Comparison of algorithm-based estimates of occupational diesel exhaust exposure to those of multiple independent raters in a population-based case-control study.
Algorithm-based exposure assessments based on patterns in questionnaire responses and professional judgment can readily apply transparent exposure decision rules to thousands of jobs quickly. However, we need to better understand how algorithms compare to a one-by-one job review by an exposure assessor. We compared algorithm-based estimates of diesel exhaust exposure to those of three independent raters within the New England Bladder Cancer Study, a population-based case-control study, and identified conditions under which disparities occurred in the assessments of the algorithm and the raters. Occupational diesel exhaust exposure was assessed previously using an algorithm and a single rater for all 14 983 jobs reported by 2631 study participants during personal interviews conducted from 2001 to 2004. Two additional raters independently assessed a random subset of 324 jobs that were selected based on strata defined by the cross-tabulations of the algorithm and the first rater's probability assessments for each job, oversampling their disagreements. The algorithm and each rater assessed the probability, intensity and frequency of occupational diesel exhaust exposure, as well as a confidence rating for each metric. Agreement among the raters, their aggregate rating (average of the three raters' ratings) and the algorithm were evaluated using proportion of agreement, kappa and weighted kappa (κw). Agreement analyses on the subset used inverse probability weighting to extrapolate the subset to estimate agreement for all jobs. Classification and Regression Tree (CART) models were used to identify patterns in questionnaire responses that predicted disparities in exposure status (i.e., unexposed versus exposed) between the first rater and the algorithm-based estimates. For the probability, intensity and frequency exposure metrics, moderate to moderately high agreement was observed among raters (κw = 0.50-0.76) and between the algorithm and the individual raters (κw = 0.58-0.81). For these metrics, the algorithm estimates had consistently higher agreement with the aggregate rating (κw = 0.82) than with the individual raters. For all metrics, the agreement between the algorithm and the aggregate ratings was highest for the unexposed category (90-93%) and was poor to moderate for the exposed categories (9-64%). Lower agreement was observed for jobs with a start year <1965 versus ≥1965. For the confidence metrics, the agreement was poor to moderate among raters (κw = 0.17-0.45) and between the algorithm and the individual raters (κw = 0.24-0.61). CART models identified patterns in the questionnaire responses that predicted a fair-to-moderate (33-89%) proportion of the disagreements between the raters' and the algorithm estimates. The agreement between any two raters was similar to the agreement between an algorithm-based approach and individual raters, providing additional support for using the more efficient and transparent algorithm-based approach. CART models identified some patterns in disagreements between the first rater and the algorithm. Given the absence of a gold standard for estimating exposure, these patterns can be reviewed by a team of exposure assessors to determine whether the algorithm should be revised for future studies.


Tension pneumoventricle: Reversible cause for aphasia.
Pneumocephalus is air in the cranium commonly seen in postcraniotomy and in head injury patients. When this air causes an increase in intracranial pressure leading to neurological deterioration, it is called tension pneumocephalus. Similarly, intraventricular air causing compression on vital centers and increasing intracranial pressure is called tension pneumoventricle, and this causes expressive aphasia, which is rarely described in the literature. This study reported a case of a traumatic cerebrospinal fluid (CSF) leak leading to tension pneumoventricle and aphasia. Case: A young male patient sustained severe head injury and had extradural hematoma (EDH) and multiple skull and skull base fractures. EDH was drained, and he recovered and was discharged with a Glasgow coma scale score of 15. He presented to neurosurgical outpatient with CSF leak, aphasia, and loss of bowel and bladder control for a duration of three days. Computed tomography brain scan showed tension pneumoventricles, and he was started on conservative management. His general condition deteriorated, and the next day, his pupils became unequal, and Glasgow coma scale (GCS) dropped to 8/15. He was immediately taken to theater, and the air was aspirated from the ventricles, and an external ventricular drain was inserted. The patient woke up in the immediate postoperative period and started talking normally by day four. Conclusion: Tension pneumoventricles should be considered a cause of aphasia. Immediate intervention and reduction of intracranial pressure are crucial to reverse neurological abnormality and improve patient's outcome.


