Mendelian Randomization: Concepts and Scope.
Mendelian randomization (MR) is a method of studying the causal effects of modifiable exposures (i.e., potential risk factors) on health, social, and economic outcomes using genetic variants associated with the specific exposures of interest. MR provides a more robust understanding of the influence of these exposures on outcomes because germline genetic variants are randomly inherited from parents to offspring and, as a result, should not be related to potential confounding factors that influence exposure-outcome associations. The genetic variant can therefore be used as a tool to link the proposed risk factor and outcome, and to estimate this effect with less confounding and bias than conventional epidemiological approaches. We describe the scope of MR, highlighting the range of applications being made possible as genetic data sets and resources become larger and more freely available. We outline the MR approach in detail, covering concepts, assumptions, and estimation methods. We cover some common misconceptions, provide strategies for overcoming violation of assumptions, and discuss future prospects for extending the clinical applicability, methodological innovations, robustness, and generalizability of MR findings.


Induced accumulation of glucuronosyldiacylglycerol in tomato and soybean under phosphorus deprivation.
Glucuronosyldiacylglycerol (GlcADG) is a plant glycolipid that accumulates in Arabidopsis and rice in response to phosphorus (P) starvation. It has been suggested that GlcADG functions to mitigate the stress induced by P depletion. Biosynthesis of GlcADG requires sulfolipid (SQDG) synthase, which is coded for in plant genomes. This indicates the possibility that GlcADG may be a general constituent of membrane lipids in plants. In this study, we investigated the SQDG synthases found in the genomes of higher plants, ferns, mosses, algae and cyanobacteria. In addition, we analyzed GlcADG accumulation, and the expression of SQDG synthase homologs in tomato and soybean plants grown under P-limited conditions. LC-MS analysis of lipids from these plants confirmed that GlcADG accumulated during P deprivation, as previously observed in Arabidopsis and rice. We also observed upregulation of SQDG synthase transcripts in these plants during P deprivation. These data suggest that GlcADG is present not only in model plants, but also in various other plant species, and that this lipid molecule performs an important physiological function as a mitigator of P-deprivation stress in plants.


Linewidth measurement technique using through-focus optical images.
We present a detailed experimental study of a new through-focus technique to measure critical dimension linewidth with nanometer sensitivity using a bright field optical microscope. This method relies on analyzing intensity gradients in optical images at different focus positions, here defined as the focus metric (FM) signature. The contrast of an optical image of a structured target, where a particular structure is repeated several times, varies greatly as it is moved through-focus if the spacing between the structures is such that the scattered field from the features interferes. Complex, distinguishable through-focus optical response occurs under this condition giving rise to the formation of several cyclic high and low contrast images. As a result it exhibits several FM signature peaks as opposed to a single FM peak for structures nearly isolated. This complex optical behavior is very sensitive to the dimensions of the target geometry. By appropriately analyzing the through-focus optical image, information can be obtained regarding the target. An array of lines is used as a structured target. Linewidth measurements were made by using experimental through-focus optical data obtained using a bright field microscope and simulated optical data. The optical results are compared with reference metrology tools such as a critical dimension atomic force microscope and critical dimension scanning electron microscope.


Advanced glycation end product 3 (AGE3) suppresses the mineralization of mouse stromal ST2 cells and human mesenchymal stem cells by increasing TGF-β expression and secretion.
In diabetic patients, advanced glycation end products (AGEs) cause bone fragility because of deterioration of bone quality. We previously showed that AGEs suppressed the mineralization of mouse stromal ST2 cells. TGF-β is abundant in bone, and enhancement of its signal causes bone quality deterioration. However, whether TGF-β signaling is involved in the AGE-induced suppression of mineralization during the osteoblast lineage remains unknown. We therefore examined the roles of TGF-β in the AGE-induced suppression of mineralization of ST2 cells and human mesenchymal stem cells. AGE3 significantly (P < .001) inhibited mineralization in both cell types, whereas transfection with small interfering RNA for the receptor for AGEs (RAGEs) significantly (P < .05) recovered this process in ST2 cells. AGE3 increased (P < .001) the expression of TGF-β mRNA and protein, which was partially antagonized by transfection with RAGE small interfering RNA. Treatment with a TGF-β type I receptor kinase inhibitor, SD208, recovered AGE3-induced decreases in osterix (P < .001) and osteocalcin (P < .05) and antagonized the AGE3-induced increase in Runx2 mRNA expression in ST2 cells (P < .001). Moreover, SD208 completely and dose dependently rescued AGE3-induced suppression of mineralization in both cell types. In contrast, SD208 intensified AGE3-induced suppression of cell proliferation as well as AGE3-induced apoptosis in proliferating ST2 cells. These findings indicate that, after cells become confluent, AGE3 partially inhibits the differentiation and mineralization of osteoblastic cells by binding to RAGE and increasing TGF-β expression and secretion. They also suggest that TGF-β adversely affects bone quality not only in primary osteoporosis but also in diabetes-related bone disorder.


Perihepatic lymph node enlargement is a negative predictor of liver cancer development in chronic hepatitis C patients.
Perihepatic lymph node enlargement (PLNE) is a common ultrasound finding in chronic hepatitis C patients. Although PLNE is considered to reflect the inflammatory response to hepatitis C virus (HCV), its clinical significance remains unclear. Between December 2004 and June 2005, we enrolled 846 chronic hepatitis C patients in whom adequate ultrasound examinations had been performed. PLNE was defined as a perihepatic lymph node that was at least 1 cm in the longest axis by ultrasonography. We analyzed the clinical features of patients with PLNE and prospectively investigated the association between PLNE and hepatocellular carcinoma (HCC) development. We detected PLNE in 169 (20.0%) patients. Female sex, lower body mass index (BMI), and HCV serotype 1 were independently associated with the presence of PLNE. However, there were no significant differences in liver function tests, liver stiffness, and hepatitis C viral loads between patients with and without PLNE. During the follow-up period (mean 4.8 years), HCC developed in 121 patients. Unexpectedly, patients with PLNE revealed a significantly lower risk of HCC development than those without PLNE (p = 0.019, log rank test). Multivariate analysis revealed that the presence of PLNE was an independent negative predictor of HCC development (hazard ratio 0.551, p = 0.042). In addition, the sustained viral response rate in patients who received interferon (IFN) therapy was significantly lower in patients with PLNE than in patients without PLNE. Patients with PLNE had a lower risk of HCC development than those without PLNE. This study may provide new insights into daily clinical practice and the pathophysiology of HCV-induced hepatitis and hepatocarcinogenesis.


Children's language learning: an interactionist perspective.
This review of children's language learning considers historical accounts of acquisition and individual variation, recent advances in methods for studying language learning, research on genetic and environmental input that have contributed to the interactionist perspective, and the relevance of cross-disciplinary work on language disorders and the biology of learning to future theories. It concludes that the study of children's language development is converging on an interactionist perspective of how children learn to talk, incorporating the contributions of both nature and nurture to emergent, functional language systems. Language learning is viewed as an integration of learning in multiple domains.


OVCAR-3 spheroid-derived cells display distinct metabolic profiles.
Recently, multicellular spheroids were isolated from a well-established epithelial ovarian cancer cell line, OVCAR-3, and were propagated in vitro. These spheroid-derived cells displayed numerous hallmarks of cancer stem cells, which are chemo- and radioresistant cells thought to be a significant cause of cancer recurrence and resultant mortality. Gene set enrichment analysis of expression data from the OVCAR-3 cells and the spheroid-derived putative cancer stem cells identified several metabolic pathways enriched in differentially expressed genes. Before this, there had been little previous knowledge or investigation of systems-scale metabolic differences between cancer cells and cancer stem cells, and no knowledge of such differences in ovarian cancer stem cells. To determine if there were substantial metabolic changes corresponding with these transcriptional differences, we used two-dimensional gas chromatography coupled to mass spectrometry to measure the metabolite profiles of the two cell lines. These two cell lines exhibited significant metabolic differences in both intracellular and extracellular metabolite measurements. Principal components analysis, an unsupervised dimensional reduction technique, showed complete separation between the two cell types based on their metabolite profiles. Pathway analysis of intracellular metabolomics data revealed close overlap with metabolic pathways identified from gene expression data, with four out of six pathways found enriched in gene-level analysis also enriched in metabolite-level analysis. Some of those pathways contained multiple metabolites that were individually statistically significantly different between the two cell lines, with one of the most broadly and consistently different pathways, arginine and proline metabolism, suggesting an interesting hypothesis about cancerous and stem-like metabolic phenotypes in this pair of cell lines. Overall, we demonstrate for the first time that metabolism in an ovarian cancer stem cell line is distinct from that of more differentiated isogenic cancer cells, supporting the potential importance of metabolism in the differences between cancer cells and cancer stem cells.


Direct constraints on charged excitations of dark matter.
If the neutral component of weak-scale dark matter is accompanied by a charged excitation separated by a mass gap of less than ~20 MeV, weakly interacting massive particles (WIMPs) can form stable bound states with nuclei. We show that the recent progress in experiments searching for neutrinoless double-beta decay sets the first direct constraint on the exoergic reaction of WIMP-nucleus bound state formation. We calculate the rate for such a process in representative models and show that the double-beta decay experiments provide unique sensitivity to a large fraction of parameter space of the WIMP doublet model, complementary to constraints imposed by cosmology and direct collider searches.


