A CMOS wireless biomolecular sensing system-on-chip based on polysilicon nanowire technology.
As developments of modern societies, an on-field and personalized diagnosis has become important for disease prevention and proper treatment. To address this need, in this work, a polysilicon nanowire (poly-Si NW) based biosensor system-on-chip (bio-SSoC) is designed and fabricated by a 0.35 μm 2-Poly-4-Metal (2P4M) complementary metal-oxide-semiconductor (CMOS) process provided by a commercialized semiconductor foundry. Because of the advantages of CMOS system-on-chip (SoC) technologies, the poly-Si NW biosensor is integrated with a chopper differential-difference amplifier (DDA) based analog-front-end (AFE), a successive approximation analog-to-digital converter (SAR ADC), and a microcontroller to have better sensing capabilities than a traditional Si NW discrete measuring system. In addition, an on-off key (OOK) wireless transceiver is also integrated to form a wireless bio-SSoC technology. This is pioneering work to harness the momentum of CMOS integrated technology into emerging bio-diagnosis technologies. This integrated technology is experimentally examined to have a label-free and low-concentration biomolecular detection for both Hepatitis B Virus DNA (10 fM) and cardiac troponin I protein (3.2 pM). Based on this work, the implemented wireless bio-SSoC has demonstrated a good biomolecular sensing characteristic and a potential for low-cost and mobile applications. As a consequence, this developed technology can be a promising candidate for on-field and personalized applications in biomedical diagnosis.


Meeting sexual partners online: associated sexual behaviour and prevalent chlamydia infection among adolescents in Norway: a cross-sectional study.
Evidence is mixed as to whether meeting sexual partners online ('internet-partners') is associated with risky sexual behaviour and/or sexually transmitted infection transmission. Accordingly, we sought to estimate the prevalence of reporting various online romantic and sexual activities among Norwegian adolescents, including internet-partners, and the reason for meeting them and to examine differences in sexual behaviour, partnership characteristics and chlamydia infection prevalence among those reporting internet-partners versus those reporting only offline partners. Population-based cross-sectional survey among sexually experienced girls and boys, 15-20 years, using electronic questionnaires and collecting urine samples for Chlamydia trachomatis PCR testing (79% provided both, n=1023). We used logistic regression to examine associations, adjusting for potentially confounding variables. Overall, 30% of both genders reported internet-partners (ever). Boys (but not girls) with internet-partners had higher chlamydia prevalence than those reporting meeting sexual partners only offline (8.1%, 95% CI 4.3% to 13.7% vs 1.6%, 0.5% to 3.7%). Two-thirds of girls and 37% of boys reported meeting their most recent internet-partner to start a romantic relationship, while the remainder did so with the specific intention of having sex. Among both genders, reporting sexual (vs romantic) reasons for meeting their most recent internet-partners was associated with reporting several risky sexual behaviours, including multiple recent sex partners (adjusted OR girls: 3.27, boys: 2.48) and three-fold higher chlamydia prevalence. This population-based study suggests that internet-partners are common among adolescents in Norway, and the reason for meeting them was more strongly associated with additionally reporting sexual risk behaviours and prevalent chlamydia infection than the internet itself as a meeting venue.


Evolution of granular materials under isochoric cyclic simple shearing.
By means of 3D particle dynamics simulations, we analyze the microstructure of granular materials subjected to isochoric (constant volume) cyclic shearing, which drives the system towards a liquefaction state characterized by loops of jamming-unjamming transition with periodic loss of strength and irreversible accumulation of shear strain. We first show that the macroscopic response obtained by these simulations agrees well with the most salient features of the well-known cyclic behavior of granular materials both before and after liquefaction. Then we investigate the evolution of particle connectivity, force transmission, and anisotropies of contact and force networks. The onset of liquefaction is marked by partial collapse of the force-bearing network with rapid drop of the coordination number and nonrattler fraction of particles, and significant broadening of the contact force probability density function, which begins in the preliquefaction period. We find that the jamming transition in each cycle occurs for a critical value of the coordination number that can be interpreted as the percolation threshold of the contact network and appears to be independent of the initial mean stress, void ratio, and cyclic shear amplitude. We show that upon unjamming in each cycle an isotropic loss of contacts occurs and is followed by the development of high contact anisotropy and a large proportion of particles with only two or three contacts. The higher mobility of the particles also involves a lower degree of frustration of particle rotations and thus lower friction mobilization and tangential force anisotropy. These findings are relevant to both undrained cyclic deformations of saturated soils and rheology of dense non-Brownian suspensions where volume change is coupled with pore liquid drainage conditions.


The role of the sports and exercise medicine physician in the National Health Service: a questionnaire-based survey.
To investigate the opinions of general practitioners, orthopaedic surgeons, rheumatologists, sport and exercise medicine (SEM) registrars and public health consultants on training, caseload, the most appropriate setting and the position of SEM within the National Health Service (NHS) in the UK. A cross-sectional questionnaire-based survey investigated the opinions of the above professionals from three primary care trusts and associated hospitals in London and Birmingham. With a 50% response rate (n = 226), 93% (208/224) of participants felt that there was a role for SEM in the NHS. 56% (124/223) agreed that this role should be in both primary and secondary care. 64% (136/212) of participants felt that their practice would benefit from the input of a SEM physician and 95% (191/202) would consider referring patients to SEM services. 74% (165/222) agreed that SEM should have a public health role, and 63% (140/222) believed that these responsibilities should be evenly balanced with the treatment of sports injuries. Despite the emphasis on public health work from SEM policy makers, none of the SEM registrars selected public health as an important training area. 31% (44/140) of participants felt that a lack of education in the medical profession regarding SEM represented the greatest hindrance to its development in the NHS. Several areas of agreement were demonstrated across the specialties, many of which matched the views of policy makers. This study involved participants from a range of cognate disciplines and was the first to investigate this issue since SEM was recognised as a specialty in 2005.


Acid/base switching of the tautomerism and conformation of a dioxoporphyrin for integrated binary subtraction.
Compared with most of the reported logic devices based on the supramolecular approach, systems based on individual molecules can avoid challenging construction requirements. Herein, a novel dioxoporphyrin DPH22 was synthesized and two of its tautomers were characterized by single-crystal X-ray diffraction studies. Compound DPH22 exhibits multichannel controllable stepwise tautomerization, protonation, and deprotonation processes through interactions with H(+) and F(-) ions. By using the addition of H(+) and F(-) ions as inputs and UV/Vis absorption values at λ=412, 510, 562, and 603 nm as outputs, the controlled tautomerism of DPH22 has been successfully used for the construction of an integrated molecular level half-subtractor and comparator. In addition, this acid/base-switched tautomerism is reversible, thus endowing the system with ease of reset and recycling; consequently, there is no need to modulate complicated intermolecular interactions and electron-/charge-transfer processes.


A randomized double-blind controlled trial of automated term dissection.
To compare the accuracy of an automated mechanism for term dissection to represent the semantic dependencies within a compositional expression, with the accuracy of a practicing Internist to perform this same task. We also compare the results of four evaluators to determine the inter-observer variability and the variance between term sets, with respect to the accuracy of the mappings and the consistency of the failure analysis. 500 terms, which required a compositional expression to effect an exact match, were randomly distributed into two sets of 250 terms (Set A and Set B). Set A was dissected using the Automated Term Dissection (ATD) Algorithm. A physician specializing in Internal Medicine dissected set B. He had no prior knowledge of the dissection algorithm or how it functioned. In this manuscript, the authors use Human Term Dissection (HTD) to refer to this method. Set A was randomized to two sets of 125 terms (Set A1 and Set A2). Set B was randomized to two sets of 125 terms (Set B1 and Set B2). A new set of 250 terms Set C was created from Set A1 and Set B2. A second new set of 250 terms Set D was created from Set A2 and Set B1. Two expert Indexers reviewed Set C and another two expert Indexers reviewed Set D. They were blinded to which terms were dissected by the clinician and which terms were dissected by the automated term dissection algorithm. The person providing the files for review to the Indexers was also unaware of which terms were dissected by ATD vs. the HTD method. The Indexers recorded whether or not the dissection was the best possible representation of the input concept. If not, a failure analysis was conducted. They recorded whether or not the dissection was in error and if so was a modifier not subsumed or was a Kernel concept subsumed when it should not have been. If a concept was missing, the Indexers recorded whether it was a Kernel concept, a modifier, a qualifier or a negative qualifier. The ATD method was judged to be accurate and readable in 265 out of the 424 terms with adequate content (62.7%). The HTD method was judged to be accurate in 272 out of 414 terms with adequate content (65.7%). There was no statistically significant difference between the rates of acceptability of the ATD and HTD methods (p = 0.33). There was a non-significant trend toward greater acceptability of the ATD method in the subgroup of terms with three or more compositional elements. ATD was acceptable in 53.6% of the terms where the HTD was only acceptable in 43.6% (p = 0.11). The failure analysis showed that both methods misrepresented kernel concepts and modifiers much more commonly than qualifiers (p < 0.001). There is no statistically significant difference in the accuracy and readability of terms dissected using the automated term dissection method when compared with human term dissection, as judged by four expert medical indexers. There is a non-significant trend toward improved performance of the ATD method in the subset of more complex terms. The authors submit that this may be due to a tendency for users to be less compulsive when the time to complete the task is long. Automated term dissection is a useful and perhaps preferable method for representing readable and accurate compound terminological expressions.


CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice.
The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow and their roles in BMSCs' differentiation. Antibody array revealed that CC chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSC differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypomethylation. Moreover, CCL3 inhibited BMSCs' osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated Dickkopf-related protein 1 upregulation. Blocking CCL3 in vivo via neutralizing antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis and lays a foundation for the identification of new targets for senile osteoporosis treatment.