Fertility decline in sub-Saharan Africa: Does remarriage matter?
The interplay between remarriage and fertility is among the most poorly documented subjects in sub-Saharan Africa (SSA), despite remarriage being one of the fundamental aspects of marriage dynamics in this region. We use Demographic and Health Survey data from 34 countries in SSA to document the association between remarriage and fertility during the reproductive years and over the fertility transition. The findings show that in 29 countries, remarried women end up having fewer children than women in intact unions, despite attaining similar or higher levels of fertility at early reproductive ages. However, remarriage is found to have a positive effect on fertility in Sierra Leone. The effects of remarriage on fertility diminish as fertility declines, with smaller effects generally observed in countries that are relatively advanced in their fertility transition and larger effects found elsewhere. These findings shed light on the role that remarriage might play in country-level fertility declines.


The structure and intermolecular forces of DNA condensates.
Spontaneous assembly of DNA molecules into compact structures is ubiquitous in biological systems. Experiment has shown that polycations can turn electrostatic self-repulsion of DNA into attraction, yet the physical mechanism of DNA condensation has remained elusive. Here, we report the results of atomistic molecular dynamics simulations that elucidated the microscopic structure of dense DNA assemblies and the physics of interactions that makes such assemblies possible. Reproducing the setup of the DNA condensation experiments, we measured the internal pressure of DNA arrays as a function of the DNA-DNA distance, showing a quantitative agreement between the results of our simulations and the experimental data. Analysis of the MD trajectories determined the DNA-DNA force in a DNA condensate to be pairwise, the DNA condensation to be driven by electrostatics of polycations and not hydration, and the concentration of bridging cations, not adsorbed cations, to determine the magnitude and the sign of the DNA-DNA force. Finally, our simulations quantitatively characterized the orientational correlations of DNA in DNA arrays as well as diffusive motion of DNA and cations.


Exercise and recovery ventilatory and VO2 responses of patients with McArdle's disease.
This study was designed to determine whether patients with McArdle's disease, who do not increase their blood lactate levels during and after maximal exercise, have a slow "lactacid" component to their recovery O2 consumption (VO2) response after high-intensity exercise. VO2 was measured breath by breath during 6 min of rest before exercise, a progressive maximal cycle ergometer test, and 15 min of recovery in five McArdle's patients, six age-matched control subjects, and six maximal O2 consumption- (VO2 max) matched control subjects. The McArdle's patients' ventilatory threshold occurred at the same relative exercise intensity [71 +/- 7% (SD) VO2max] as in the control groups (60 +/- 13 and 70 +/- 10% VO2max) despite no increase and a 20% decrease in the McArdle's patients' arterialized blood lactate and H+ levels, respectively. The recovery VO2 responses of all three groups were better fit by a two-, than a one-, component exponential model, and the parameters of the slow component of the recovery VO2 response were the same in the three groups. The presence of the same slow component of the recovery VO2 response in the McArdle's patients and the control subjects, despite the lack of an increase in blood lactate or H+ levels during maximal exercise and recovery in the patients, provides evidence that this portion of the recovery VO2 response is not the result of a lactacid mechanism. In addition, it appears that the hyperventilation that accompanies high-intensity exercise may be the result of some mechanism other than acidosis or lung CO2 flux.


Identification of novel genes involved in sarcopenia through RNAi screening in Caenorhabditis elegans.
Aging in humans is characterized by a progressive loss of muscle mass and strength known as sarcopenia. Although considered to be a normal aspect of aging, the loss of strength can have significant effects on the health, functioning, and independence of elderly individuals. Although these aspects of sarcopenia have been well studied, the molecular mechanisms leading to its development are still unclear. The nematode Caenorhabditis elegans might be a novel animal model for sarcopenia as worms experience sarcopenia during aging and mutations affecting the daf-2/insulin-like signaling pathway are able to delay this process. Via the use of RNA interference, we screened a total of 43 genes, most of which have been shown to be required for the enhanced longevity of daf-2 mutants, to assess for the effects of these genes on muscle function and worm mobility during aging. We identified 17 novel genes that are essential for the delay in the onset of sarcopenia in daf-2 mutants. The identified genes include splicing factors, vacuolar sorting proteins, transcription factors, and metabolic enzymes. Using a transgenic strain that only responds to RNA interference in the body wall muscle, we also found that most of the identified genes act in muscle to prevent the onset of sarcopenia. Our results demonstrate that at least in worms, specific genetic pathways that modify the development of sarcopenia can be identified. Interestingly, almost all the identified genes also have a known human homolog, and hence, our findings may offer significant leads toward the identification of genes involved in sarcopenia in people.