Intra-articular findings in symptomatic minor instability of the lateral elbow (SMILE).
Lateral epicondylitis is generally considered an extra-articular condition. The role of minor instability in the aetiology of lateral elbow pain has rarely been considered. The aim of this study was to evaluate the correlation of lateral ligamentous laxity with aspects of intra-articular lateral elbow pathology and investigate the role of minor instability in lateral elbow pain. Thirty-five consecutive patients aged between 20 and 60 years with recalcitrant lateral epicondylitis who had failed conservative therapy and had no previous trauma or overt instability, were included. The presence of three signs of lateral ligamentous patholaxity and five intra-articular findings were documented during arthroscopy. The relative incidence of each of these was calculated, and the correlation between patholaxity and intra-articular pathology was evaluated. At least one sign of lateral ligamentous laxity was observed in 48.6% of the studied cohort, and 85.7% demonstrated at least one intra-articular abnormal finding. Radial head ballottement was the most common sign of patholaxity (42.9%). Synovitis was the most common intra-articular aspect of pathology (77.1%), followed by lateral capitellar chondropathy (40.0%). A significant correlation was found between the presence of lateral ligamentous patholaxity signs and capitellar chondropathy (p = 0.0409), as well as anteromedial synovitis (p = 0.0408). Almost one half of patients suffering from recalcitrant lateral epicondylitis display signs of lateral ligamentous patholaxity, and over 85% demonstrate at least one intra-articular abnormality. The most frequent intra-articular findings are synovitis and lateral capitellar chondropathy, which correlate significantly with the presence of lateral ligamentous patholaxity. The fact that several patients demonstrated multiple intra-articular findings in relation to laxity provides support to a sequence of pathologic changes that may result from a symptomatic minor instability of the lateral elbow (SMILE) condition. III.


Evaluating the Combined Toxicity of Cu and ZnO Nanoparticles: Utility of the Concept of Additivity and a Nested Experimental Design.
Little is understood regarding the effects of mixtures of different metal-based nanoparticles (NPs). Using concentration-addition (CA) and independent-action (IA) models, we evaluated the combined toxicity of Cu and ZnO NPs based on five nested combinations, i.e., Cu(NO3)2-CuNPs, Zn(NO3)2-ZnONPs, Cu(NO3)2-ZnONPs, Zn(NO3)2-CuNPs, and CuNPs-ZnONPs on root elongation of Lactuca sativa L. The CA and IA models performed equally well in estimating the toxicity of mixtures of Cu(NO3)2-CuNPs, Zn(NO3)2-ZnONPs, and Zn(NO3)2-CuNPs, whereas the IA model was significantly better for fitting the data of Cu(NO3)2-ZnONPs and CuNPs-ZnONPs mixtures. Dissolved Cu proved to be the most toxic metal species to lettuce roots in the tests, followed by Cu NPs, dissolved Zn, and ZnO NPs, respectively. An antagonistic effect was observed for ZnO NPs on the toxicity of Cu NPs. This antagonistic effect is expected to be the result of interactions between dissolved Cu and dissolved Zn, particulate Zn and dissolved Zn, particulate Cu and dissolved Zn, and between particulate Zn and dissolved Cu. In general terms, assuming additivity gives a first indication of the combined toxicity with soluble and insoluble metal particles, both being important in driving the toxicity of metal-based NPs to higher plants.


Virus-plasmid interactions: mutants of bacteriophage T3 that abortively infect plasmid F-containing (F+) strains of Escherichia coli.
Bacteriophage T7 and many closely related phages abortively infect plasmid F-containing (F+) strains of Escherichia coli. However phage T3, which is also closely related to T7, grows normally in F+ hosts. Mutants of phage T3 that, like T7, are subject to F-mediated restriction have been isolated. These T3 mutants lack or are defective in one or both of two genes that are nonessential for phage growth in F-, wild-type strains. Our results show that the products of phage T3 gene 1.1 or 1.2, or both, are essential for growth and suggest that the comparable phage T7 genes are naturally defective in their ability to counteract the inhibitory effects of F-encoded proteins.


Carbon Monoxide: A Second Biomarker to Couple with Viscosity for the Construction of "Dual-Locked" Near-Infrared Fluorescent Probes for Accurately Diagnosing Non-Alcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) can progress to cirrhosis and liver cancer if left untreated. Therefore, it is of great importance to develop useful tools for the noninvasive and accurate diagnosis of NAFLD. Increased microenvironmental viscosity was considered as a biomarker of NAFLD, but the occurrence of increased viscosity in other liver diseases highly reduces the diagnosis accuracy of NAFLD by a single detection of viscosity. Hence, it is very necessary to seek a second biomarker of NAFLD. It has been innovatively proposed that the overexpressed heme oxygenase-1 enzyme in NAFLD would produce abnormally high concentrations of CO in hepatocytes and that CO could serve as a potential biomarker. In this work, we screened nine lactam Changsha dyes (HCO-1-HCO-9) with delicate structures to obtain near-infrared (NIR), metal-free, and "dual-locked" fluorescent probes for the simultaneous detection of CO and viscosity. Changsha dyes with a 2-pyridinyl hydrazone substituent could sense CO, and the 5-position substituents on the 2-pyridinyl moiety had a great electron effect on the reaction rate. The double bond in these dyes served as the sensing group for viscosity. Probe HCO-9 was utilized for precise diagnosis of NAFLD by simultaneous detection of CO and viscosity. Upon reacting with CO in a high-viscosity microenvironment, strong fluorescence at 745 nm of probe HCO-9 was turned on with NIR excitation at 700 nm. Probe HCO-9 was proven to be an effective tool for imaging CO and viscosity. Due to the advantages of NIR absorption and low toxicity, probe HCO-9 was successfully applied to image NAFLD in a mouse model.


Limitations of PLX3397 as a microglial investigational tool: peripheral and off-target effects dictate the response to inflammation.
Microglia, the resident macrophages of the central nervous system (CNS), play a critical role in CNS homeostasis and neuroinflammation. Pexidartinib (PLX3397), a colony-stimulating factor 1 (CSF1) receptor inhibitor, is widely used to deplete microglia, offering flexible options for both long-term depletion and highly versatile depletion-repopulation cycles. However, the potential impact of PLX3397 on peripheral (immune) cells remains controversial. Until now, the microglia-specificity of this type of compounds has not been thoroughly evaluated, particularly in the context of peripherally derived neuroinflammation. Our study addresses this gap by examining the effects of PLX3397 on immune cells in the brain, liver, circulation and bone marrow, both in homeostasis and systemic inflammation models. Intriguingly, we demonstrate that PLX3397 treatment not only influences the levels of tissue-resident macrophages, but also affects circulating and bone marrow immune cells beyond the mononuclear phagocyte system (MPS). These alterations in peripheral immune cells disrupt the response to systemic inflammation, consequently impacting the phenotype irrespective of microglial depletion. Furthermore, we observed that a lower dose of PLX3397, which does not deplete microglia, demonstrates similar (non-)MPS effects, both in the periphery and the brain, but fails to fully replicate the peripheral alterations seen in the higher doses, questioning lower doses as a 'peripheral control' strategy. Overall, our data highlight the need for caution when interpreting studies employing this compound, as it may not be suitable for specific investigation of microglial function in the presence of systemic inflammation.


Erythropoietic properties of human induced pluripotent stem cells-derived red blood cells in immunodeficient mice.
Transfusion of red blood cells (RBCs) is a life-saving intervention for anemic patients. Human induced pluripotent stem cells (iPSC) have the capability to expand and differentiate into RBCs (iPSC-RBCs). Here we developed a murine model to investigate the in vivo properties of human iPSC-RBCs. iPSC lines were produced from human peripheral blood mononuclear cells by transient expression of plasmids containing OCT4, SOX2, MYC, KLF4, and BCL-XL genes. Human iPSC-RBCs were generated in culture supplemented with human platelet lysate, and were CD34- CD235a+ CD233+ CD49dlow CD71low ; about 13% of iPSC-RBCs were enucleated before transfusion. Systemic administration of clodronate liposomes (CL) and cobra venom factor (CVF) to NOD scid gamma (NSG) mice markedly promoted the circulatory survival of human iPSC-RBCs following transfusion. While iPSC-RBCs progressively decreased with time, 90% of circulating iPSC-RBCs were enucleated 1 day after transfusion (CD235a+ CD233+ CD49d- CD71- ). Surprisingly, human iPSC-RBCs reappeared in the peripheral circulation at 3 weeks after transfusion at levels more than 8-fold higher than at 1 h after transfusion. Moreover, a substantial portion of the transfused nucleated iPSC-RBCs preferentially homed to the bone marrow, and were detectable at 24 days after transfusion. These results suggest that nucleated human iPSC-derived cells that homed to the bone marrow of NSG mice retained the capability to complete differentiation into enucleated erythrocytes and egress the bone marrow into peripheral blood. The results offer a new model using human peripheral blood-derived iPSC and CL/CVF-treated NSG mice to investigate the development and circulation of human erythroid cells in vivo.


Clinical predictors of recovery and complications in the management of recent-onset renal failure in lupus nephritis: a Chinese experience.
To investigate the potential clinical predictors associated with the recovery of renal function in recent-onset uremia in patients with lupus nephritis. Factors possibly influencing the recovery of renal function in patients with lupus nephritis were examined in a 6 month retrospective cohort study. Records of a sample of 198 consecutive inpatients of recently diagnosed renal failure with lupus nephritis admitted to the University Hospital between 1991 and 2001 were examined. Complete records to assess followup were available for 162 (81.8%). The main outcome factor was recovery of renal function, which was defined as discontinuation of dialysis and over 50% reduction of serum creatinine 3 months after discontinuation of dialysis. Collection of clinical and laboratory data and outcome variables was conducted by 2 separate, blinded groups of clinical specialists with 2 structured abstracting forms. After 6 months of followup, 96 patients (59.3%) recovered their renal function and 18 (11.1%) had died. After adjustment with Cox proportional hazards models, sex, renal dysfunction duration, renal size, anemia, level of serum phosphate, and intravenous cyclophosphamide (i.v. CYC) therapy were found to be significantly associated with recovery of renal function. There was significant association between i.v. CYC therapy and infections. However, in logistic regression analysis, neither CYC therapy nor infections were significantly associated with mortality, and only severe edema and lower serum albumin level were associated with mortality. Male sex, postponing hospital admission after onset of renal failure, atrophic renal size, and high concentrations of serum phosphate were all predictors of poor recovery of renal function. i.v. CYC therapy at higher dose had a protective effect on the recovery of renal function.


