relation to phosphorus metabolism was revealed in experiments on guinea-pigs. Both drugs possessed a hypophosphatemic effect. The influence of epithalamin on calcium metabolism was mediated by changes in parathyroid function. An elevation of the parathyroid hormone in the blood was noted after the administration of epithalamin.


Marital stress: immunologic, neuroendocrine, and autonomic correlates.
Ninety newlywed couples (mean age = 25), selected on the basis of extremely stringent mental and physical health criteria, were admitted to a hospital research unit for 24 hours to provide a detailed assessment of conflict-resolution behaviors and changes in autonomic, endocrine, and immune function. Among these newlyweds, negative or hostile behaviors during marital conflict (coded from videotaped interactions) were associated with increased levels of epinephrine, norepinephrine, growth hormone, and ACTH as well as greater immunological change over the subsequent 24 hours. Wives demonstrated greater and more persistent physiological changes related to marital conflict than husbands. To assess the generalizability of these physiological changes, a similar laboratory paradigm was used with 31 older couples (mean age = 67) who had been married an average of 42 years. Consistent with the data from newlyweds, both endocrinological and immunological data showed significant relationships to negative behavior during marital conflict in these older couples. These findings suggest that abrasive marital interactions have important endocrinological and immunological correlates.


Comparing Binaural Pre-processing Strategies I: Instrumental Evaluation.
In a collaborative research project, several monaural and binaural noise reduction algorithms have been comprehensively evaluated. In this article, eight selected noise reduction algorithms were assessed using instrumental measures, with a focus on the instrumental evaluation of speech intelligibility. Four distinct, reverberant scenarios were created to reflect everyday listening situations: a stationary speech-shaped noise, a multitalker babble noise, a single interfering talker, and a realistic cafeteria noise. Three instrumental measures were employed to assess predicted speech intelligibility and predicted sound quality: the intelligibility-weighted signal-to-noise ratio, the short-time objective intelligibility measure, and the perceptual evaluation of speech quality. The results show substantial improvements in predicted speech intelligibility as well as sound quality for the proposed algorithms. The evaluated coherence-based noise reduction algorithm was able to provide improvements in predicted audio signal quality. For the tested single-channel noise reduction algorithm, improvements in intelligibility-weighted signal-to-noise ratio were observed in all but the nonstationary cafeteria ambient noise scenario. Binaural minimum variance distortionless response beamforming algorithms performed particularly well in all noise scenarios.


Durability of urethral bulking agent injection for female stress urinary incontinence: 2-year multicenter study results.
We evaluated the durability of the urethral bulking agent Macroplastique for stress urinary incontinence in a 24-month study in women with a previously documented successful outcome 12 months after the last injection. In a multicenter study females diagnosed with stress urinary incontinence primarily due to intrinsic sphincter deficiency successfully treated with Macroplastique, defined as 1 or greater Stamey grade improvement 12 months from baseline, were followed for 24 months to assess the sustained therapeutic response. Outcome measures were Stamey grade, Patient Global Impression of Improvement, Physician Assessment of Improvement, 1-hour pad weight, Incontinence Quality of Life scores and safety assessment. At 24 months 56 of 67 patients (84%) had sustained success since 12 months, of whom 45 of 67 (67%) were dry (Stamey grade 0). Of the dry patients at 12 months 33 of 38 (87%) maintained cure at 24 months. Also, 12 of 29 patients (41%) considered improved at 12 months were dry at 24 months. Overall Incontinence Quality of Life scores and all subscales showed statistically significant improvement from baseline (p <0.001). Mean pad weight was 24 gm at baseline, and 4 gm at 12 and 24 months. Patient and physician assessments rated 85% of patients dry or markedly improved 24 months after the last treatment. Substantial, durable results were sustained during 2 years with 84% of patients maintaining significant Stamey grade improvement from the 12-month assessment. Two-thirds of patients were dry at 24 months. The durability of Macroplastique shows its effectiveness as a viable long-term therapy for female stress urinary incontinence primarily due to intrinsic sphincter deficiency.