Influence of a caffeine mouth rinse on sprint cycling following glycogen depletion.
Attenuated performance during intense exercise with limited endogenous carbohydrate (CHO) is well documented. Therefore, this study examined whether caffeine (CAF) mouth rinsing would augment performance during repeated sprint cycling in participants with reduced endogenous CHO. Eight recreationally active males (aged 23 ± 2 yr, body mass 84 ± 4 kg, stature 178 ± 7 cm) participated in this randomized, single-blind, repeated-measures crossover investigation. Following familiarization, participants attended two separate evening glycogen depletion sessions. The following morning, participants completed five, 6 s sprints on a cycle ergometer (separated by 24 s active recovery), with mouth rinsing either (1) a placebo solution or (2) a 2% CAF solution. During a fifth visit, participants completed the sprints without prior glycogen depletion. Repeated-measures ANOVA identified significant main effect of condition (CAF, placebo, and control [P < .05; effect size (ES) = 0.850-0.897]), sprint (1-5 [P < .005; ES = 0.871-0.986]), and interaction (condition × sprint [P < .05; ES = 0.831-0.846]), for peak and mean power. The control condition exhibited the highest peak power (overall mean 760 ± 77 W) and mean power (overall mean 699 ± 83W) over the five sprints (P < .001 in both instances). CAF peak power (overall mean 643 ± 79 W) was significantly greater than placebo (mean 573 ± 79 W [P < .05; ES = 0.850]). Additionally, CAF mean power (overall mean 589 ± 80 W) was significantly greater than placebo (519 ± 82 W [P < .05; ES = 0.397]). These data indicate that mouth rinsing a caffeinated solution reduces decrements caused by CHO reduction, which may benefit athletes wishing to train in a low-CHO state.


Suspension of medullary thick ascending limb tubules from the rabbit kidney.
A procedure for isolating a suspension of tubules derived from the rabbit medullary thick ascending limb is described. The purity of the preparation was assessed by microscopy and enzyme assays and the viability of the preparation was assessed by measuring oxygen consumption. Microscopy revealed that the suspension contains 95% thick ascending limbs and that the isolation procedure preserves the structure of the epithelium except for the loss of the basement membrane. The preparation had a high activity of calcitonin-sensitive adenylate cyclase, a marker enzyme for the medullary thick ascending limb. Control oxygen consumption was considerably higher than that reported for proximal tubules in the literature, and nystatin or carbonyl cyanide p-trifluoromethoxyphenylhydrazone addition produced a more than 100% increase in oxygen consumption. Furosemide inhibited the oxygen consumption by 43% and ouabain inhibited it by 42%. Furosemide inhibited sodium chloride entry without directly affecting the Na-K-ATPase or cellular metabolism. Chloride removal depressed oxygen consumption to the same extent as furosemide, but some of this action was through direct inhibition of cellular metabolism.


Plant hormone profiling in developing seeds of common wheat (Triticum aestivum L.).
This study examined contents of nine plant hormones in developing seeds of field-grown wheat varieties (Triticum aestivum L.) with different seed dormancy using liquid chromatography-mass spectrometry. The varieties showed marked diversity in germination indices at 15°C and 20°C. Contents of the respective hormones in seeds showed a characteristic pattern during seed maturation from 30-day post anthesis to 60-day post anthesis. Principal component analysis and hierarchical clustering analysis revealed that plant hormone profiles were not correlated with dormancy levels, indicating that hormone contents were not associated with preharvest sprouting (PHS) susceptibility. Indole acetic acid (IAA) contents of mature seeds showed positive correlation with the germination index, but no other hormone. Response of embryo-half seeds to exogenous abscisic acid (ABA) indicates that ABA sensitivity is correlated with whole-seed germinability, which can be explained in part by genotypes of MOTHER OF FT AND TFL (MFT) allele modulating ABA signaling of wheat seeds. These results demonstrate that variation in wheat seed dormancy is attributable to ABA sensitivity of mature seeds, but not to ABA contents in developing seeds.


Characterizing the use of osteopathic manipulative medicine in the obstetric population by trimester and indications for use.
Osteopathic manipulative medicine (OMM) has been shown to successfully alleviate some pregnancy-related pain. However, most of the published data focuses on the third trimester and postpartum period or musculoskeletal indications. To explore OMM use among obstetrical providers and determine the frequency of use by trimester and by clinical indications across multiple types of women's healthcare practices in Southern and Central Maine. An anonymous, 43-item survey, presented in English, was emailed to 172 eligible providers (physicians, nurse practitioners, and certified nurse midwives with obstetrics privileges at one of two main delivery centers in southern and central Maine) via an encrypted database system in January 2018. Follow-up email reminders were sent weekly for three weeks. Questions addressed use of OMM for specific indications, knowledge of OMM, and perceived barriers use of OMM. The survey response rate was 73 of 172 (42%); 95% of respondents were physicians (n=69). Due to the low response rate of non-physicians, only data from physicians was included in the study. Data were summarized descriptively as frequencies (n [%]). The highest rates of OMM utilization were during the third trimester (35 [51.5%]) and postpartum (41 [60.3%]) periods, while the lowest rates of utilization were in the intrapartum (eight [11.9%]) and first trimester periods (26 [38.3%]). Osteopathic physicians (n=19) used OMM more frequently in the first, second, and third trimesters, as well as the intrapartum period (10 [52.6%]; 11 [57.9%]; 14 [73.7%]; and six [31.6%], respectively) compared with their allopathic physician (n=50) counterparts (nine [8%]; 15 [30%]; 21 [42%]; and two [4%], respectively). While osteopathic physicians reported higher frequencies of OMM use and referral for non-musculoskeletal indications such as constipation, edema, and nasal congestion (13 [68.4%]; 11 [57.9%]; 10 [52.6%], respectively), musculoskeletal complaints were the most frequently cited indication for OMM use among both osteopathic and allopathic physicians (low back, 67 [97.1%]; pelvis, 65 [94.2%]; coccyx, 50 [72.5%]; and head, 49 [71%]). These results suggest that more education is needed about OMM use in the obstetric population, particularly during early trimesters and the intrapartum period, as well as for visceral and lymphatic complaints of pregnancy.


Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.
No therapies have been shown to accelerate recovery or prevent fibrosis after acute kidney injury (AKI). In part, this is because most therapeutic candidates have to be given at the time of injury and the diagnosis of AKI is usually made too late for drugs to be efficacious. Strategies to enhance post-AKI repair represent an attractive approach to address this. Using a phenotypic screen in zebrafish, we identified 4-(phenylthio)butanoic acid (PTBA), which promotes proliferation of embryonic kidney progenitor cells (EKPCs), and the PTBA methyl ester UPHD25, which also increases postinjury repair in ischemia-reperfusion and aristolochic acid-induced AKI in mice. In these studies, a new panel of PTBA analogs was evaluated. Initial screening was performed in zebrafish EKPC assays followed by survival assays in a gentamicin-induced AKI larvae zebrafish model. Using this approach, we identified UPHD186, which in contrast to UPHD25, accelerates recovery and reduces fibrosis when administered several days after ischemia-reperfusion AKI and reduces fibrosis after unilateral ureteric obstruction in mice. UPHD25 and 186 are efficiently metabolized to the active analog PTBA in liver and kidney microsome assays, indicating both compounds may act as PTBA prodrugs in vivo. UPHD186 persists longer in the circulation than UPHD25, suggesting that sustained levels of UPHD186 may increase efficacy by acting as a reservoir for renal metabolism to PTBA. These findings validate use of zebrafish EKPC and AKI assays as a drug discovery strategy for molecules that reduce fibrosis in multiple AKI models and can be administered days after initiation of injury.


Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: results from a multicenter study in Italy.
Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs. By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p=0.002) and rs445114 (p=0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p=0.011), rs614367/11q13.3 (p=0.016) and rs1314913/14q24.1 (p<0.0001). Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p=0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p=0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p=0.041). In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers.


Enrichment procedure based on graphitized carbon black and liquid chromatography-high resolution mass spectrometry for elucidating sulfolipids composition of microalgae.
Microalgae have recently become a popular functional food due to their health benefits. Sulfolipids, a class of substances abundant in this matrix, have been reported to have interesting bioactivities, such as anti-carcinogenic activity. However, despite the potential interest in sulfolipids, a dedicated analytical method for their characterization is currently lacking but would significantly increase the coverage of sulfolipids with respect to the direct lipidomic analysis. To achieve this goal, in this work a procedure, based on graphitized carbon black solid phase extraction, was developed for clean-up and enrichment of sulfolipids (sulfoquinovosyldiacylglycerols and sulfoquinovosylmonoacylglycerols) and it was applied to spirulina (Arthrospira platensis) microalgae. A careful study of the solid phase extraction conditions was performed, first to maximize the recovery of reference standards, then to increase the total number of identified sulfolipids from the spirulina lipid extract. All samples were analysed by ultra-high performance liquid chromatography coupled to high resolution mass spectrometry and lipids were tentatively identified by Lipostar, for a reliable lipid structure assignment. The developed method was compared to the direct lipidomic analysis without enrichment, to establish the enrichment efficiency in terms of number of identifications. From the comparison, the enrichment procedure proved better and allowed the tentative identification of 199 sulfolipids, which is the largest number reported so far for the Arthrospira platensis species. The described method was validated in terms of precision, accuracy, recovery, limit of quantitation and detection for two sulfolipids. Finally, a relative lipid quantitation based on peak area was carried out on the microalgae sample, which indicated nine abundant sulfolipids as representing ca. 60% of sulfolipids in spirulina microalgae.