Nitric oxide metabolite production in the cranial cruciate ligament, synovial membrane, and articular cartilage of dogs with cranial cruciate ligament rupture.
To measure concentrations of nitric oxide metabolites (nitrite-nitrate [NOt]) in cartilage, synovial membrane, and cranial cruciate ligament (CCL) in dogs and evaluate associations with osteoarthritis in dogs with CCL rupture. 46 dogs with CCL rupture and 54 control dogs without joint disease. Tissue specimens for histologic examination and explant culture were harvested during surgery in the CCL group or immediately after euthanasia in the control group; NOt concentrations were measured in supernatant of explant cultures and compared among dogs with various degrees of osteoarthritis and between dogs with and without CCL rupture. Osteoarthritic cartilage had significantly higher NOt concentration (1,171.6 nmol/g) than did healthy cartilage (491.0 nmol/g); NOt concentration was associated with severity of macroscopic and microscopic lesions. Synovial membrane NOt concentration did not differ between dogs with and without CCL rupture. Ruptured CCL produced less NOt than did intact ligaments. In control dogs, NOt concentrations were similar for intact ligaments (568.1 nmol/g) and articular cartilage (491.0 nmol/g). Synthesis of NOt was inhibited substantially by coincubation with inhibitors. Results suggest that NOt in canine joint tissues originates from the inducible nitric oxide synthase pathway. Nitric oxide metabolite production in cartilage was greater in dogs with osteoarthritis than in healthy dogs and was associated with lesion severity, suggesting that nitric oxide inhibitors may be considered as a treatment for osteoarthritis. The CCL produces substantial concentrations of NOt; the importance of this finding is unknown.


A qualitative study of patient-centered goal-setting in geriatric rehabilitation: patient and professional perspectives.
To characterize how rehabilitation goals of older patients change over time and to explore professionals' attitudes toward patient-centered goal-setting and their perspectives on rehabilitation goals. Qualitative interview study. Three geriatric rehabilitation centers. Ten patients (aged ⩾ 80), who had recently received inpatient geriatric rehabilitation, and seven professionals were purposively recruited. Semi-structured interviews. Patients were interviewed in the third or fourth week after discharge from inpatient rehabilitation, to reflect on their inpatient goals and to investigate long-term goals now that they were at home. A thematic analysis was performed. During inpatient rehabilitation, participants' main goals were regaining independence in self-care activities and going home. Post-discharge, patients were not at their baseline functioning level. Rehabilitation goals appeared to shift over time, and once at home, patients formulated more ambitious rehabilitation goals that were related to regaining full independence and being able to perform activities. Although professionals thought goal-setting together with the patient is important, they also stated that older individuals often are either unable to formulate goals or they set unrealistic ones. In addition, professionals indicated that goals have to be related to discharge criteria, such as performing basic self-care activities, and rehabilitation revolves around getting patients ready for discharge. During inpatient rehabilitation, patient goals are related to going home. After discharge, patients have ambitious goals, related to their premorbid functioning level. Rehabilitation services should distinguish between goals that are important while patients are inpatient and goals that are important after discharge.


Construct stiffness of different fixation methods for supracondylar femoral fractures above total knee prostheses.
Supracondylar fracture of the femur after total knee arthroplasty has an estimated frequency of 0.6%-2.5% among total knee recipients and presents an extremely difficult problem when encountered. The goal of this study is to determine the most stable method of fixation of these supracondylar fractures among currently available devices. Synthetic composite femurs with properties similar to human bone were used, and identical, unstable supracondylar fractures were created in each. Osteotomized specimens were placed into four groups of five. Each group was then tested with one of four devices: the Green-Seligson-Henry (GSH) intramedullary nail, AO 95 degrees blade plate, dynamic condylar screw and sideplate, and condylar buttress plate. After stabilization with the different types of fixation, the constructs were tested individually for bending stiffness in four modes: flexion, extension, varus, and valgus bending. The stiffest fixation was determined in each of the four bending planes. Resistance to all tested directions was greatest for the condylar screw and sideplate construct. Resistance to flexion (stiffness = 30.96 N/mm), extension (stiffness = 36.36 N/mm), varus (stiffness = 35.46 N/mm), and valgus forces (stiffness = 32.26 N/mm) was highest in the group fixed with the dynamic condylar screw. This may be due to the purchase gained by the large lag screw into the distal femur, or it may be the result of the total rigidity of the implant. Although the femoral samples used in this study do not duplicate the typical osteopenic bone encountered at the site of a total knee arthroplasty, they do allow direct comparison of the fixation devices by removing the variability associated with cadaveric bone samples.


How has COVID-19 impacted cancer screening? Adaptation of services and the future outlook in Australia.
The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions to many aspects of life in Australia and globally. This includes actual and potential future impacts on Australia's three national screening programs for breast, bowel and cervical cancer. These programs aim to improve cancer outcomes through an organised approach to the early detection of cancer and precancer in asymptomatic populations. The design of each program varies according to biological differences in the three cancers, the available screening technology, the target population, and variations in their administration of Australia's federal, state and territory jurisdictions. The observed and potential impacts of COVID-19 on these programs, and on related activities such as the current national enquiry into lung cancer screening feasibility, therefore vary significantly. This article focuses on observed short-term impacts, adaptations and the longer-term outlook for cancer screening in relation to COVID-19. It summarises potential responses to minimise the harms of disruptions caused by COVID-19, and highlights research and policy opportunities in the pandemic response and recovery which could inform and accelerate optimisation of cancer screening in the long term.


An energy-dense complementary food is associated with a modest increase in weight gain when compared with a fortified porridge in Malawian children aged 6-18 months.
Poor complementary feeding practices are associated with stunting and growth faltering throughout the developing world. The objective was to compare the effect of using peanut-/soy-based fortified spread (FS) and corn porridge fortified with fish powder (FP) as complementary foods on growth in rural Malawian children. A total of 240 children were enrolled at the age of 6 mo and randomized to receive FS or FP. Both complementary foods provided 836 kJ/d from 6 to 9 mo of age and 1254 kJ/d from 9 to 18 mo of age. Children were followed monthly for anthropometry and fortnightly for the symptoms of fever, cough, or diarrhea until they were 18 mo old. Zn and Se status were assessed at 6 and 12 mo. The primary outcomes were the rates of weight and length gain from 6-12 mo and from 12-18 mo. Children who received FS gained 110 g more (95% CI 220 to 10) from 6-12 mo of age than children receiving FP. Weight gain did not differ between children receiving FS and FP between 12 and 18 mo of age, nor did statural growth from 6 to 12 mo or 12 to 18 mo. A total of 23% of all children were Zn deficient at 6 mo of age and this increased to 37% at 12 mo of age. Neither FS nor FP was associated with significantly improved Zn status. FS was associated with better weight gain from 6-12 mo of age and may be useful in conjunction with additional interventions to improve infant growth in the developing world.


Validity, reliability and discriminative capacity of an electronic quality of life instrument (Pelican) for childhood asthma in the Netherlands.
To assess psychometric properties of the Pelican instrument, an online Dutch self-administered Quality of Life instrument for childhood asthma for scientific and clinical use. A cohort study was done in two asthma populations and healthy children. One asthma population had assessment at start, 4 and 8 weeks. The other asthma population and healthy children had one assessment. All children were aged 6-12 years. Children completed the Pelican instrument, Paediatric Asthma Quality of Life Questionnaire, feeling thermometer and Childhood Asthma Control Test. Lung function and fraction exhaled nitric oxide were measured. Parents completed Functional Status II, Asthma Control Questionnaire, Childhood Asthma Control Test questionnaires and symptom diaries. We assessed interpretability, structural validity, internal consistency, reliability, construct and discriminative validity of the Pelican instrument. Eighty-five asthmatic (mean age 8.5 years) and 49 healthy children (mean age 8.4 years) participated. The Pelican instrument has 5 domains with 21 items after factor analysis. Internal consistency was 0.89 (CI 0.85-0.92), domain reliability showed Cronbach's α's from 0.64 to 0.76 and item-to-scale correlations from 0.61 to 0.81. Test-retest reliability was confirmed ICC = 0.88 (CI 0.79-0.93). Construct validity was demonstrated by significant moderate correlations with other relevant asthma outcomes like PAQLQ (r = -0.59, p < 0.01). Discriminative capacity between controlled or uncontrolled asthma (t = 3.20, p < 0.01, Δ = 0.64) and asthma versus healthy subjects (t = 6.31, p < 0.01, Δ = 0.94) was found. The psychometric properties of the Pelican instrument were acceptable in Dutch paediatric asthma patients between 6 and 12 years old.