Medication documentation in a primary care network serving North Carolina medicaid patients: results of a cross-sectional chart review.
Medical records that do not accurately reflect the patient's current medication list are an open invitation to errors and may compromise patient safety. This cross-sectional study compares primary care provider (PCP) medication lists and pharmacy claims for 100 patients seen in 8 primary care practices and examines the association of congruence with demographic, clinical, and practice characteristics. Medication list congruence was measured as agreement of pharmacy claims with the entire PCP chart, including current medication list, visit notes, and correspondence sections. Congruence between pharmacy claims and the PCP chart was 65%. Congruence was associated with large chronic disease burden, frequent PCP visits, group practice, and patient age ≥45 years. Agreement of medication lists between the PCP chart and pharmacy records is low. Medication documentation was more accurate among patients who have more chronic conditions, those who have frequent PCP visits, those whose practice has multiple providers, and those at least 45 years of age. Improved congruence among patients with multiple chronic conditions and in group practices may reflect more frequent visits and reviews by providers.


How patient-centred am I? A new method to measure physicians' patient-centredness.
To describe a new method to determine physicians' self-perceived degree of patient-centredness. A pilot study combining qualitative and quantitative methods. Forty-one general practitioners (GPs) answered a questionnaire consisting of three open-ended questions about their view of the consultation and by choosing among 28 roles of the physician in the physician-patient relationship. Twenty of the GPs had participated in Balint groups while 21 had had no access to Balint group. Patient-centredness is central to Balint groups and consequently Balint group participants would be expected to be patient-centred. The answers to the two parts were divided into three groups each, patient-centred, non-patient-centred and intermediary, and analysed statistically. Significantly more Balint participants were patient-centred than the reference group. The instrument describes physicians' self-perceptions of their patient-centredness and can distinguish a group of patient-centred physicians from a group of non-patient-centred physicians. The instrument can be useful to evaluate educational programmes and detect decline in patient-centredness as early sign of burnout.


A comparison of the Mogen and Gomco clamps in combination with dorsal penile nerve block in minimizing the pain of neonatal circumcision.
1) To compare the Mogen and Gomco clamps with regard to pain experienced during neonatal circumcision, and 2) to assess neonatal circumcision pain with and without dorsal penile nerve block (DPNB). A randomized, controlled, nonblinded clinical trial; 48 healthy, full-term infants were randomized into one of the following four groups: Gomco vs Mogen with (+) or without (-) DPNB. DPNB+ infants were injected with 0.8 mL of 1% lidocaine before circumcision. DPNB- infants received no placebo injection. Heart rate, respiratory rate, and oxygen saturation (SaO2) during the procedure were monitored and data transferred to computer files by using the Datalab software system. Crying was recorded on videotape. Pre- and postcircumcision saliva samples for cortisol analysis were collected. Heart rate, respiratory rate, SaO2, cortisol changes, and duration of crying were evaluated statistically with two-way analyses of variance and t tests. The type of clamp but not the use of anesthesia was significantly associated with the length of the procedure (mean Mogen time, 81 seconds; mean Gomco time, 209 seconds) and percentage of respiratory rate change. The use of anesthesia but not the type of clamp was significantly associated with percentage of crying time and percentage of SaO2 change during the procedure. Heart rate changes and total crying time were significantly associated with both the type of clamp and the use of anesthesia. Neither clamp type nor anesthesia status was significantly associated with salivary cortisol changes, although the mean increase for the DPNB- group was approximately twice that for the DPNB+ group. Fifty-six percent of infants circumcised with the Mogen clamp and DPNB did not cry at all during the procedure. DPNB is effective in reducing neonatal circumcision pain with either the Mogen or the Gomco clamp. For a given anesthesia condition, the Mogen clamp is associated with a less painful procedure than the Gomco. The Mogen clamp with DPNB causes the least discomfort during neonatal circumcision.