Facile access to large-scale, self-assembled, nacre-inspired, high-performance materials with tunable nanoscale periodicities.
Although advances have been reported to mimic the mechanically excellent structure of natural nacre, larger-scale applications are still limited due to time and energy-intensive preparation pathways. Herein, we demonstrate that simple high-shear homogenization of dispersions containing biobased high molecular weight sodium carboxymethyl cellulose (700 kg/mol, CMC) and natural sodium montmorillonite (MTM), serving as the soft energy-dissipating phase and reinforcing platelets, respectively, can be used to prepare large-area and thick films with well-aligned hard/soft nacre-mimetic mesostructure. During this process, core-shell nanoplatelets with intrinsic hard/soft structure form, which then self-assemble into a layered nanocomposite during water removal. The nanoscale periodicities of the alternating hard/soft layers can be precisely tuned by changing the ratio of CMC to MTM, which allows studying the evolution of mechanical properties as a function of the lamellar nanoscale periodicity and fractions of hard to soft material. Remarkable mechanical stiffness (25 GPa) and strength (320 MPa) can be obtained placing these materials among the top end of nacre-inspired materials reported so far. Mechanical homogenization also allows direct preparation of concentrated, yet homogeneous, gel-like dispersions of high nanoclay content, suited to doctor-blade large-area and thick films with essentially the same properties as films cast from dilute dispersions. In terms of functional properties, we report high-transparency, shape-persistent fire-blocking and the ability to surface-pattern via inkjet printing. Considering the simple, fully scalable, waterborne preparation pathway, and the use of nature-based components, we foresee applications as ecofriendly, bioinspired materials to promote sustainable engineering materials and novel types of functional barrier coatings and substrates.


Development of a new reproductive tissue cryopreservation clinical service for children: the Oxford programme.
This article describes the development of a new reproductive tissue cryopreservation clinical service for children at high risk of infertility in the NHS during times of severe financial constraints in the health service. A development plan with two phases was drawn up. Phase 1 restricted the service to childhood cancer patients referred to the Oxford Paediatric Oncology and Haematology Principle Treatment Centre. It was estimated that there would be 10 patients/year and used existing staff and facilities from paediatric oncology, surgery, anaesthetics radiology, pathology, psychology, teenage-young adult gynaecology, and an existing Human Tissue Authority tissue bank with a licence for storage of tissue under a Human Sector Licence. Phase 2 extended the service to include children and young adults across England, Wales and Ireland-patients from Scotland having access to a research programme in Edinburgh. The main challenge in phase 2 being resources and the need for patients to be able to be treated as close to home as safely as possible. The Oxford team developed information resources and eligibility criteria based on published best practice, referral and treatment pathways, multidisciplinary team meetings, a network of third party sites, and a dedicated case management and database. As the programme expanded, the Oxford team was able to justify to management the need for a dedicated theatre list. Patient feedback through questionnaires, qualitative work conducted as part of a Ph.D. thesis as well as direct patient stories and interviews in TV, and radio features underpins the positive impact the programme has on patients and their families. The Oxford Reproductive Cryopreservation programme delivers fertility preservation treatment to children and young adults at high risk of infertility safely, effectively and as close to home as possible. The onward view is to apply for national funding for this programme for recognition and sustainability.


Idiopathic pulmonary fibrosis in small cell lung cancer as a predictive factor for poor clinical outcome and risk of its exacerbation.
Lung cancer frequently co-exists with idiopathic interstitial pneumonia (IIP), which can be subdivided into idiopathic pulmonary fibrosis (IPF) and IIP other than IPF (other IIP). Although chemotherapy in small cell lung cancer (SCLC) patients with IIP may result in the exacerbation of IIP, these patients commonly receive chemotherapy. This study aimed to assess the risks and benefits of chemotherapy in SCLC patients with IIP. We retrospectively analyzed the medical records of 122 patients with SCLC who received chemotherapy. Patients with secondary interstitial lung disease (ILD) of known etiology were excluded. Eligible patients were divided into two groups: SCLC with and without IIP. The former group was subdivided into those with IPF and other IIP. Of the 47 (39.2%) SCLC patients with IIP, 20 had IPF and 27 had other IIP. The frequency of chemotherapy-induced ILD development or IIP exacerbation was higher in patients with IPF (40.0%) than in those with other IIP (3.7%) and non-IIP (1.4%). Logistic regression analysis demonstrated that ILD development or IIP exacerbation was independently associated with IPF (P = 0.007). Time to treatment failure (P < 0.001) and overall survival (P = 0.001) were different among the groups., Cox proportional hazard model revealed that IPF was independently associated with time to treatment failure (P = 0,017) and overall survival (P = 0.006). Other IIP had no impact on time to treatment failure or overall survival. Development of ILD or exacerbation of IIP independently reduced time to treatment failure and overall survival. Comorbid IPF can be an independent, negative prognostic indicator and at high risk of ILD development or IIP exacerbation in SCLC patients. Early diagnosis and intervention for chemotherapy-induced IIP exacerbation will be beneficial for SCLC patients with IPF, who need close monitoring for its onset.


Reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3' untranslated region of dengue virus type-2 RNA.
Sphingosine kinase 1 (SphK1) is a lipid kinase with important roles including regulation of cell survival. We have previously shown reduced SphK1 activity in cells with an established dengue virus type-2 (DENV-2) infection. In this study, we examined the effect of alterations in SphK1 activity on DENV-2 replication and cell death and determined the mechanisms of the reduction in SphK1 activity. Chemical inhibition or overexpression of SphK1 after established DENV-2 infection had no effect on infectious DENV-2 production, although inhibition of SphK1 resulted in enhanced DENV-2-induced cell death. Reduced SphK1 activity was observed in multiple cell types, regardless of the ability of DENV-2 infection to be cytopathic, and was mediated by a post-translational mechanism. Unlike bovine viral diarrhea virus, where SphK1 activity is decreased by the NS3 protein, SphK1 activity was not affected by DENV-2 NS3 but, instead, was reduced by expression of the terminal 396 bases of the 3' UTR of DENV-2 RNA. We have previously shown that eukaryotic elongation factor 1A (eEF1A) is a direct activator of SphK1 and here DENV-2 RNA co-localized and co-precipitated with eEF1A from infected cells. We propose that the reduction in SphK1 activity late in DENV-2-infected cells is a consequence of DENV-2 out-competing SphK1 for eEF1A binding and hijacking cellular eEF1A for its own replication strategy, rather than a specific host or virus-induced change in SphK1 to modulate viral replication. Nonetheless, reduced SphK1 activity may have important consequences for survival or death of the infected cell.


Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist.
SQ 29,548, [1S-[1 alpha,2 beta (5Z),3 beta,4 alpha]-7-[3-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid, and the racemic modification, +/- SQ 29,548, were identified as active inhibitors of human platelet aggregation induced by arachidonic acid, collagen, epinephrine (2 degrees phase) and the thromboxane A2 mimics, 9,11-azo prostaglandin (PG) H2 and 11,9-epoxymethano PGH2. SQ 29,548 did not inhibit aggregation induced by ADP, and it did not prevent PGD2 from inhibiting ADP-induced platelet aggregation. Inhibition of platelet function by +/- SQ 29,548 was not associated with inhibition of cyclooxygenase or thromboxane synthetase or with changes in platelet cyclic AMP. In guinea-pig trachea and rat aorta, +/- SQ 29,548 competitively antagonized the activity of 9,11-azo PGH2 with pA2 values of 7.8 and 8.4, respectively. The chiral compound, SQ 29,548 competitively antagonized contractions of guinea-pig tracheal spirals caused by 11,9-epoxymethano PGH2 with a pA2 value of 9.1. The +/- SQ 29,548 competitively antagonized tracheal responses to 11,9-epoxymethano PGH2 and PGD2 with pA2 values of 8.2 and 8.3, respectively, indicating that PGD2 and the thromboxane A2 mimic probably act at the same receptor in guinea-pig tracheal smooth muscle. Contractions of guinea-pig tracheal spirals induced by PGE2 were not antagonized, and those caused by PGF2 alpha were only partially antagonized by +/- SQ 29,548. The +/- SQ 29,548 also significantly inhibited the aorta contracting activity of 11,9-epoxymethano PGH2 (pA2 = 9.1) and thromboxane A2 released from perfused guinea-pig lungs upon arachidonic acid challenge.(ABSTRACT TRUNCATED AT 250 WORDS)


Dependence of viscosity of suspensions of ceramic nanopowders in ethyl alcohol on concentration and temperature.
: This work presents results of measurements of viscosity of suspensions including yttrium oxide (Y2O3), yttrium aluminum garnet (Y3Al5O12) and magnesium aluminum spinel (MgAl2O4) nanopowders in ethanol. Nanoparticles used in our research were either commercially available (Baikowski) or nanopowders newly developed in the Institute of Ceramics and Building Materials in Warsaw, Poland. The study was conducted in a wide range of shear rates (0.01 to 2,000 s-1) and temperature interval from -15°C to 20°C. A Haake Mars 2 rheometer from Thermo Fisher, Germany, was used in the Biophysics Laboratory at Rzeszów University of Technology. Most of the samples show a non-Newtonian behaviour. It was confirmed with a Rheo-NMR system from Bruker that 10% by weight of Y2O3 suspension is a non-Newtonian fluid. In this work, we also report an unexpected behaviour of the viscosity of some samples (Y2O3 and Y3Al5O12) due to sedimentation effect.


Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative, ECMO and hypothermia patients.
Adequate postoperative analgesia in pediatric patients in the intensive care unit (ICU) matters, since untreated pain is associated with negative outcomes. Compared to routine postoperative patients, children undergoing hypothermia (HT) or extracorporeal membrane oxygenation (ECMO), or recovering after cardiac surgery likely display non-maturational differences in pharmacokinetics (PK) and pharmacodynamics (PD). These differences warrant additional dosing recommendations to optimize pain treatment. Areas covered: Specific populations within the ICU will be discussed with respect to expected variations in PK and PD for various analgesics. We hereby move beyond maturational changes and focus on why PK/PD may be different in children undergoing HT, ECMO or cardiac surgery. We provide a stepwise manner to develop PK-based dosing regimens using population PK approaches in these populations. Expert opinion: A one-dose to size-fits-all for analgesia is suboptimal, but for several commonly used analgesics the impact of HT, ECMO or cardiac surgery on average PK parameters in children is not yet sufficiently known. Parameters considering both maturational and non-maturational covariates are important to develop population PK-based dosing advices as part of a strategy to optimize pain treatment.