ATHENA, ARTEMIS, HEPHAESTUS: data analysis for X-ray absorption spectroscopy using IFEFFIT.
A software package for the analysis of X-ray absorption spectroscopy (XAS) data is presented. This package is based on the IFEFFIT library of numerical and XAS algorithms and is written in the Perl programming language using the Perl/Tk graphics toolkit. The programs described here are: (i) ATHENA, a program for XAS data processing, (ii) ARTEMIS, a program for EXAFS data analysis using theoretical standards from FEFF and (iii) HEPHAESTUS, a collection of beamline utilities based on tables of atomic absorption data. These programs enable high-quality data analysis that is accessible to novices while still powerful enough to meet the demands of an expert practitioner. The programs run on all major computer platforms and are freely available under the terms of a free software license.


Vascular endothelium does not activate CD4+ direct allorecognition in graft rejection.
Expression of MHC class II by donor-derived APCs has been shown to be important for allograft rejection. It remains controversial, however, whether nonhemopoietic cells, such as vascular endothelium, possess Ag-presenting capacity to activate alloreactive CD4(+) T lymphocytes. This issue is important in transplantation, because, unlike hemopoietic APCs, allogeneic vascular endothelium remains present for the life of the organ. In this study we report that cytokine-activated vascular endothelial cells are poor APCs for allogeneic CD4(+) T lymphocytes in vitro and in vivo despite surface expression of MHC class II. Our in vitro observations were extended to an in vivo model of allograft rejection. We have separated the allostimulatory capacity of endothelium from that of hemopoietic APCs by using bone marrow chimeras. Hearts that express MHC class II on hemopoietic APCs are acutely rejected in a mean of 7 days regardless of the expression of MHC class II on graft endothelium. Alternatively, hearts that lack MHC class II on hemopoietic APCs are acutely rejected at a significantly delayed tempo regardless of the expression of MHC class II on graft endothelium. Our data suggest that vascular endothelium does not play an important role in CD4(+) direct allorecognition and thus does not contribute to the vigor of acute rejection.


Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family.
Age-related macular degeneration (AMD) is a common cause of severe vision loss. Identification of the genes involved in AMD will lead to a better understanding of this disease at the molecular level, which will eventually lead to early detection, prevention and treatment. Previously, we mapped the ARMD1 gene to 1q25-31 in a large family with AMD. Here, we narrow the ARMD1 locus to 14.9 Mb between LAMB2 and D1S3469, a region containing 50 known genes. Twenty candidate genes within this region were screened for mutations. Only one DNA variation, an A16,263G transition in exon 104 of HEMICENTIN-1, was found to segregate exclusively with the disease haplotype in members of this large family with AMD. This variation produces a non-conservative substitution of arginine for glutamine at amino acid position 5345 (Gln5345Arg). It was also identified in 11 other individuals, all of whom share a haplotype, which envelops HEMICENTIN-1, with the large AMD family. The affected status of all but one of those individuals conforms to the age-dependent penetrance observed in AMD. The amino acid at position 5345 of HEMICENTIN-1 was conserved as glutamine in eight species analyzed. RT-PCR analysis demonstrated that exon 104 of HEMICENTIN-1 is alternatively spliced in various cell types. Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene.


Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury.
Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we have found an overall increase in host hippocampal neuron survival in hNSC transplanted animals and demonstrate that a correlation exists between hippocampal neuron survival and cognitive performance. Together, these findings support the use of immunodeficient rodents in models of TBI that involve the transplantation of human cells, and suggest that hNSC transplantation may be a viable, long-term therapy to restore cognition after brain injury.


Which Techniques Work in Behavioral Parent Training for Children with ADHD? A Randomized Controlled Microtrial.
Behavioral parent training (BPT) is an evidence-based intervention for children with attention-deficit/hyperactivity disorder (ADHD), but little is known about the effects of separate techniques parents learn in BPT. In a three-armed randomized controlled microtrial including parents of 92 children (4-12 years) with ADHD, we examined the efficacy of two sessions parent training involving either stimulus control techniques (antecedent-based condition (AC)) or contingency management techniques (consequent-based condition (CC)), compared to a waitlist. Primary outcome was daily parent-rated problem behaviors, secondary outcomes were parent-rated symptoms of ADHD and oppositional defiant disorder (ODD), and mental health-care consumption. Measures were completed at baseline (T0), immediately after the training (T1), at two weeks (T2) and three months (T3) follow-up. We also explored whether child and parent characteristics moderated treatment effects. Compared to the waitlist, in the AC, daily rated problem behaviors improved at T1 (d= .56) and T2 (d= .65); in the CC, these behaviors only improved at T2 (d= .53). Daily rated problem behaviors within both conditions remained stable between T2 and T3. In the AC compared to the other conditions, inattention symptoms decreased at T1 and T2. For both active conditions compared to waitlist, hyperactivity-impulsivity symptoms decreased only at T2 and ODD symptoms did not decrease. No moderators were identified. Mental health-care consumption after training was low and did not differ between the active conditions. Brief training of parents in antecedent- or consequent-based techniques improves problem behaviors of children with ADHD. Antecedent-based techniques appear to be especially important to target inattention.


A conserved functional domain of Drosophila coracle is required for localization at the septate junction and has membrane-organizing activity.
The protein 4.1 superfamily is comprised of a diverse group of cytoplasmic proteins, many of which have been shown to associate with the plasma membrane via binding to specific transmembrane proteins. Coracle, a Drosophila protein 4.1 homologue, is required during embryogenesis and is localized to the cytoplasmic face of the septate junction in epithelial cells. Using in vitro mutagenesis, we demonstrate that the amino-terminal 383 amino acids of Coracle define a functional domain that is both necessary and sufficient for proper septate junction localization in transgenic embryos. Genetic mutations within this domain disrupt the subcellular localization of Coracle and severely affect its genetic function, indicating that correct subcellular localization is essential for Coracle function. Furthermore, the localization of Coracle and the transmembrane protein Neurexin to the septate junction display an interdependent relationship, suggesting that Coracle and Neurexin interact with one another at the cytoplasmic face of the septate junction. Consistent with this notion, immunoprecipitation and in vitro binding studies demonstrate that the amino-terminal 383 amino acids of Coracle and cytoplasmic domain of Neurexin interact directly. Together these results indicate that Coracle provides essential membrane-organizing functions at the septate junction, and that these functions are carried out by an amino-terminal domain that is conserved in all protein 4.1 superfamily members.


Increased pituitary adenylate cyclase-activating polypeptide in the central bed nucleus of the stria terminalis in mood disorders in men.
The mood disorders major depressive disorder (MDD) and bipolar disorder (BD) are highly prevalent worldwide. Women are more vulnerable to these psychopathologies than men. The bed nucleus of the stria terminalis (BNST), the amygdala, and the hypothalamus are the crucial interconnected structures involved in the stress response. In mood disorders, stress systems in the brain are put into a higher gear. The BNST is implicated in mood, anxiety, and depression. The stress-related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is highly abundant in the central BNST (cBNST). In this study, we investigated alterations in PACAP in the cBNST of patients with mood disorders. Immunohistochemical (IHC) staining of PACAP and in situ hybridization (ISH) of PACAP mRNA were performed on the cBNST of post-mortem human brain samples. Quantitative IHC revealed elevated PACAP levels in the cBNST in both mood disorders, MDD and BD, but only in men, not in women. The PACAP ISH was negative, indicating that PACAP is not produced in the cBNST. The results support the possibility that PACAP innervation of the cBNST plays a role in mood disorder pathophysiology in men.


Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study.
The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation. The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts. Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.


Impact of an early 1000-day intervention for obesity prevention on adiposity and BMI at two years of age: A quasi-experimental study.
The 1000-day period encompassing pregnancy and the first two years of postnatal life is critical for preventing childhood obesity. Existing interventions targeting this period have been characterised by great variability in duration, objectives, and evaluation indicators. We aimed to evaluate the impact of an intervention developed during the entire 1000-day period on body mass index and body fat percentage at two years of age. We designed a prospective, interventional, quasi-experimental study (ie, without randomisation or blinding of both groups) targeting mother-child pairs from the beginning of pregnancy up to two years of age belonging to the basic health area of Puerto Real (Cádiz). We developed and delivered an intervention from pregnancy to two years and assessed its effect. The duration of breastfeeding and vitamin D supplementation increased significantly after the intervention. The intervention group showed lowed skinfolds values, a significantly lower body fat percentage, as well as a lower accumulation of factor at two years than the control group. The intervention has had an impact on body fat percentage at two years, potentially justified through its overall effect and the lower accumulation of early risk factors.


Relationship between dysfunctional beliefs and stress coping methods in drug-addicted patients: A sample of Turkey.
Dysfunctional beliefs are believed to have an effect on substance abuse. Drug-addicted individuals experience difficulties with coping in stressful situations and therefore, start reusing these drugs. This study was conducted to determine the relationship between dysfunctional beliefs and stress coping methods in drug-addicted patients. The population of this descriptive and cross-sectional research study comprised 51 patients who were admitted to the Alcohol and Drug Addiction Treatment Center of a state hospital, diagnosed with drug addiction, and consented to participate in our study. The data were collected by using the Sociodemographic Information Form, the Dysfunctional Attitude Scale (DAS), and the Coping Assessment Questionnaire (COPE). The data obtained were evaluated by percentage, correlation, one-way analysis of variance, Mann-Whitney U-test, and Kruskal-Wallis test. The average COPE score of the drug-addicted patients was found to be 171.60 ± 23.35. The average DAS score of the drug-addicted patients was determined to be 161.66 ± 36.94. A statistically significant difference was found between the DAS and COPE scores of the patients (P < 0.05). It can be concluded that these patients have dysfunctional beliefs and exhibit emotion-focused coping attitudes. More comparative studies investigating the dysfunctional beliefs of alcohol- and drug-addicted people and coping methods should be conducted.