Interaction between the type III effector VopO and GEF-H1 activates the RhoA-ROCK pathway.
Vibrio parahaemolyticus is an important pathogen that causes food-borne gastroenteritis in humans. The type III secretion system encoded on chromosome 2 (T3SS2) plays a critical role in the enterotoxic activity of V. parahaemolyticus. Previous studies have demonstrated that T3SS2 induces actin stress fibers in various epithelial cell lines during infection. This stress fiber formation is strongly related to pathogenicity, but the mechanisms that underlie T3SS2-dependent actin stress fiber formation and the main effector have not been elucidated. In this study, we identified VopO as a critical T3SS2 effector protein that activates the RhoA-ROCK pathway, which is an essential pathway for the induction of the T3SS2-dependent stress fiber formation. We also determined that GEF-H1, a RhoA guanine nucleotide exchange factor (GEF), directly binds VopO and is necessary for T3SS2-dependent stress fiber formation. The GEF-H1-binding activity of VopO via an alpha helix region correlated well with its stress fiber-inducing capacity. Furthermore, we showed that VopO is involved in the T3SS2-dependent disruption of the epithelial barrier. Thus, VopO hijacks the RhoA-ROCK pathway in a different manner compared with previously reported bacterial toxins and effectors that modulate the Rho GTPase signaling pathway.


Neuroprediction, Violence, and the Law: Setting the Stage.
In this paper, our goal is to (a) survey some of the legal contexts within which violence risk assessment already plays a prominent role, (b) explore whether developments in neuroscience could potentially be used to improve our ability to predict violence, and (c) discuss whether neuropredictive models of violence create any unique legal or moral problems above and beyond the well worn problems already associated with prediction more generally. In "Violence Risk Assessment and the Law", we briefly examine the role currently played by predictions of violence in three high stakes legal contexts: capital sentencing ("Violence Risk Assessment and Capital Sentencing"), civil commitment hearings ("Violence Risk Assessment and Civil Commitment"), and "sexual predator" statutes ("Violence Risk Assessment and Sexual Predator Statutes"). In "Clinical vs. Actuarial Violence Risk Assessment", we briefly examine the distinction between traditional clinical methods of predicting violence and more recently developed actuarial methods, exemplified by the Classification of Violence Risk (COVR) software created by John Monahan and colleagues as part of the MacArthur Study of Mental Disorder and Violence [1]. In "The Neural Correlates of Psychopathy", we explore what neuroscience currently tells us about the neural correlates of violence, using the recent neuroscientific research on psychopathy as our focus. We also discuss some recent advances in both data collection ("Cutting-Edge Data Collection: Genetically Informed Neuroimaging") and data analysis ("Cutting-Edge Data Analysis: Pattern Classification") that we believe will play an important role when it comes to future neuroscientific research on violence. In "The Potential Promise of Neuroprediction", we discuss whether neuroscience could potentially be used to improve our ability to predict future violence. Finally, in "The Potential Perils of Neuroprediction", we explore some potential evidentiary ("Evidentiary Issues"), constitutional ("Constitutional Issues"), and moral ("Moral Issues") issues that may arise in the context of the neuroprediction of violence.


Implementation of an on-demand app-based heart rate and rhythm monitoring infrastructure for the management of atrial fibrillation through teleconsultation: TeleCheck-AF.
During the coronavirus 2019 (COVID-19) pandemic, outpatient visits in the atrial fibrillation (AF) clinic of the Maastricht University Medical Centre (MUMC+) were transferred into teleconsultations. The aim was to develop anon-demand app-based heart rate and rhythm monitoring infrastructure to allow appropriatmanagement of AF through teleconsultation. In line with the fundamental aspects of integrated care, including actively involving patients in the care process and providing comprehensive care by a multidisciplinary team, we implemented a mobile health (mHealth) intervention to support teleconsultations with AF patients: TeleCheck-AF. The TeleCheck-AF approach guarantees the continuity of comprehensive AF management and supports integrated care through teleconsultation during COVID-19. It incorporates three important components: (i) a structured teleconsultation ('Tele'), (ii) a CE-marked app-based on-demand heart rate and rhythm monitoring infrastructure ('Check'), and (iii) comprehensive AF management ('AF'). In this article, we describe the components and implementation of the TeleCheck-AF approach in an integrated and specialized AF-clinic through teleconsultation. The TeleCheck-AF approach is currently implemented in numerous European centres during COVID-19.


Consequences of a poecilogonous life history for genetic structure in coastal populations of the polychaete Streblospio benedicti.
In many species, alternative developmental pathways lead to the production of two distinct phenotypes, promoting the evolution of morphological novelty and diversification. Offspring type in marine invertebrates influences transport time by ocean currents, which dictate dispersal potential and gene flow, and thus has sweeping evolutionary effects on the potential for local adaptation and on rates of speciation, extinction and molecular evolution. Here, we use the polychaete Streblospio benedicti to investigate the effects of dimorphic offspring type on gene flow and genetic structure in coastal populations. We use 84 single nucleotide polymorphism (SNP) markers for this species to assay populations on the East and West Coasts of the United States. Using these markers, we found that in their native East Coast distribution, populations of S. benedicti have high-population genetic structure, but this structure is associated primarily with geographic separation rather than developmental differences. Interestingly, very little genetic differentiation is recovered between individuals of different development types when they occur in the same or nearby populations, further supporting that this is a true case of poecilogony. In addition, we were able to demonstrate that the recently introduced (~100 ya) West Coast populations probably originated from a lecithotrophic population near Delaware.