The development of infants' use of novel verbal information when reasoning about others' actions.
How sophisticated are infants at using novel verbal information when reasoning about which of two objects an agent is likely to select? The present research examined the development of infants' ability to interpret a change from one novel word to another as signaling a possible change in which object the agent would choose next. In three experiments, 7- and 12-month-olds were familiarized to an event in which they heard a novel word ("A dax!") and then saw an agent reach for one of two distinct objects. During test, the infants heard a different novel word ("A pilk!") and then saw the agent grasp the same object or the other object. At 7 months, infants ignored the change in word and expected the agent to continue reaching for the same object. At 12 months, however, infants attended to the change in word: They realized that it signaled a possible change in the agent's upcoming actions, though they were unable to form a specific expectation about what these new actions might be, most likely due to their limited mutual-exclusivity assumption. Control conditions supported these interpretations. Together, these results suggest that by 12 months of age, infants understand not only that words are selected for communicative purposes, but also that a change from one novel word to another may signal a change in an agent's upcoming actions.


Legal and Ethical Aspects of Pain Management.
In this manuscript we presented legal and ethical aspects of pain management. Pain is a global public health problem because the burden of acute and chronic pain is considerable and is continuously increasing. It has been postulated that pain management is a fundamental human right, and that health systems are obliged to ensure universal access to pain management services. The suggestion that pain management is a right was fuelled by ample evidence about inadequate treatment of pain. Undertreatment and underprescribing in the context of pain can potentially have serious legal consequences, including charges about negligence, elder abuse, manslaughter and euthanasia. Multiple international declarations by professional societies have outlined pain management as a core ethical duty in medicine. Therefore, healthcare professionals need to be aware of multiple facets of pain-related ethics, including appraisal of patient's decision-making capacity. The worldwide opioid crisis also calls for careful consideration of specific ethical issues. Finally, healthcare workers need to be aware of the the risks associated with promoting pain management as a human right because patients and their caretakers can mistakenly perceive that they have right to total analgesia. Patients do have the right to pain management, but patient rights have limits, which may interfere with other competing rights, and also rights of their physicians. Treatment of pain must be medically, ethically and economically justified. Healthcare workers have an obligation to continuously improve their knowledge about pain management, including medical, legal and ethical aspects of pain.


A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex.
The mammalian prefrontal cortex comprises a set of highly specialized brain areas containing billions of cells and serves as the centre of the highest-order cognitive functions, such as memory, cognitive ability, decision-making and social behaviour. Although neural circuits are formed in the late stages of human embryonic development and even after birth, diverse classes of functional cells are generated and migrate to the appropriate locations earlier in development. Dysfunction of the prefrontal cortex contributes to cognitive deficits and the majority of neurodevelopmental disorders; there is therefore a need for detailed knowledge of the development of the prefrontal cortex. However, it is still difficult to identify cell types in the developing human prefrontal cortex and to distinguish their developmental features. Here we analyse more than 2,300 single cells in the developing human prefrontal cortex from gestational weeks 8 to 26 using RNA sequencing. We identify 35 subtypes of cells in six main classes and trace the developmental trajectories of these cells. Detailed analysis of neural progenitor cells highlights new marker genes and unique developmental features of intermediate progenitor cells. We also map the timeline of neurogenesis of excitatory neurons in the prefrontal cortex and detect the presence of interneuron progenitors in early developing prefrontal cortex. Moreover, we reveal the intrinsic development-dependent signals that regulate neuron generation and circuit formation using single-cell transcriptomic data analysis. Our screening and characterization approach provides a blueprint for understanding the development of the human prefrontal cortex in the early and mid-gestational stages in order to systematically dissect the cellular basis and molecular regulation of prefrontal cortex function in humans.


Mapping single-cell data to reference atlases by transfer learning.
Large single-cell atlases are now routinely generated to serve as references for analysis of smaller-scale studies. Yet learning from reference data is complicated by batch effects between datasets, limited availability of computational resources and sharing restrictions on raw data. Here we introduce a deep learning strategy for mapping query datasets on top of a reference called single-cell architectural surgery (scArches). scArches uses transfer learning and parameter optimization to enable efficient, decentralized, iterative reference building and contextualization of new datasets with existing references without sharing raw data. Using examples from mouse brain, pancreas, immune and whole-organism atlases, we show that scArches preserves biological state information while removing batch effects, despite using four orders of magnitude fewer parameters than de novo integration. scArches generalizes to multimodal reference mapping, allowing imputation of missing modalities. Finally, scArches retains coronavirus disease 2019 (COVID-19) disease variation when mapping to a healthy reference, enabling the discovery of disease-specific cell states. scArches will facilitate collaborative projects by enabling iterative construction, updating, sharing and efficient use of reference atlases.


2-Nitropyrrole cross-coupling enables a second generation synthesis of the heronapyrrole antibiotic natural product family.
The heronapyrroles are a family of antibiotic natural products containing the rare 2-nitropyrrole motif. We report here a second generation total synthesis that circumvents problems of selective pyrrole nitration and alkene formation that limited the utility of previous approaches. Stille sp3-sp2 cross coupling of a novel 2-nitropyrrole fragment was developed to install the key C7,8 olefin with complete regiochemical control. An unusual Hunsdiecker-type decarboxylative halogenation was also identified, providing access to the complex vinyl stannane coupling partners required for formation of the natural product.


Does obesity affect intraocular pressure during laparoscopic surgery?
Obesity is accepted as a risk factor for postoperative visual loss due to possible perioperative elevations in intraocular pressure. This study investigated whether intraocular pressure changes differed according to the body mass index of patients undergoing laparoscopic cholecystectomy. Thirty obese and 30 non-obese patients (body mass index cutoff point, 30 kg/m2) undergoing laparoscopic cholecystectomy were enrolled. Intraocular pressure was measured at baseline (T1), after induction of anesthesia (T2), 5 min after initiation of mechanical ventilation (T3), 5 min after pneumoperitoneum inflation (T4), 5 min after the patient was placed in the head-up position (T5), 5 min after deflation with the patient in the supine position (T6), and 5 min after extubation with the patient in the 30 degrees upright position (T7). The mean intraocular pressure values of the obese and non-obese groups were similar at T1 (16.60 ± 2.93 and 16.87 ± 2.85 mmHg respectively). In both groups, intraocular pressure decreased following initiation of anesthesia (T2) (p<0.001, T2 vs T1). Intraocular pressure values at T7 were significantly higher than those at T1 in the obese (20.38 ± 4.11 mmHg, p<0.001) and non-obese (20.93 ± 4.37 mmHg, p<0.01) groups. There were no significant differences between intraocular pressure values of obese and non-obese patients at any time point. Obesity is not correlated with intraocular pressure during short laparoscopic surgeries with the patient in the head-up position.


The hydrodynamic regime drives flow reversals in suction-feeding larval fishes during early ontogeny.
Fish larvae are the smallest self-sustaining vertebrates. As such, they face multiple challenges that stem from their minute size, and from the hydrodynamic regime in which they dwell. This regime, of intermediate Reynolds numbers, was shown to affect the swimming of larval fish and impede their ability to capture prey. Prey capture is impeded because smaller larvae produce weaker suction flows, exerting weaker forces on the prey. Previous observations on feeding larvae also showed prey exiting the mouth after initially entering it (hereafter 'in-and-out'), although the mechanism causing such failures had been unclear. In this study, we used numerical simulations to investigate the hydrodynamic mechanisms responsible for the failure to feed caused by this in-and-out prey movement. Detailed kinematics of the expanding mouth during prey capture by larval Sparus aurata were used to parameterize age-specific numerical models of the flows inside the mouth. These models revealed that for small larvae which expand their mouth slowly, fluid entering the mouth cavity is expelled through the mouth before it is closed, resulting in flow reversal at the orifice. This relative efflux of water through the mouth was >8% of the influx through the mouth for younger ages. However, similar effluxes were found when we simulated slow strikes by larger fish. The simulations can explain the observations of larval fish failing to feed because of the in-and-out movement of the prey. These results further highlight the importance of transporting the prey from the gape deeper into the mouth cavity in determining suction-feeding success.


Active Bragg angle compensation for shaping ultrafast mid-infrared pulses.
Active Bragg angle compensation is demonstrated for shaping ultrafast, mid-infrared pulses. The effects of angular dispersion introduced by the acousto-optic modulator on the temporal characteristics of the pulse are measured by autocorrelating the output from the pulse shaper. The time duration of the output pulses were measured to be thirty times shorter than pulses produced with a constant frequency amplitude waveform. This approach acts to mitigate angular dispersion in Bragg-regime acousto-optic devices, thus affording the ability to shape ultrafast pulses of light with broad bandwidths that are centered at mid-IR wavelengths and longer.


The nature of expertise in fingerprint matching: experts can do a lot with a little.
Expert decision making often seems impressive, even miraculous. People with genuine expertise in a particular domain can perform quickly and accurately, and with little information. In the series of experiments presented here, we manipulate the amount of "information" available to a group of experts whose job it is to identify the source of crime scene fingerprints. In Experiment 1, we reduced the amount of information available to experts by inverting fingerprint pairs and adding visual noise. There was no evidence for an inversion effect-experts were just as accurate for inverted prints as they were for upright prints-but expert performance with artificially noisy prints was impressive. In Experiment 2, we separated matching and nonmatching print pairs in time. Experts were conservative, but they were still able to discriminate pairs of fingerprints that were separated by five-seconds, even though the task was quite different from their everyday experience. In Experiment 3, we separated the print pairs further in time to test the long-term memory of experts compared to novices. Long-term recognition memory for experts and novices was the same, with both performing around chance. In Experiment 4, we presented pairs of fingerprints quickly to experts and novices in a matching task. Experts were more accurate than novices, particularly for similar nonmatching pairs, and experts were generally more accurate when they had more time. It is clear that experts can match prints accurately when there is reduced visual information, reduced opportunity for direct comparison, and reduced time to engage in deliberate reasoning. These findings suggest that non-analytic processing accounts for a substantial portion of the variance in expert fingerprint matching accuracy. Our conclusion is at odds with general wisdom in fingerprint identification practice and formal training, and at odds with the claims and explanations that are offered in court during expert testimony.