Cell-Free DNA: An Upcoming Biomarker in Transplantation.
After organ transplantation, donor-derived cell-free DNA (ddcfDNA) can be detected in the recipient's blood and urine. Different ddcfDNA quantification techniques have been investigated but a major breakthrough was made with the introduction of digital droplet PCR and massive parallel sequencing creating the opportunity to increase the understanding of ddcfDNA kinetics after transplantation. The observations of increased levels of ddcfDNA during acute rejection and even weeks to months before histologic features of graft rejection point to a possible role of ddcfDNA as an early, noninvasive rejection marker. In this review, we summarize published research on ddcfDNA in the transplantation field thereby elaborating on its clinical utility.


Aggregate blood pressure responses to serial dietary sodium and potassium intervention: defining responses using independent component analysis.
Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies. In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A "heat map" protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64%) and general hypertension (56%) components. There is a pattern of higher heritability for the component response to intervention (40-42%) as compared to those for the traditional intervention responses computed as delta scores (24%-40%). In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications.


Definition of five new simian immunodeficiency virus cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I molecules: evidence for an influence on disease progression.
Simian immunodeficiency virus (SIV) infection of the rhesus macaque is currently the best animal model for AIDS vaccine development. One limitation of this model, however, has been the small number of cytotoxic T-lymphocyte (CTL) epitopes and restricting major histocompatibility complex (MHC) class I molecules available for investigating virus-specific CTL responses. To identify new MHC class I-restricted CTL epitopes, we infected five members of a family of MHC-defined rhesus macaques intravenously with SIV. Five new CTL epitopes bound by four different MHC class I molecules were defined. These included two Env epitopes bound by Mamu-A*11 and -B*03 and three Nef epitopes bound by Mamu-B*03, -B*04, and -B*17. All four restricting MHC class I molecules were encoded on only two haplotypes (b or c). Interestingly, resistance to disease progression within this family appeared to be associated with the inheritance of one or both of these MHC class I haplotypes. Two individuals that inherited haplotypes b and c separately survived for 299 and 511 days, respectively, while another individual that inherited both haplotypes survived for 889 days. In contrast, two MHC class I-identical individuals that did not inherit either haplotype rapidly progressed to disease (survived <80 days). Since all five offspring were identical at their Mamu-DRB loci, MHC class II differences are unlikely to account for their patterns of disease progression. These results double the number of SIV CTL epitopes defined in rhesus macaques and provide evidence that allelic differences at the MHC class I loci may influence rates of disease progression among AIDS virus-infected individuals.


A comparison of laparoscopic and open cholecystectomy in patients with compensated cirrhosis and symptomatic gallstone disease.
The purpose of this study was to compare the risks and benefits of performing open cholecystectomy (OC) and laparoscopic cholecystectomy (LC) in patients with compensated cirrhosis. Data on 50 patients who underwent cholecystectomy for the treatment of symptomatic gallstone disease between 1990 and 1997 were collected retrospectively. These patients were divided into 2 groups: Group I included 24 patients who underwent OC, and Group II included 26 patients who underwent LC. The cohorts were well-matched for age, sex, race, clinical presentation, and Child-Turcotte-Pugh (CTP) class. Twelve patients in Group I had a concomitant surgical procedure in contrast to only 2 patients in Group II. No patient in this study had CTP Class C cirrhosis. There was no operative mortality. Conversion to OC was necessary in 3 patients (12%) during LC because of uncontrollable liver bed bleeding in 2 of the patients and insufficient visualization of the anatomy in 1 of the patients. Mean surgical times were significantly longer in Group I when comparing patients from both groups without concomitant surgical procedures (mean +/- SD, 177 +/- 91.3 minutes vs 116.8 +/- 42.3 minutes, P = .037). No patient in Group II required any blood component replacement in contrast to 9 patients (38%) in Group I. Intraoperative bleeding remained significantly higher in Group I when comparing patients without concomitant surgical procedures (P = .043). No patients in Group II had a wound complication, compared with 2 patients (8%) in Group I. The 12 patients without concomitant surgical procedures in Group I had significantly longer hospital stays when compared with 24 patients without concomitant surgical procedures in Group II (mean +/- SD, 6.9 days +/- 3.3 [median 6] vs 2.4 days +/- 1.8 [median 2.0]); P = .001. Our results demonstrate that laparoscopic cholecystectomy can be performed safely in patients with CTP Class A and B cirrhosis. It offers several advantages over open cholecystectomy, including lower morbidity, shorter operative time, and reduced hospital stay with less need for transfusions.


Novel implant design for initial stability of dental implants inserted in fresh extraction sockets: a preliminary study.
To evaluate a novel implant design for immediate implantation. This implant presents a specially designed expanded diameter midcrestal "wing" thread, which is aimed to provide added bone contact for greater insertion torque and primary stability. Mandibular premolars were extracted in 2 mongrel dogs, and immediate dental implants were inserted into the fresh extraction sockets. Implants were evaluated for stability using a resonance frequency analysis device immediately after insertion and after 4 and 8 weeks. Removal torque of 1 randomly selected implant in each hemimandible was measured as well. At 8 weeks, the remaining 6 implants were processed histologically. Mean implant stability quotient at implant placement was 64.38 (5.03) and 74.5 (3.08) at 8 weeks. Average removal torque immediately after implant placement was 49.65 (20.3) N.cm and 98.33 (12.34) N.cm at 8 weeks. The mean bone-to-implant contact value at 8 weeks was 38.89% (7.65%). The examined implant with the expanded diameter midcrestal "wing" thread showed good results of resonance frequency analysis and removal torque during the initial healing phase, and as such, it might be used for immediate implantation and loading.


Surgery and adjuvant chemotherapy use among veterans with colon cancer: insights from a California study.
US veterans have been shown to be a vulnerable population with high cancer rates, and cancer care quality in Veterans Affairs (VA) hospitals is the focus of a congressionally mandated review. We examined rates of surgery and chemotherapy use among veterans with colon cancer at VA and non-VA facilities in California to gain insight into factors associated with quality of cancer care. A retrospective cohort of incident colon cancer patients from the California Cancer Registry, who were > or = 66 years old and eligible to use VA and Medicare between 1999 and 2001, were observed for 6 months after diagnosis. Among 601 veterans with colon cancer, 72% were initially diagnosed and treated in non-VA facilities. Among veterans with stage I to III cancer, those diagnosed and initially treated in VA facilities experienced similar colectomy rates as those at non-VA facilities. Stage III patients diagnosed and initially treated in VA versus non-VA facilities had similar odds of receiving adjuvant chemotherapy. In both settings, older patients had lower odds of receiving chemotherapy than their younger counterparts even when race and comorbidity were considered (age 76 to 85 years: odds ratio [OR] = 0.18; 95% CI, 0.07 to 0.46; age > or = 86 years: OR = 0.17; 95% CI, 0.04 to 0.73). In California, older veterans with colon cancer used both VA and non-VA facilities for cancer treatment, and odds of receiving cancer-directed surgery and chemotherapy were similar in both systems. Among stage III patients, older age lowered odds of receiving adjuvant chemotherapy in both systems. Further studies should continue to explore potential health system effects on quality of colon cancer care across the United States.


Relaxed trait covariance in interspecific cichlid hybrids predicts morphological diversity in adaptive radiations.
The process of adaptive radiation involves multiple events of speciation in short succession, associated with ecological diversification. Understanding this process requires identifying the origins of heritable phenotypic variation that allows adaptive radiation to progress. Hybridization is one source of genetic and morphological variation that may spur adaptive radiation. We experimentally explored the potential role of hybridization in facilitating the onset of adaptive radiation. We generated first- and second-generation hybrids of four species of African cichlid fish, extant relatives of the putative ancestors of the adaptive radiations of Lakes Victoria and Malawi. We compared patterns in hybrid morphological variation with the variation in the lake radiations. We show that significant fractions of the interspecific morphological variation and the major trajectories in morphospace that characterize whole radiations can be generated in second-generation hybrids. Furthermore, we show that covariation between traits is relaxed in second-generation hybrids, which may facilitate adaptive diversification. These results support the idea that hybridization can provide the heritable phenotypic diversity necessary to initiate adaptive radiation.


Identification of Alzheimer's disease-associated rare coding variants in the ECE2 gene.
Accumulation of amyloid β protein (Aβ) due to increased generation and/or impaired degradation plays an important role in Alzheimer's disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in Aβ degradation. We further evaluated the effect of the R186C mutation in mutant APP-knockin mice. Overexpression of wild-type ECE2 in the hippocampus reduced amyloid load and plaque formation, and improved learning and memory deficits in the AD model mice. However, the effect was abolished by the R186C mutation in ECE2. Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing Aβ degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that ECE2 is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.


Circulating Tumor Cells Prediction in Hormone Receptor Positive HER2-Negative Advanced Breast Cancer: A Retrospective Analysis of the MONARCH 2 Trial.
The MONARCH 2 trial (NCT02107703) showed the efficacy of abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor (CDK4/6i), in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). The aim of this analysis was to explore the prediction of circulating tumor cells (CTCs) stratification using machine learning for hypothesis generation of biomarker-driven clinical trials. Predicted CTCs were computed in the MONARCH 2 trial through a K nearest neighbor (KNN) classifier trained on a dataset comprising 2436 patients with MBC. Patients were categorized into predicted Stage IVaggressive (pStage IVaggressive, ≥5 predicted CTCs) or predicted Stage IVindolent (pStage IVindolent, <5 predicted CTCs). Prognosis was tested in terms of progression-free-survival (PFS) and overall survival (OS) through Cox regression. Patients classified as predicted pStage IVaggressive and predicted pStage Stage IVindolent were, respectively, 183 (28%) and 461 (72%). After multivariable Cox regression, predicted CTCs were confirmed as independently associated with prognosis in terms of OS, together with ECOG performance status, liver involvement, bone-only disease, and treatment arm. Patients in the pStage Stage IVindolent subgroup treated with abemaciclib experienced the best prognosis both in terms of PFS and OS. The treatment effect of abemaciclib on OS was then explored through subgroup analysis, showing a consistent benefit across all subgroups. This study is the first analysis of CTCs modeling for stage IV disease stratification. These results show the need to expand biomarker profiling in combination with CTCs stratification for improved biomarker-driven drug development.