Pulmonary infections in the returned traveller.
Pulmonary infections in the returned traveller are a common presentation. A wide variety of infections may present with pulmonary symptoms. It is important for clinicians to differentiate the cause of these symptoms. The risk of contracting certain travel-related pulmonary diseases depends on travel destination, length of stay, activities undertaken and co-morbidities. Some pathogens are found worldwide, whilst others are related to specific locations. This review article will discuss the approach to diagnosing and treating pulmonary infections in the returned traveller.


Seconds for care: evaluation of five health supervision visit topics using a new method.
To describe content and time devoted to 5 preventive health topics during health supervision visits (HSVs). New software (Pediatric Health Supervision Timer Software, PHSTS) run in handheld computers was developed to record time and content while observing HSVs. 185 visits of children ages 2 to 10 years (58% Medicaid/self-pay) to 28 clinicians were observed at 6 practices. Parents were surveyed on demographics. Data on times and actions related to assessments and counseling of growth, diet, physical activity, safety, and tobacco were collected using PHSTS. The PHSTS method was well accepted (89% participation rate). Most visits included assessment/counseling for diet (95%), growth (84%), and safety (71%) and less often physical activity (52%) and tobacco (43%). Discussions occurring were short (median time [25th to 75th percentiles]: diet, 42 seconds [21 to 85 seconds]; safety, 24 seconds [11 to 61 seconds]; growth, 15 seconds [7 to 31 seconds]; physical activity, 12 seconds [5 to 22 seconds]; and tobacco, 3 seconds [2 to 6 seconds]). Clinicians expressed concerns about child weight during 18 of 33 visits (55%) that included an obese child and provided tobacco-related counseling at 6 of 30 visits (20%) that included a child living with a smoker. The PHSTS method was successfully used. Our observations found that limited time was devoted to assessment and counseling on key health topics during HSVs.


Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids.
Cancer cell lines grown as two-dimensional (2D) cultures have been an essential model for studying cancer biology and anticancer drug discovery. However, 2D cancer cell cultures have major limitations, as they do not closely mimic the heterogeneity and tissue context of in vivo tumors. Developing three-dimensional (3D) cell cultures, such as multicellular tumor spheroids, has the potential to address some of these limitations. Here, we combined a high-throughput gene expression profiling method with a tumor spheroid-based drug-screening assay to identify context-dependent treatment responses. As a proof of concept, we examined drug responses of quiescent cancer cells to oxidative phosphorylation (OXPHOS) inhibitors. Use of multicellular tumor spheroids led to discovery that the mevalonate pathway is upregulated in quiescent cells during OXPHOS inhibition, and that OXPHOS inhibitors and mevalonate pathway inhibitors were synergistically toxic to quiescent spheroids. This work illustrates how 3D cellular models yield functional and mechanistic insights not accessible via 2D cultures.


WTP and WTA: do people think differently?
Contingent valuation (CV) studies in health care have used the willingness to pay (WTP) approach, to the virtual exclusion of willingness to accept (WTA). Outside the health care field, disparities between WTP and WTA values have been observed. Were such disparities to be demonstrated for health care technologies, the conventional assumption of a linear cost-effectiveness plane would be invalidated. This paper employs data derived from interviews with users of the UK's paediatric cochlear implantation (PCI) programme based in Nottingham (i) to assess the feasibility of estimating WTA for the potential discontinuation of an existing technology, and (ii) to investigate any WTA-WTP disparity which might be revealed. Only one-third of subjects providing WTP values were willing and able to offer a corresponding WTA value. Our qualitative data revealed that modes of response differed between the two valuation approaches. In particular, the presumption of fungibility of the health care intervention was a far more serious obstacle to completing the WTA task than it was for WTP. Among those prepared to offer values under both approaches, mean WTA was approximately four times mean WTP. Until more health studies are conducted, it remains unclear whether or not the findings are specific both to the intervention and to the elicitation format.


The clinical translation gap in child health exercise research: a call for disruptive innovation.
In children, levels of play, physical activity, and fitness are key indicators of health and disease and closely tied to optimal growth and development. Cardiopulmonary exercise testing (CPET) provides clinicians with biomarkers of disease and effectiveness of therapy, and researchers with novel insights into fundamental biological mechanisms reflecting an integrated physiological response that is hidden when the child is at rest. Yet the growth of clinical trials utilizing CPET in pediatrics remains stunted despite the current emphasis on preventative medicine and the growing recognition that therapies used in children should be clinically tested in children. There exists a translational gap between basic discovery and clinical application in this essential component of child health. To address this gap, the NIH provided funding through the Clinical and Translational Science Award (CTSA) program to convene a panel of experts. This report summarizes our major findings and outlines next steps necessary to enhance child health exercise medicine translational research. We present specific plans to bolster data interoperability, improve child health CPET reference values, stimulate formal training in exercise medicine for child health care professionals, and outline innovative approaches through which exercise medicine can become more accessible and advance therapeutics across the broad spectrum of child health.


A nested case-control study of dietary factors and the risk of incident cytological abnormalities of the cervix.
Several earlier case-control studies reported inverse associations of cervical squamous intraepithelial lesions (SIL) with high dietary or biomarker levels of carotenoids, folate, and vitamins C and E. However, most studies did not measure the primary causal factor, cancer-associated genital human papillomaviruses (HPV), now detected by sensitive viral DNA tests. This nested case-control study assessed whether high dietary intakes of these nutrients, plus zinc and vitamin A, reduced SIL risk in cancer-associated HPV DNA-positive women. Using a 60-item food-frequency questionnaire, nutrient estimates were obtained for 33 incident cases with high-grade lesions, 121 with low-grade lesions, 97 with equivocal SIL, and 806 cytologically normal controls sampled from a large prospective cohort study. Baseline cervicovaginal lavages were tested for HPV DNA by the polymerase chain reaction. Among DNA-positive cases (n = 68) and controls (n = 69), age-adjusted odds ratios (ORs) of SIL in the highest vs. the lowest nutrient quartiles were 1.4 [95% confidence interval (CI) = 0.5-4.2] for vitamin A, 0.6 (CI = 0.2-2.0) for beta-carotene, 1.3 (CI = 0.4-3.6) for vitamin C, 1.0 (CI = 0.4-3.6) for vitamin E, 0.7 (CI = 0.3-2.1) for folate, and 0.8 (CI = 0.3-2.2) for zinc. ORs in HPV DNA-negative women approximated 1.0, with the exception of vitamin E (OR = 0.5, CI = 0.3-0.9). These results do not support a protective role for the above nutrients against low-grade or equivocal SIL, which constituted the majority of diagnoses in this study.


Characterization of synonymous codon usage bias in the pseudorabies virus US1 gene.
In the present study, we examined the codon usage bias between pseudorabies virus (PRV) US1 gene and the US1-like genes of 20 reference alphaherpesviruses. Comparative analysis showed noticeable disparities of the synonymous codon usage bias in the 21 alphaherpesviruses, indicated by codon adaptation index, effective number of codons (ENc) and GC3s value. The codon usage pattern of PRV US1 gene was phylogenetically conserved and similar to that of the US1-like genes of the genus Varicellovirus of alphaherpesvirus, with a strong bias towards the codons with C and G at the third codon position. Cluster analysis of codon usage pattern of PRV US1 gene with its reference alphaherpesviruses demonstrated that the codon usage bias of US1-like genes of 21 alphaherpesviruses had a very close relation with their gene functions. ENc-plot revealed that the genetic heterogeneity in PRV US1 gene and the 20 reference alphaherpesviruses was constrained by G+C content, as well as the gene length. In addition, comparison of codon preferences in the US1 gene of PRV with those of E. coli, yeast and human revealed that there were 50 codons showing distinct usage differences between PRV and yeast, 49 between PRV and human, but 48 between PRV and E. coli. Although there were slightly fewer differences in codon usages between E.coli and PRV, the difference is unlikely to be statistically significant, and experimental studies are necessary to establish the most suitable expression system for PRV US1. In conclusion, these results may improve our understanding of the evolution, pathogenesis and functional studies of PRV, as well as contributing to the area of herpesvirus research or even studies with other viruses.


The suitability of an uncemented hydroxyapatite coated (HAC) hip hemiarthroplasty stem for intra-capsular femoral neck fractures in osteoporotic elderly patients: the Metaphyseal-Diaphyseal Index, a solution to preventing intra-operative periprosthetic fracture.
This study will seek to identify a measurable radiographic index, the Metaphyseal-Diaphyseal Index (MDI) score to determine whether intra-operative fracture in osteoporotic bone can be predicted.A 5 year prospective cohort of 560 consecutive patients, undergoing hemiarthroplasty (cemented or uncemented), was evaluated. A nested case-control study to determine risk factors affecting intra-operative fracture was carried out. The Vancouver Classification was used to classify periprosthetic fracture. The MDI score was calculated using radiographs from the uncemented group. As a control (gold standard), Yeung et al's Canal Bone Ratio (CBR) score was also calculated. From this, a receiver operating characteristic (ROC) curve was formulated for both scores and area under the curve (AUC) compared. Intra and inter-observer correlations were determined. Cost analysis was also worked out for adverse outcomes. Four hundred and seven uncemented and one hundred and fifty-three cemented stems were implanted. The use of uncemented implants was the main risk factor for intra-operative periprosthetic fracture. Sixty-two periprosthetic fractures occurred in the uncemented group (15.2%), nine occurred in the cemented group (5.9%), P < 0.001. The revision rate for sustaining a periprosthetic fracture (uncemented group) was 17.7%, P < 0.001 and 90 day mortality 19.7%, P < 0.03. MDI's AUC was 0.985 compared to CBR's 0.948, P < 0.001. The MDI score cut-off to predict fracture was 21, sensitivity 98.3%, specificity 99.8%, positive predictive value 90.5% and negative predictive value 98%. Multivariate regression analysis ruled out any other confounding factors as being significant. The intra and inter-observer Pearson correlation scores were r = 0.99, P < 0.001. JRI uncemented hemiarthroplasty has a significantly higher intra-operative fracture rate. We recommend cemented arthroplasty for hip fractures. We propose a radiographic system that may allow surgeons to select patients who are good candidates for uncemented arthroplasty, but it needs prospective validation.


Honouring the donor: in death and in life.
Elective ventilation (EV) is ventilation-not to save a patient's life, but with the expectation that s/he will die-in the hope that organs can be retrieved in the best possible state. The arguments for doing such a thing rest on the value of the lives being saved by the donated organs, maximally honouring the donor's wishes where the patient can be reasonably thought to wish to donate, and a general principle in favour of organ donation where possible as an expression of human solidarity. Arguments against include difficulties surrounding the patient's consent to donation (including the risk of them surviving in an unacceptably bad state), the possibility of changing our perception of organ donation and care in dying, and the moral distress potentially caused to intensive care unit (ICU) staff involved in EV. EV can occur before or after the patient is declared dead and it is EV before the declaration of death (EVb) that occasions the ethical worries. I argue that when we acknowledge the tragedy involved, attend sensitively to the grief proper to human death, and ensure that we are not working in an ethical and legal climate that increases the likelihood of inadvertent survival in an unacceptably bad state, EVb is ethically defensible.


Analysis of monoaminergic genes, childhood abuse, and dimensions of psychopathy.
Psychopathy is a multidimensional construct characterized by an interpersonally manipulative and emotionally detached personality profile that differentiates it from other antisocial syndromes. Previous research with youth has linked the long allele of the serotonin transporter gene in the presence of environmental stress with the interpersonal and affective traits of psychopathy, but these relationships have yet to be examined in relation to adult psychopathy. Consequently, we examined how serotonin transporter (5-HTTLPR) polymorphisms, monoamine oxidase-A (MAO-A) variants, and childhood abuse measured with the Childhood Trauma Questionnaire relate to dimensions of psychopathy in a forensic sample of 237 men with elevated levels of environmental adversity. We found that the emotional deficits characterizing the affective factor of psychopathy, as measured by the Psychopathy Checklist: Screening Version, were highest among carriers of the 5-HTT long allele. Furthermore, the impulsive and irresponsible lifestyle features of psychopathy were higher among low-activity than high-activity MAO-A carriers. These genetic effects were unexpectedly not moderated by a history of childhood abuse. Results provide evidence on the molecular genetics correlates of psychopathic traits in adulthood, relationships that should be investigated further in future research.


Reproductive effects of 4-vinylcyclohexene in Swiss mice assessed by a continuous breeding protocol.
4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene, was evaluated for reproductive toxicity in Swiss (CD-1) mice using the continuous breeding protocol (NTP, 1989). VCH in corn oil was administered by gavage at doses of 0, 100, 250, and 500 mg/kg/day to animals that were housed in same sex pairs for 1 week and then cohabited in breeding pairs for 14 weeks. During cohabitation, newborn litters were euthanized immediately after evaluation on postnatal Day (PND) 0. Litters born after Week 15 were reared until PND 21, when all F0 animals and low- and mid-dose F1 weanlings were humanely killed without a necropsy. At PND 74 +/- 10, control and high-dose F1 animals were cohabited within groups for 1 week and necropsied after delivery of the litters. In F0 breeding pairs, VCH did not affect measures of reproductive competence, including initial fertility, litters per pair, live litter size, or the proportion of pups born alive. Pup weight was decreased (4%) in the high-dose group relative to controls. High-dose F0 females exhibited slight general toxicity, manifested as an 8% difference in body weight compared to controls. VCH did not adversely affect preweaning growth or survival in the F1 generation. VCH had no effect on the reproductive competence of the F1 generation. High-dose F1 adult males and females had decreased body weight. At necropsy, increased relative liver weight (males 9% and females 8%) and sperm motility (although not thought to be biologically significant) were observed in the 500 mg/kg VCH group.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of T cell receptor testing in lymphoid neoplasms: results of a multicenter study of 29 extracted DNA and paraffin-embedded samples.
To evaluate current diagnostic methods used for the evaluation of T cell receptor (TCR) gene rearrangements, 24 different laboratories analyzed 29 lymphoid neoplasm samples of extracted DNA and paraffin-embedded tissue and were asked to complete a technical questionnaire related to the testing. Participating laboratories performed Southern blot and polymerase chain reaction (PCR) testing for rearrangements of the TCRbeta chain gene and PCR for the TCRgamma chain gene rearrangements. Of 14 laboratories performing TCRbeta Southern blot analysis, there was complete agreement in 10 of 14 cases, with some false negative results obtained in 4 cases. No false positive results were obtained by Southern blot analysis. TCRbeta PCR analysis was only performed by two laboratories, and only 47.1% of positive samples were detected. Twenty-one laboratory results were obtained for TCRgamma PCR. This method showed an overall detection rate of 77.9% for T cell gene rearrangements with a 4.1% false positive rate, as compared to both TCRgamma Southern blot analysis results and immunophenotyping. The detection rate for TCRgamma PCR, however, significantly differed when extracted DNA samples from frozen tissue were compared to paraffin-embedded tissue (85.4% versus 65.9%; P = 0.0005). Significant differences in true positive results were obtained when laboratories using primers directed against multiple TCRgamma variable regions (V1-8 plus one to three other primer sets) were compared to laboratories that used only a single set of TCR primers directed against the V1-8 (P < 0.0001). Other technical factors significantly affecting results were also identified. These findings provide useful data on the current state of diagnostic TCR testing, highlight the risk of false negative results for TCR testing directed against only portions of the TCRgamma gene, and identify limitations of testing of paraffin-embedded tissues in some laboratories.


In California, not-for-profit hospitals spent more operating expenses on charity care than for-profit hospitals spent.
In exchange for sizable tax exemptions, not-for-profit hospitals must engage in activities that meet the Internal Revenue Service's community benefit standard. The provision of charity care-free care to those unable to pay-can help meet that standard. Bad debt, the other form of uncompensated care, cannot be used to meet the standard, although Medicaid shortfalls can. However, the ACA lacks guidelines for providing charity care, and federal law sets no minimum requirements for community benefit activities. Using data from California, we examined whether the levels of charity and uncompensated care provided differed across general acute care hospitals by profit status and other characteristics during 2011-13. The mean proportion of total operating expenses spent on charity care differed significantly between not-for-profit (1.9 percent) and for-profit hospitals (1.4 percent), in contrast to the mean proportion spent on uncompensated care. Both types of spending varied widely across hospitals. Policy makers should consider measures that remove disincentives to meeting the persistent considerable need for charity care-for example, increasing supports to offset rising Medicaid shortfalls resulting from program expansion-and facilitate the tracking of ACA impacts on the distribution of charity care and uncompensated care delivery.


Pharmacists' satisfaction with their work: Analysis of an alumni survey.
The level of job satisfaction among practicing pharmacists is important because it has been found to affect job performance and employee turnover. The Swedish pharmacy market has undergone major changes in recent years, and little is known about pharmacists' job satisfaction. The objective of this study was to investigate the level of job satisfaction and associated factors among graduates from the web-based pharmacy programs at Umeå University. Job satisfaction of pharmacists was measured as part of an alumni survey conducted with those who graduated from the pharmacy programmes between 2006 and 2014. Data analysis included descriptive statistics, and logistic regression was used to explore factors affecting job satisfaction. The total number of graduates who completed the survey was 222 (response rate 43%.) The majority of respondents were female (95%), and most were employed at a community pharmacy (85%). The mean age was 39.7 years. The majority of graduates (91%) were satisfied with their job "most of the time" or "all of the time", and 87% of the respondents would "definitely" or "maybe" choose the same career again. The multivariate analysis showed that increasing years in the current position (OR: 0.672 (0.519-0.871)) was associated with lower job satisfaction. Older age (OR: 1.123 (1.022-1.234)), the perception that the knowledge and skills acquired during university education is useful in the current job (OR: 4.643 (1.255-17.182)) and access to continuing professional development (OR: 9.472 (1.965-45.662)) were associated with higher job satisfaction. Most graduates from the web-based pharmacy programmes were satisfied with their current job. Access to continuing professional development seems to be important for the level of job satisfaction among pharmacists.


Levels of acute phase proteins remain stable after ischemic stroke.
Inflammation and inflammatory biomarkers play an important role in atherosclerosis and cardiovascular disease. Little information is available, however, on time course of serum markers of inflammation after stroke. First ischemic stroke patients > or =40 years old had levels of high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), and fibrinogen measured in plasma samples drawn at 1, 2, 3, 7, 14, 21 and 28 days after stroke. Levels were log-transformed as needed, and parametric and non-parametric statistical tests were used to test for evidence of a trend in levels over time. Levels of hsCRP and SAA were also compared with levels in a comparable population of stroke-free participants. Mean age of participants with repeated measures (n = 21) was 65.6 +/- 11.6 years, and 13 (61.9%) were men, and 15 (71.4%) were Hispanic. Approximately 75% of patients (n = 15) had mild strokes (NIH Stroke Scale score 0-5). There was no evidence of a time trend in levels of hsCRP, SAA, or fibrinogen for any of the markers during the 28 days of follow-up. Mean log(hsCRP) was 1.67 +/- 1.07 mg/L (median hsCRP 6.48 mg/L) among stroke participants and 1.00 +/- 1.18 mg/L (median 2.82 mg/L) in a group of 1176 randomly selected stroke-free participants from the same community (p = 0.0252). Levels of hsCRP are higher in stroke patients than in stroke-free subjects. Levels of inflammatory biomarkers associated with atherosclerosis, including hsCRP, appear to be stable for at least 28 days after first ischemic stroke.