A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD).
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the size reduction of a polymorphic repeat array on 4q35. Probe p13E-11 recognises this chromosomal rearrangement and is generally used for diagnosis. However, diagnosis of FSHD is complicated by three factors. First, the probe cross hybridises to a highly homologous repeat array locus on chromosome 10q26. Second, although a BlnI polymorphism allows discrimination between the repeat units on chromosomes 4 and 10 and greatly facilitates FSHD diagnosis, the occurrence of translocations between chromosomes 4 and 10 further complicates accurate FSHD diagnosis. Third, the recent identification of deletions of p13E-11 in both control and FSHD populations is an additional complicating factor. Although pulsed field gel electrophoresis is very useful and sometimes necessary to detect these rearrangements, this technique is not operational in most FSHD diagnostic laboratories. Moreover, repeat arrays >200 kb are often difficult to detect and can falsely suggest a deletion of p13E-11. Therefore, we have developed an easy and reliable Southern blotting method to identify exchanges between 4 type and 10 type repeat arrays and deletions of p13E-11. This BglII-BlnI dosage test addresses all the above mentioned complicating factors and can be carried out in addition to the standard Southern blot analysis for FSHD diagnosis as performed in most laboratories. It will enhance the specificity and sensitivity of conventional FSHD diagnosis to the values obtained by PFGE based diagnosis of FSHD. Moreover, this study delimits the FSHD candidate gene region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit.


Mechanisms shaping the mutational landscape of the FRA3B/FHIT-deficient cancer genome.
Genome instability is an enabling characteristic of cancer that facilitates the acquisition of oncogenic mutations that drive tumorigenesis. Underlying much of the instability in cancer is DNA replication stress, which causes both chromosome structural changes and single base-pair mutations. Common fragile sites are some of the earliest and most frequently altered loci in tumors. Notably, the fragile locus, FRA3B, lies within the fragile histidine triad (FHIT) gene, and consequently deletions within FHIT are common in cancer. We review the evidence in support of FHIT as a DNA caretaker and discuss the mechanism by which FHIT promotes genome stability. FHIT increases thymidine kinase 1 (TK1) translation to balance the deoxyribonucleotide triphosphates (dNTPs) for efficient DNA replication. Consequently, FHIT-loss causes replication stress, DNA breaks, aneuploidy, copy-number changes (CNCs), small insertions and deletions, and point mutations. Moreover, FHIT-loss-induced replication stress and DNA breaks cooperate with APOBEC3B overexpression to catalyze DNA hypermutation in cancer, as APOBEC family enzymes prefer single-stranded DNA (ssDNA) as substrates and ssDNA is enriched at sites of both replication stress and DNA breaks. Consistent with the frequent loss of FHIT across a broad spectrum of cancer types, FHIT-deficiency is highly associated with the ubiquitous, clock-like mutation signature 5 occurring in all cancer types thus far examined. The ongoing destabilization of the genome caused by FHIT loss underlies recurrent inactivation of tumor suppressors and activation of oncogenes. Considering that more than 50% of cancers are FHIT-deficient, we propose that FRA3B/FHIT fragility shapes the mutational landscape of cancer genomes.


Depth of central venous catheterization by intracardiac electrocardiogram in adults.
Central venous catheterization is done frequently in cardiac surgery and intensive care settings. Faulty positioning of the catheter can cause many complications. The aim of our study was to study the average depth of insertion and formulate a general guideline through the right internal jugular vein (IJV). The right IJV was cannulated over a period of four months and catheter tip positioning was guided by means of an intracardiac electrocardiogram (ECG). Insertion depth was registered at the position of maximum P wave amplitude and the catheter was fixed after withdrawing 2 cm. Pearson's correlation coefficient was calculated to categorize any relationship between plots of distance versus patient's height, and regression lines and equations were also calculated. Bland-Altman analysis of data was done to compare the old formulae with our derived formulae. A total of 155 adult patients were studied. Distances measured were found to be highly correlated with a patient's height, followed by body surface area (BSA) and weight. For right IJV cannulation in valvular surgeries in adults, the depth of insertion (cm) was (height in cm / 15) + 2 ± 1.58 (SD) and in non-valvular surgeries in adults, it was (height in cm/15) + 1.4 ± 1.47 (SD). The bias was very small when the new formulae were compared to the existing formulae. The devised formulae predicted the required depth of catheters thereby reducing the possibility of complications and need for radiographic confirmation.


Development of a Breastfeeding Effectiveness Scale (BES).
The purpose of this study was to develop and evaluate breastfeeding effectiveness scale to measure effectiveness of breastfeeding for mothers in the early postpartum period. A conceptual framework was constructed from properties of effective breastfeeding (Yang and Seo, 2011), and item construction was derived from literature review and analysis of the data along with interviews with breastfeeding mothers. Content validity was tested by experts. Each item was scored on a five-point Likert scale. The preliminary questionnaire was administered to 248 breastfeeding mothers. Data were analyzed using item analysis, factor analysis, Pearson correlation coefficients, and Cronbach's α. From the factor analysis, 20 items in seven factors were derived. The factors were identified as mother's satisfaction, suckling, assurance of milk quantity, infant's satisfaction, latching on, infant's feeding desire, and breastfeeding positioning. The seven factors explained 65.1% of total variance, Cronbach's α of the total items was .83 and the factors ranged from .44 to .75. Results of this study suggest that breastfeeding effectiveness scale is a reliable and valid instrument to measure breastfeeding effectiveness of mothers in the early postpartum period.


Induction of oligo-2',5'-adenylate synthetase in human lymphoid cells treated with 5-azacytosine and 5-iododeoxyuridine.
Oligo-2',5'-adenylate synthetase activity was investigated in several human lymphoblastoid cell lines of B cell origin treated with reagents having effects on gene expression, 5-azacytosine (5AZct), 5-azacytidine (5AZcd) and 5-iodo-2'-deoxyuridine (IUdR). Enzyme activity did not increase in cells treated with 5AZcd, but the other reagents induced significant levels of activity. Interferon (IFN) activity was not detected in culture fluids of cells treated with 5AZcd or 5AZct. On the other hand, treatment of cells with IUdR led to the production of 5 to 10 units/ml IFN by NC-37 and Raji cells, but not by other human B cell lines. Enzyme induction by IUdR occurred in IFN-producing cells, NC-37 and Raji, exposed to anti-IFN-alpha sera and also in IFN-non-producing human B cells. The effect of 5AZct on enzyme induction was observed only after cultivation of cells for more than 1 month. This compound could not induce enzyme activity in Epstein-Barr virus (EBV)-negative cells, BJAB, but only in the EBV-positive cell lines NC-37 and Raji. In contrast, treatment of cells with IUdR for only 3 days induced the enzyme in all human lymphoblastoid cell lines of B cell origin except P3HR-1, but not in other human cell lines, FL, HeLa and K562. Oligo-2',5'-adenylate synthetase activity in P3HR-1 cells, which produce EBV particles, was hardly affected by IUdR or IFN treatment.


Efficacy of clomipramine in the treatment of canine compulsive disorder.
To assess the efficacy of clomipramine for treatment of canine compulsive disorder (CCD). Randomized, placebo-controlled, double-blind, balanced AB-BA crossover clinical study. 51 dogs with CCD. Dogs were given clomipramine (3 mg/kg [1.3 mg/lb] of body weight, PO, q 12 h) for 4 weeks and placebo for 4 weeks. At the end of each treatment each owner rated the severity of their dog's behavior, using 2 validated rating scales. Statistical analysis was made by ordinal regression. Compliance, adverse effects, and the effectiveness of masking were also assessed. Each dog's behavior was reevaluated 1 to 2 years after completing the study. Behaviors included spinning (n = 17) and self-mutilation by licking (acral lick dermatitis, 12). Both rating scales demonstrated a treatment effect. Compliance was satisfactory, and masking was effective. Sedation and reduced appetite were reported more commonly when dogs were given clomipramine than when they were given placebo. Forty-five dogs available for follow-up evaluation still had their behaviors; 6 dogs were lost to follow-up evaluation. Results suggest that clomipramine was effective in dogs with CCD and was not associated with serious adverse effects. However, treatment for 4 weeks was not curative. Behavior modification is likely to be necessary to manage CCD.