FusionCancer: a database of cancer fusion genes derived from RNA-seq data.
Fusion genes are chimeric results originated from previous separate genes with aberrant functions. The resulting protein products may lead to abnormal status of expression levels, functions and action sites, which in return may cause the abnormal proliferation of cells and cancer development. With the emergence of next-generation sequencing technology, RNA-seq has spurred gene fusion discovery in various cancer types. In this work, we compiled 591 recently published RNA-seq datasets in 15 kinds of human cancer, and the gene fusion events were comprehensively identified. Based on the results, a database was developed for gene fusion in cancers (FusionCancer), with the attempt to provide a user-friendly utility for the cancer research community. A flexible query engine has been developed for the acquisition of annotated information of cancer fusion genes, which would help users to determine the chimera events leading to functional changes. FusionCancer can be accessible at the following hyperlink website: http://donglab.ecnu.edu.cn/databases/FusionCancer/ To the best of our knowledge, FusionCancer is the first comprehensive fusion gene database derived only from cancer RNA-seq data.


The Calcineurin Inhibitor Tacrolimus Specifically Suppresses Human T Follicular Helper Cells.
T follicular helper (Tfh) cells are key players in the production of antibody-producing B cells via the germinal center reaction. Therapeutic strategies targeting Tfh cells are important where antibody formation is implicated in disease, such as transplant rejection and autoimmune diseases. We investigated the impact of the immunosuppressive agent tacrolimus on human Tfh cell differentiation and function in transplant recipients. Paired blood and lymph node (LN) samples were obtained from 61 transplant recipients immediately prior to organ implantation. Living-donor recipients received a week of tacrolimus prior to kidney transplantation. Deceased-donor recipients served as controls, as tacrolimus was not administered until after the transplant operation. Flow cytometry was used to compare LN and circulating cell subsets. The calcineurin inhibitor (CNIs) tacrolimus specifically suppresses both LN Tfh cells and circulating Tfh cells, but not their regulatory counterparts or other CD4 T cell subsets. Our findings suggest that CNIs may have a more important role in the prevention of antibody formation than previously understood and, therefore, have potential for antibody-associated conditions in which aberrant Tfh function has been implicated in disease.


Congenital subaxial cervical subluxation presenting as a bilateral Erb's palsy: surgical management, rehabilitation, and outcome.
Subaxial spine injuries during infancy are uncommon. We present the case of an infant referred to our brachial plexus clinic with proximal weakness of both arms noted immediately following a complicated breech delivery. Nerve conduction studies were consistent with bilateral proximal upper plexus injury; however, radiological evaluation revealed a C4-C5 subluxation and MRI features of bilateral C5 root avulsions. He was immobilized in a cervical-body orthosis and underwent open reduction and posterior C4-C5-C6 fixation at 10 weeks age using luque rods, sublaminar wires, and rib graft. The spine was immobilized in a custom molded cervicothoracic brace for a total of 3 months, and a home exercise program prescribed. Follow-up radiographic evaluation showed good posterior bony fusion by 2 months but persistent bilateral proximal upper limb weakness with reduced compound motor action potential (CMAP) amplitudes of the axillary and musculocutaneous nerves. Bilateral supraclavicular exploration and C5 root neurotization using the ipsilateral C7 nerve roots were performed at 7 months of age. Voluntary biceps activity followed by voluntary external rotation with gravity eliminated was noted within the next 2-3 months. He progressed to develop near normal motor control of bilateral upper limbs within 1 year. We wish to report this rare entity and our favorable outcome using a strategy of early spinal stabilization and neurotization repair to restore function following proximal nerve root injury.


Signaling pathways regulating Golgi structure and function.
At the end of the cell division cycle, organelles must be equally distributed to two daughter cells. This includes the many stacks of the Golgi apparatus. Several kinases have been implicated in regulating Golgi disassembly during mitosis, but much about this process remains obscure.


The ecology and evolution of animal medication: genetically fixed response versus phenotypic plasticity.
Animal medication against parasites can occur either as a genetically fixed (constitutive) or phenotypically plastic (induced) behavior. Taking the tritrophic interaction between the monarch butterfly Danaus plexippus, its protozoan parasite Ophryocystis elektroscirrha, and its food plant Asclepias spp. as a test case, we develop a game-theory model to identify the epidemiological (parasite prevalence and virulence) and environmental (plant toxicity and abundance) conditions that predict the evolution of genetically fixed versus phenotypically plastic forms of medication. Our model shows that the relative benefits (the antiparasitic properties of medicinal food) and costs (side effects of medicine, the costs of searching for medicine, and the costs of plasticity itself) crucially determine whether medication is genetically fixed or phenotypically plastic. Our model suggests that animals evolve phenotypic plasticity when parasite risk (a combination of virulence and prevalence and thus a measure of the strength of parasite-mediated selection) is relatively low to moderately high and genetically fixed medication when parasite risk becomes very high. The latter occurs because at high parasite risk, the costs of plasticity are outweighed by the benefits of medication. Our model provides a simple and general framework to study the conditions that drive the evolution of alternative forms of animal medication.


Restoration of endodontically treated teeth.
The restoration of endodontically treated teeth has undergone significant changes in the last 20 years. Most of these changes are associated with the preservation of tooth structure, this has been achieved first of all with the increasing use of operative microscopes, nickel titanium instruments and more recently cone beam computed tomography; these instruments have allowed the clinicians to reduce significantly the amount of coronal and radicular hard tooth tissue removed in the process of cutting access cavities. The use of composites has also allowed the clinicians to restore with adhesive techniques teeth that would otherwise require extensive and destructive mechanical retentions. The use of partial crowns is becoming increasingly popular and this also helps prevent tooth structure loss. This article will focus on the choices available to restore both anterior and posterior teeth and will focus more on these contemporary adhesive techniques.


Dysfunctional attitudes and vulnerability to persistent depression.
Forty-four patients who met criteria for major depressive disorder were assessed for presence of dysfunctional attitudes and negative self-schema on admission. After six weeks, of sixteen patients who had shown high dysfunctional attitudes, six (35%) had not recovered. By contrast, of seventeen patients who had been equally severely depressed at the outset, but had low dysfunctional attitudes, only one (6%) had not recovered. The rating by the patients of themselves, as opposed to their attitudes, did not however predict. Thirty-one patients were tested six months later. Twenty-one (68%) remained asymptomatic, ten patients had relapsed or not responded to treatment, but neither type of admission measure predicted the state at this point. This is consistent with previous evidence which suggests that vulnerable attitudes assessed when symptomatic predict recovery, but that for prediction of relapse, cognitive measures need to be used when the patient is asymptomatic.


Recent advances in solid-contact ion-selective electrodes: functional materials, transduction mechanisms, and development trends.
From environmental monitoring to point-of-care biofluid analysis, rapid ion determination requires robust analytical tools. In recent years, driven by the development of materials science and processing technology, solid-contact ion-selective electrodes (SC-ISEs) with high-performance functional materials and creative structures have shown great potential for routine and portable ion detection. In particular, the introduction of nanomaterials as ion-to-electron transducers and the adoption of different performance enhancement strategies have significantly promoted the development of SC-ISEs. Besides, with the increasing miniaturization, flexibility, and dependability of SC-ISEs, this field has gradually begun to evolve from conventional potentiometric ion sensing to integrated sensing systems with broader application scenarios. This comprehensive review covers pioneering research on functional materials and state-of-the-art technologies for the construction of SC-ISEs, with an emphasis on new development trends and applications.


The extreme male brain revisited: gender coherence in adults with autism spectrum disorder.
The 'extreme male brain' theory suggests that autism spectrum disorder (ASD) is an extreme variant of male intelligence. However, somewhat paradoxically, many individuals with ASD display androgynous physical features regardless of gender. To assess physical measures, supposedly related to androgen influence, in adults with and without ASD. Serum hormone levels, anthropometry, the ratio of 2nd to 4th digit length (2D:4D) and psychiatric symptomatology were measured in 50 adults with high-functioning ASD and age- and gender-matched neurotypical controls. Photographs of face and body, as well as voice recordings, were obtained and assessed with respect to gender coherence, blindly and independently, by eight assessors. Women with ASD had higher total and bioactive testosterone levels, less feminine facial features and a larger head circumference than female controls. Men in the ASD group were assessed as having less masculine body characteristics and voice quality, and displayed higher (i.e. less masculine) 2D:4D ratios, but similar testosterone levels to controls. Androgynous facial features correlated strongly and positively with autistic traits measured with the Autism-Spectrum Quotient in the total sample. In males and females with ASD dehydroepiandrosterone sulfate did not decrease with age, in contrast to the control group. Women with ASD had elevated testosterone levels and several masculinised characteristics compared with controls, whereas men with ASD displayed several feminised characteristics. Our findings suggest that ASD, rather than being characterised by masculinisation in both genders, may constitute a gender defiant disorder.


Long-term regulation of signalling components of adenylyl cyclase and mitogen-activated protein kinase in the pre-frontal cortex of human opiate addicts.
Opiate addiction involves the development of chronic adaptive changes in micro -opioid receptors and associated pathways (e.g. cAMP signalling) which lead to neuronal plasticity in the brain. This study assessed the status of cAMP and mitogen-activated protein kinase (MAPK) pathways in brains (pre-frontal cortex) of chronic opiate addicts. In these subjects (n = 24), the immunodensities of adenylyl cyclase-I, PKA Calpha, total and phosphorylated CREB were not different from those in sex-, age- and PMD-matched controls. Moreover, the ratio pCREB/tCREB was similar in opiate addicts (0.74) and controls (0.76), further indicating that opiate addiction in humans is not associated with an upregulation of several key components of cAMP signalling in the pre-frontal cortex. In contrast, the components of MAPK cascade (Ras/c-Raf-1/MEK/ERK) were decreased in the same brains. Notably, pronounced downregulations of phosphorylated MEK (85%) and ERK1/2 (pERK1: 81%; pERK2: 80%) were quantitated in brains of opiate addicts. Chronic morphine treatment in rats (10-100 mg/kg for 5 days) was also associated with decreases of pERK1/2 (59-68%) in the cortex. In SH-SY5Y cells, morphine also stimulated the activity of pERK1/2 (2.5-fold) and the MEK inhibitor PD98059 blocked this effect (90%). The abnormalities of MAPK signalling might have important consequences in the long term development of various forms of neural plasticity associated with opiate addiction in humans.


The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 and is involved in crosstalk with H3 K4 and K79 methylation.
We demonstrate that RING finger protein MSL2 in the MOF-MSL complex is a histone ubiquitin E3 ligase. MSL2, together with MSL1, has robust histone ubiquitylation activity that mainly targets nucleosomal H2B on lysine 34 (H2B K34ub), a site within a conserved basic patch on H2B tail. H2B K34ub by MSL1/2 directly regulates H3 K4 and K79 methylation through trans-tail crosstalk both in vitro and in cells. The significance of MSL1/2-mediated histone H2B ubiquitylation is underscored by the facts that MSL1/2 activity is important for transcription activation at HOXA9 and MEIS1 loci and that this activity is evolutionarily conserved in the Drosophila dosage compensation complex. Altogether, these results indicate that the MOF-MSL complex possesses two distinct chromatin-modifying activities (i.e., H4 K16 acetylation and H2B K34 ubiquitylation) through MOF and MSL2 subunits. They also shed light on how an intricate network of chromatin-modifying enzymes functions coordinately in gene activation.


Diluting the dilution effect: a spatial Lyme model provides evidence for the importance of habitat fragmentation with regard to the risk of infection.
This paper aims to construct a spatially-explicit model of Ixodes scapularis infection in the State of New York, USA, based on climate traits, high-resolution landscape features and patch-connectivity according to graph theory. The degree of risk for infection is calculated based on empirical data of host abundance, previous studies on host infectivity rates and tick preferences towards a given host. The outcome signifies what is called the "recruitment of infection", i.e. an index representing the abundance of infected ticks in a particular patch of vegetation. The results show that the I. scapularis recruitment of infection (IR) index is highly dependent upon a complex array of landscape fragmentation and the presence of key hosts. Neither faunal richness nor host density alone has any reasonable effect on the recruitment of infection. The experience of Lyme disease in the State of New York shows no clear relationship between the IR as calculated at the patch level and then summarized county by county and the rates of disease over the last eight years reported for these counties. However, areas characterized by low IR have consistently been associated with locations with low disease rates. Above all, the low levels of disease are related to minimal suitability due to the climate and negligible connection between patches. Social factors, mainly activities leading to an increased contact of humans with infective foci (which can be situated far from their homes), may lead to a high rates being reported from areas with high human densities rather than areas characterized by a high recruitment of infection. The spatial model developed here may be used to study the long-term changes in infective risk and tick recruitment as a result of humaninduced changes in the landscape.


Intracellular pathogens and the actin cytoskeleton.
Many pathogens actively exploit the actin cytoskeleton during infection. This exploitation may take place during entry into mammalian cells after engagement of a receptor and/or as series of signaling events culminating in the engulfment of the microorganism. Although actin rearrangements are a common feature of most internalization events (e.g. entry of Listeria, Salmonella, Shigella, Yersinia, Neisseria, and Bartonella), bacterial and other cellular factors involved in entry are specific to each bacterium. Another step during which pathogens harness the actin cytoskeleton takes place in the cytosol, within which some bacteria (Listeria, Shigella, Rickettsia) or viruses (vaccinia virus) are able to move. Movement is coupled to a polarized actin polymerization process, with the formation of characteristic actin tails. Increasing attention has focused on this phenomenon due to its striking similarity to cellular events occurring at the leading edge of locomoting cells. Thus pathogens are convenient systems in which to study actin cytoskeleton rearrangements in response to stimuli at the plasma membrane or inside cells.


Computed body tomography with a new nonionic contrast agent. Comparison of ioversol with sodium/meglumine diatrizoate.
The authors undertook a double-blind parallel group comparative study of 80 adult patients to examine the efficacy, safety, and tolerance of ioversol and sodium/meglumine diatrizoate in patients undergoing computed body tomography (CT). All procedures were considered diagnostic, although the scan quality of four procedures enhanced with sodium/meglumine diatrizoate was rated fair. Both contrast media induced clinically insignificant postprocedure decreases in mean systolic and diastolic blood pressure. There were no statistically significant differences between the two contrast media in their effects on these or other vital signs. Ioversol was better tolerated, as evidenced by significantly lower pain and heat scores. There was a remarkable difference in adverse side effects induced by ioversol (n = 0) and sodium/meglumine diatrizoate (n = 14 [35%], including six of moderate severity). Ioversol is a safe and effective nonionic contrast agent for contrast-enhanced body CT.


Constraints faced by sex workers in use of female and male condoms for safer sex in urban zimbabwe.
We investigated whether female condoms are acceptable to sex workers in Harare and whether improved access to male and female condoms increases the proportion of protected sex episodes with clients and boyfriends. Sex workers were randomly placed in groups to receive either male and female condoms (group A, n = 99) or male condoms only (group B, n = 50) and were followed prospectively for about 3 months each. We found a considerable burden of human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) in our cohort at enrollment (86% tested HIV positive and 34% had at least one STI). Consistent male condom use with clients increased from 0% to 52% in group A and from 0% to 82% in group B between enrollment and first follow-up 2 weeks later and remained high throughout the study. Few women in group A reported using female condoms with clients consistently (3%-9%), and use of either condom was less common with boyfriends than with clients throughout the study (8%-39% for different study groups, visits, and types of condom). Unprotected sex still took place, as evidenced by an STI incidence of 16 episodes per 100 woman-months of follow-up. Our questionnaire data indicated high self-reported acceptability of female condoms, but focus group discussions revealed that a main obstacle to female condom use was client distrust of unfamiliar methods. This study shows that a simple intervention of improving access to condoms can lead to more protected sex episodes between sex workers and clients. However, more work is needed to help sex workers achieve safer sex in noncommercial relationships.


Characterization of GLUT3 protein expressed in Chinese hamster ovary cells.
We have expressed GLUT3 protein, an isoform of a facilitative glucose transporter, in Chinese hamster ovary cells by transfection of its cDNA using an expression vector. The expressed GLUT3 protein was detected by Western-blot analysis as a broad band of 45-65 kDa, indicating intensive glycosylation of the protein. The expressed GLUT3 protein was observed, by immunofluorescence staining, to be located mainly at the plasma membrane, and its expression was associated with a marked increase in glucose-transport activity. Kinetic analysis revealed that the Km value of GLUT3 protein for 3-O-methylglucose uptake was approx. 35% of that of GLUT1 protein, whereas the Km value of GLUT3 protein for 2-deoxy-D-glucose uptake was very similar to that of GLUT1 protein. The Vmax. value of GLUT3 protein for 3-O-methylglucose and 2-deoxyglucose uptake was approx. 20-50% of that of GLUT1 protein. GLUT3 protein was well photolabelled with [3H]cytochalasin B or a mannose derivative, 2-N-4-[3H](1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-(D-mannos -4-yloxy)-2- propylamine. Thus GLUT3 protein has very similar characteristics to GLUT1 protein including its subcellular localization, but exhibits lower Km and Vmax. values for 3-O-methylglucose uptake.


Holographic microinterferometer with noise suppression.
Holographic microinterferometer with the noise suppression is presented. The noise suppression method proposed consists of synchronous deflection of both beams. The method is applied on every step of the holographic process as well as during holographic interferometric investigations. A significant increase in image quality was achieved in conjunction with a parallel increase in resolution. It has been experimentally demonstrated, that the applied method can suppress the coherent noise by at least one order of magnitude, depending on the initial noise level. For the case of a high initial noise level the improvement is greater than 2 orders of magnitude.


The effect of single nucleotide polymorphism identification strategies on estimates of linkage disequilibrium.
At present there is tremendous interest in characterizing the magnitude and distribution of linkage disequilibrium (LD) throughout the human genome, which will provide the necessary foundation for genome-wide LD analyses and facilitate detailed evolutionary studies. To this end, a human high-density single-nucleotide polymorphism (SNP) marker map has been constructed. Many of the SNPs on this map, however, were identified by sampling a small number of chromosomes from a single population, and inferences drawn from studies using such SNPs may be influenced by ascertainment bias (AB). Through extensive simulations, we have found that AB is a potentially significant problem in estimating and comparing LD within and between populations. Specifically, the magnitude of AB is a function of the SNP discovery strategy, number of chromosomes used for SNP discovery, population genetic characteristics of the particular genomic region considered, amount of gene flow between populations, and demographic history of the populations. We demonstrate that a balanced SNP discovery strategy (where equal numbers of chromosomes are sampled from multiple subpopulations) is the optimal study design for generating broadly applicable SNP resources. Finally, we validate our theoretical predictions by comparing our results to publicly available data from ten genes sequenced in 24 African American and 23 European American individuals.