Specificity of QuantiFERON-TB Plus, a New-Generation Interferon Gamma Release Assay.
Interferon gamma release assays (IGRAs) are important tools in identifying prior tuberculosis exposure. The new-generation QuantiFERON-TB Gold Plus (QFT-Plus) assay, recently approved for use in the United States, differs from the current-generation QFT Gold-In-Tube (QFT-GIT) assay with the addition of a second antigen tube that also contains novel CD8+ T-cell-stimulating peptides. The QFT-Plus assay has increased sensitivity in immunocompromised populations, and we sought to assess the specificity of QFT-Plus compared to that of QFT-GIT in low-risk individuals. We enrolled adults without tuberculosis risk factors, including a subgroup with pulmonary nontuberculous mycobacterial (NTM) disease due to Mycobacterium avium complex (MAC) or Mycobacterium abscessus. The primary outcome measures included specificity, interassay concordance, and agreement between the QFT-Plus and QFT-GIT assays. Of 262 participants enrolled, 51 had pulmonary NTM. The median age was 39 years (age range, 18 to 78 years); 73% were female. Among the 262 individuals who were enrolled, 5 (1.9%) individuals had positive QFT-Plus results, and 3 of these individuals also had positive QFT-GIT results. The two individuals with discordant results (QFT-Plus positive/QFT-GIT negative) had only one tube positive in the QFT-Plus assay. The overall specificity of QFT-Plus and QFT-GIT was 98.1% (95% confidence interval [CI], 95.6, 99.4%) and 98.9% (95% CI, 96.7, 99.8%), respectively. The QFT-Plus specificity was similar in both the NTM (98.0% [95% CI, 89.4, 99.9%]) and non-NTM (98.1% [95% CI, 95.2, 99.5%]) groups. QFT-Plus has a high specificity, similar to that of the QFT-GIT assay, including in patients with pulmonary MAC or M. abscessus disease.


Comparison of excited-state energy transfer in arrays of hydroporphyrins (chlorins, oxochlorins) versus porphyrins: rates, mechanisms, and design criteria.
A set of chlorin-chlorin and oxochlorin-oxochlorin dyads has been prepared with components in the same or different metalation states. In each case a 4,4'-diphenylethyne linker spans the respective 10-position of each macrocycle. The dyads have been studied using static and time-resolved absorption and emission spectroscopy, resonance Raman spectroscopy, and electrochemical techniques. Excited-state energy transfer from a zinc chlorin to a free-base (Fb) chlorin occurs with a rate constant of (110 ps)(-1) and an efficiency of 93%; similar values of (140 ps)(-1) and 83% are found for the corresponding oxochlorin dyad. Energy transfer in both dyads is slower and less efficient than found previously for the analogous porphyrin dyad, which displays a rate of (24 ps)(-1) and a yield of 99%. The slower rates and diminished efficiencies in the ZnFb chlorin and oxochlorin dyads versus the ZnFb porphyrin dyad are attributed to substantially weaker linker-mediated through-bond (TB) electron-exchange coupling (as indicated by resonance Raman data). Although the through-space (TS, i.e., dipole-dipole) coupling in the ZnFb-chlorin and -oxochlorin dyads is enhanced relative to the ZnFb porphyrin dyad (as indicated by Förster calculations), this enhancement is insufficient to compensate for the greatly diminished TB coupling. Taken together, the chlorin and oxochlorin dyads examined herein serve as benchmarks for elucidating the energy-transfer, electrochemical, and other properties of light-harvesting arrays containing multiple chlorins or oxochlorins.


Coccidiosis in the European badger (Meles meles) from England, an epidemiological study.
In total 445 faecal samples were collected from 259 European badgers (Meles meles) in Wytham Woods, Oxfordshire, UK (462080). Microscopical examination revealed infection with 2 species of coccidia Eimeria melis and Isospora melis. From the initial examination of each animal, point prevalence rates of 0.44 and 0.35 were calculated for Eimeria and Isospora respectively. The intensity of infection was significantly greater for Eimeria than Isopora and the distribution of intensities was highly skewed for both species, with a few individuals shedding the majority of oocysts. Incidence and recovery rates for both coccidia species were calculated from longitudinal data collected at 3-monthly intervals from a subset of the adult badger population, and the predicted prevalence rates based on these were similar to the point prevalence rates. This suggests little, if any, parasite-induced mortality in the adult population. In contrast, there was a marked and significant reduction in the point prevalence and intensity of infection with Eimeria from cub to adult badger suggesting a degree of acquired immunity to Eimeria melis on initial exposure and/or that there is significant Eimeria-associated mortality in the cub population. No such relationship was found for Isospora infection. In those adult badgers with co-infections there was a direct relationship between the intensity of Eimeria and Isospora. The taxonomic status of these parasites suggests a heteroxenous life-cycle for I. melis, and direct transmission of E. melis. However, the greater than expected prevalence of co-infection is consistent with a common source of infection, such as communal latrines.


Semaphorin-Plexin signaling influences early ventral telencephalic development and thalamocortical axon guidance.
Sensory processing relies on projections from the thalamus to the neocortex being established during development. Information from different sensory modalities reaching the thalamus is segregated into specialized nuclei, whose neurons then send inputs to cognate cortical areas through topographically defined axonal connections. Developing thalamocortical axons (TCAs) normally approach the cortex by extending through the subpallium; here, axonal navigation is aided by distributed guidance cues and discrete cell populations, such as the corridor neurons and the internal capsule (IC) guidepost cells. In mice lacking Semaphorin-6A, axons from the dorsal lateral geniculate nucleus (dLGN) bypass the IC and extend aberrantly in the ventral subpallium. The functions normally mediated by Semaphorin-6A in this system remain unknown, but might depend on interactions with Plexin-A2 and Plexin-A4, which have been implicated in other neurodevelopmental processes. We performed immunohistochemical and neuroanatomical analyses of thalamocortical wiring and subpallial development in Sema6a and Plxna2; Plxna4 null mutant mice and analyzed the expression of these genes in relevant structures. In Plxna2; Plxna4 double mutants we discovered TCA pathfinding defects that mirrored those observed in Sema6a mutants, suggesting that Semaphorin-6A - Plexin-A2/Plexin-A4 signaling might mediate dLGN axon guidance at subpallial level. In order to understand where and when Semaphorin-6A, Plexin-A2 and Plexin-A4 may be required for proper subpallial TCA guidance, we then characterized their spatiotemporal expression dynamics during early TCA development. We observed that the thalamic neurons whose axons are misrouted in these mutants normally express Semaphorin-6A but not Plexin-A2 or Plexin-A4. By contrast, all three proteins are expressed in corridor cells and other structures in the developing basal ganglia. This finding could be consistent with an hypothetical action of Plexins as guidance signals through Sema6A as a receptor on dLGN axons, and/or with their indirect effect on TCA guidance due to functions in the morphogenesis of subpallial intermediate targets. In support of the latter possibility, we observed that in both Plxna2; Plxna4 and Sema6a mutants some IC guidepost cells abnormally localize in correspondence of the ventral path misrouted TCAs elongate into. These findings implicate Semaphorin-6A - Plexin-A2/Plexin-A4 interactions in dLGN axon guidance and in the spatiotemporal organization of guidepost cell populations in the mammalian subpallium.


Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study.
Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.


Case Report: Eosinophilic Bronchiolitis With Eosinophil ETosis in Mucus Plugs Successfully Treated With Benralizumab.
Eosinophilic bronchiolitis is a rare allergic disorder caused by eosinophilic inflammation in the bronchioles of the lungs. An effective treatment strategy is needed in cases resistant to steroids. However, its pathophysiology remains unclear owing to the limited number of cases. We herein present the case of a 31-year-old man who experienced eosinophilic bronchiolitis with eosinophil ETosis (EETosis) in the mucus plugs. The patient was diagnosed with asthma. His respiratory symptoms worsened with eosinophilia when treated with the standard asthma regimen, including inhaled corticosteroids, long-acting β2-agonist, long-acting muscarinic antagonist, and leukotriene receptor antagonist. Chest computed tomography revealed bronchial wall thickening and centrilobular nodules in the lower lobes of both lungs. Bronchoscopy showed obstruction of the subsegmental bronchus with mucus plugs. Histological analysis demonstrated abundant eosinophils in the mucus plugs. Cytolytic eosinophils together with Charcot-Leyden crystal formations and deposition of major basic proteins were also observed, indicating the occurrence of EETosis. Introduction of benralizumab, an anti-interleukin-5 receptor α antibody, successfully controlled the patient's condition and reduced the amount of systemic corticosteroids administered. Our findings confirm that this antibody strongly decreases airway eosinophils in patients with severe asthma. Thus, benralizumab might be an optimal therapeutic agent for the treatment of mucus plug-forming and/or EETosis-occurring eosinophilic lung diseases, including eosinophilic bronchiolitis.


Critical analysis of trends in fusion for degenerative disc disease over the past 20 years: influence of technique on fusion rate and clinical outcome.
Critical analysis of the results reported in published literature. The purpose of this study was to evaluate whether various technical advancements have affected the outcome of lumbar spinal fusion for degenerative disease by critically analyzing the available literature from the past two decades. To improve fusion rate and clinical outcome, various surgical options for lumbar spinal fusion for degenerative disc disorders have been introduced over the past 20 years. However, an important fundamental question still remains: What has been the impact of these new techniques and innovations on surgical results? A comprehensive computer search of the English literature from 1979 to 2000 concerning lumbar/lumbosacral spinal fusion was performed using the keywords degenerative, lumbar, and fusion. Numerous deficiencies were noted in the reviewed literature. Nearly half of the studies failed to specify methodologic design, and documentation of brace use, graft source, fusion location, and fusion rate was missing in 38, 10, 2, and 4 of the 84 articles reviewed, respectively. From the data gathered, a noticeable trend toward the increasing use of internal fixation was noted, accounting for 23% of fusions in the 1980s versus 41% in the 1990s. Despite this trend, an improvement in overall fusion rate or clinical outcome could not be demonstrated. Numerous technologic advancements in lumbar spine fusion have been made over the past 20 years. Future advances in care are dependent on review of reported results. The numerous deficiencies detected in the analyzed literature herald the necessity for a uniform system of outcomes reporting containing a core of critical demographic, perioperative, and postsurgical information. Although a shift toward a greater use of technology was noted in the published literature, the clinical benefit of this trend remains unclear.


Sarcolemmal Ca2+ transport in streptozotocin-induced diabetic cardiomyopathy in rats.
Heart sarcolemmal membranes were isolated by the sucrose density gradient method from rats with chronic diabetes induced by a streptozotocin (65 mg/kg iv) injection. Na+-dependent Ca2+-uptake activities were significantly depressed in diabetic sarcolemmal membranes; such alterations were evident at different incubation times and at different concentrations of Ca2+. Administration of insulin to diabetic rats normalized the Na+-dependent Ca2+-uptake activities. ATP-dependent Ca2+ accumulation and Ca2+-stimulated Mg2+-dependent ATPase, which represents Ca2+-pump mechanisms, were significantly depressed in sarcolemmal preparations for diabetic rats and these changes were also reversible upon insulin treatment. An increase in lysophosphatidylcholine and a decrease in phosphatidylethanolamine as well as diphosphatidylglycerol contents were observed in heart membranes isolated from diabetic rats but other phospholipids were unchanged. Cholesterol-to-phospholipid ratio was significantly increased in preparations from diabetic rats. These results indicate a depression in the ability of the cell to remove Ca2+ through Na+-Ca2+ exchange and Ca2+-pump mechanisms in sarcolemma, and these defects may contribute to the occurrence of intracellular Ca2+ overload and diabetic cardiomyopathy.


Polymorphisms in the IL-4 and IL-4R [alpha] genes and allergic asthma.
Allergic asthma is caused by genetic and environmental factors that interact to determine disease susceptibility and severity. Several lines of evidence suggest that the interleukin (IL-4 gene and the IL-4-receptor alpha (IL-4Ralpha) gene are involved in the development of atopic diseases. We sought to determine whether two polymorphism sites in IL-4 and IL-4Ralpha chain were associated with allergic asthma in a Chinese population. We obtained DNA and clinical data from allergic asthma patients, which were compared with those of a group of healthy control subjects. The subjects were genotyped for the IL-4 C-590T promoter polymorphism and the IL-4R alpha chain Q576R by polymerase chain reaction-restriction fragment length polymorphism. The results showed that the IL-4 C-590T was not associated with allergic asthma in a Chinese population. However, the IL-4R alpha chain 576R/R was significantly increased in allergic asthma patients compared with control subjects (chi2 = 21.16; p < 0.01), and also total plasma immunoglobulin E (IgE) level was increased in allergic asthma patients. These data suggest that the IL-4R alpha chain 576R/R genotypes confer genetic susceptibility to allergic asthma in Chinese.


Mesenchymal Stromal Cells (MSCs): A Promising Tool for Cell-Based Angiogenic Therapy.
The Mesenchymal stromal cells (MSCs) are a diverse subset of adult multipotent precursors, known for their potential therapeutic properties in regenerative medicine mainly sustained by paracrine effects through secretion of a variety of biologically active molecules. MSC secretome includes a wide range of soluble protein factors, composed of growth factors and cytokines, and vesicular components, which transfer proteins and genetic material modulating the host microenvironment. In particular, MSC-derived secretome mediates the different steps of the angiogenic process, inducing endothelial cell functions in vitro and promoting angiogenesis in vivo. As a result, MSCs have been widely explored as a promising cell-based therapy in diseases caused by insufficient angiogenesis. Numerous studies of myocardial infarction, ischemic stroke, and critical limb ischemia in animals have shown that human MSCs can enhance angiogenesis and accelerate tissue regeneration. This extensive preclinical work encouraged the study of these remarkable cells for the treatment of these disorders in human clinical settings. The present review provides a comprehensive overview of the pro-angiogenic potential of MSCs and paracrine effectors of their secretome. In addition, bioengineering strategies, including ex vivo preconditioning and genetic modification approaches, to enhance MSC innate angiogenic properties, and thereby therapeutic potency, will be presented. Finally, an update on completed preclinical and clinical studies with MSCs for the treatment of ischemia-related diseases will be discussed.


UV waveguides light fabricated in fluoropolymer CYTOP by femtosecond laser direct writing.
We have fabricated optical waveguides inside the UV-transparent polymer, CYTOP, by femtosecond laser direct writing for propagating UV light in biochip applications. Femtosecond laser irradiation is estimated to increase the refractive index of CYTOP by 1.7 x 10(-3) due to partial bond breaking in CYTOP. The waveguide in CYTOP has propagation losses of 0.49, 0.77, and 0.91 dB/cm at wavelengths of 632.8, 355, and 266 nm, respectively.


Abstracting human control strategy in projecting light source.
In this paper, we present a method of modeling human strategy in controlling a light source in a dynamic environment. We take a simple example of how to control the light source to avoid a shadow and maintain appropriate illumination conditions on the target area of attention to illustrate the procedure and method. This work is valuable to various applications of automatic light control from surgical room and space applications to inspections.


Determination of sulfated biogenic amines: emphasis on dopamine sulfate isomers.
Investigations concerning the specific conjugates of dopamine (DA) in the body have been hampered by the lack of specific and sensitive methodology for their detection. Because there is increasing interest in the occurrence and measurement of sulfated metabolites of DA and the other catecholamines (CA) norepinephrine and epinephrine, reliable methods for the detection and quantitation of these compounds in biological samples are needed. This paper reviews recently developed methods for the measurement of the two sulfate conjugates of DA in the body, DA-3-O-sulfate and DA-4-O-sulfate. The methods are sensitive enough for most, if not all, routine applications relating to DA sulfate. With minor modifications, some of the methods should be applicable to measurement of sulfate conjugates of many other electrochemically active compounds, such as other CA or indoles, their metabolites, and some drugs and metabolites.


Mental health care in the primary care setting: family physicians' perspectives.
To assess family physicians' interactions with mental health professionals (MHPs), their satisfaction with the delivery of mental health care in primary health care settings, and their perceptions of areas for improvement. Mailed survey. Province of Saskatchewan. All FPs in Saskatchewan (N = 816) were invited to participate in the study; 31 were later determined to be ineligible because they were specialist physicians, were no longer practising regularly, or could not be located. Family physicians' self-reported satisfaction with and interest in mental health care; perceived strengths and areas for improvement in the quality of mental health care delivery in primary health care settings. The response rate was 48%, with 375 FPs completing the survey. More than half of the responding FPs (56%) reported seeing 11 or more patients with mental health problems per week. Although 83% of responding FPs were interested or very interested in identifying or treating mental health problems, fewer than half (46%) reported being satisfied with the mental health care they were able to deliver. Family physician satisfaction was significantly higher among those with on-site MHPs (P < .05) and those who saw fewer patients with mental health problems per week (P < .01). The most common mode of interaction that FPs reported having with MHPs was through written correspondence; somewhat less common were telephone and face-to-face interactions. The most common strength FPs identified in their provision of mental health care was having access to psychiatrists, community mental health nurses, and other MHPs. The most common area for improvement in primary mental health care also fell under the category of access. Specifically, FPs felt access to psychiatrists needed to be improved. Mental health problems are very common in primary care. Most FPs are very interested in the detection and treatment of mental health problems. Despite this high level of interest, however, FPs are generally dissatisfied with the quality of mental health care they are able to provide. Access to MHPs was cited as a critical element in improving the delivery of mental health services in primary care.


SARS-CoV-2 pseudotyped virus persists on the surface of multiple produce but can be inactivated with gaseous ozone.
Due to the immense societal and economic impact that the COVID-19 pandemic has caused, limiting the spread of SARS-CoV-2 is one of the most important priorities at this time. The global interconnectedness of the food industry makes it one of the biggest concerns for SARS-CoV-2 outbreaks. Although fomites are currently considered a low-risk route of transmission for SARS-CoV-2, new variants of the virus can potentially alter the transmission dynamics. In this study, we compared the survival rate of pseudotyped SARS-CoV-2 on plastic with some commonly used food samples (i.e., apple, strawberry, grapes, tomato, cucumber, lettuce, parsley, Brazil nut, almond, cashew, and hazelnut). The porosity level and the chemical composition of different food products affect the virus's stability and infectivity. Our results showed that tomato, cucumber, and apple offer a higher survival rate for the pseudotyped viruses. Next, we explored the effectiveness of ozone in deactivating the SARS-CoV-2 pseudotyped virus on the surface of tomato, cucumber, and apple. We found that the virus was effectively inactivated after being exposed to 15 ppm of ozone for 1 h under ambient conditions. SEM imaging revealed that while ozone exposure altered the wax layer on the surface of produce, it did not seem to damage the cells and their biological structures. The results of our study indicate that ozonated air can likely provide a convenient method of effectively disinfecting bulk food shipments that may harbour the SARS-CoV-2 virus.


Socialization, Relaxation, and Leisure across the Day by Social Determinants of Health: Results from the American Time Use Survey, 2014-2016.
This study used the American Time Use Survey (ATUS) to examine socialization, relaxation, and leisure activities throughout the day as related to social determinants of health (SDOH). The study population was adults aged 25 years and older who participated in the ATUS in 2014-2016, the most recent years for collecting SDOH. Descriptive analyses provide characteristics of the study population. Graphical analyses display socialization by SDOH across the hours of the day based on adjusted regression models. Quasi-binomial models analyzed the association between the numbers of minutes of various activities and SDOH. Associations between SDOH and sleeplessness (yes or no) were explored using logistic regression. For much of the day, being female, having less education, living in poverty, and having food insecurity were associated with more time socializing and relaxing. The major activities under socializing and relaxation are watching television and movies. Having a college degree was strongly associated with increased minutes of sports activity, whereas living in poverty and food insecurity were associated with fewer minutes. Less education, living in poverty, and having food insecurity were associated with sleeplessness. A possible mechanism of the effects of SODH on health is by its altering of the patterns of daily life.