Studies of membrane formation in Tetrahymena pyriformis. II. Isolation and lipid analysis of cell fractions.
A method has been devised to fractionate cells of Tetrahymena pyriformis, yielding pure or highly enriched preparations of cilia, cilia-associated soluble material, pellicles, mitochondria, microsomes, and postmicrosomal supernatant. The method prevents the destructive action of lipolytic enzymes commonly associated with this organism. Analysis of the membrane lipids of these fractions reveals significant differences in lipid composition. Most noteworthy are the high concentrations of phosphonolipid and tetrahymanol in the surface membranes.


Neutrophil calprotectin identifies severe pulmonary disease in COVID-19.
Severe cases of coronavirus disease 2019 (COVID-19) are regularly complicated by respiratory failure. Although it has been suggested that elevated levels of blood neutrophils associate with worsening oxygenation in COVID-19, it is unknown whether neutrophils are drivers of the thrombo-inflammatory storm or simple bystanders. To better understand the potential role of neutrophils in COVID-19, we measured levels of the neutrophil activation marker S100A8/A9 (calprotectin) in hospitalized patients and determined its relationship to severity of illness and respiratory status. Patients with COVID-19 (n = 172) had markedly elevated levels of calprotectin in their blood. Calprotectin tracked with other acute phase reactants including C-reactive protein, ferritin, lactate dehydrogenase, and absolute neutrophil count, but was superior in identifying patients requiring mechanical ventilation. In longitudinal samples, calprotectin rose as oxygenation worsened. When tested on day 1 or 2 of hospitalization (n = 94 patients), calprotectin levels were significantly higher in patients who progressed to severe COVID-19 requiring mechanical ventilation (8039 ± 7031 ng/ml, n = 32) as compared to those who remained free of intubation (3365 ± 3146, P < 0.0001). In summary, serum calprotectin levels track closely with current and future COVID-19 severity, implicating neutrophils as potential perpetuators of inflammation and respiratory compromise in COVID-19.


Evaluation of pentraxin 3 level and cardiac functions in psoriatic children.
Psoriasis is a chronic inflammatory disorder affecting the skin, nails, and joints. Its lifetime prevelance has been estimated to be at 1% to 3%. This study was designed to examine the association between serum pentraxin 3 (PTX3) and cardiovascular function in psoriatic children. Thirty-three children who were diagnosed with psoriasis, and 29 healthy children, between 4 and 18 years of age, were included in the study. Both patient and control group was evaluated by the pulsed wave tissue doppler imaging (TDI) echocardiography as well as with conventional Doppler echocardiography (CDE). PTX3 values of the groups were evaluated. There was no difference between cases and controls for age (9.67±3.72, 9.60±2.84 years, p=0.916, respectively). In evaluation of the left ventricle (LV) CDE; A wave, isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly higher in the study group (p < 0.05). Ejection time (ET) was significantly lower in the study group compared to the control group (p < 0.05). In evaluation of LV TDI; Deceleration time (DT`), IVRT`, E/E` and MPI` were found to be significantly higher in the study group (p < 0.05). In addition to, E`, E`/A` and ET` were siginificantly lower in study group. PTX3 level was significantly higher in the study group compared to the control group (p=0.009) (Table III). However, no correlation was found between PTX3 level and cardiovascular parameters. In conclusion; both doppler echocardiography and PTX3 may be useful tools for the screening of cardiovascular (CV) risk in these patients. Psoriasis itself may be an independent risk factor for cardiac dysfunction in the pediatric population.


Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma.
Between 1971 and 1991, 247 patients with stage I osteosarcoma were treated at UCLA. Patients were treated in four sequential groups, with group 1 receiving surgery alone, and groups 2 through 4 receiving various adjuvant chemotherapeutic regimens. The incidence of lung metastases in these patients decreased from 92% (group 1) to 31% (group 4), while the proportion of patients undergoing pulmonary resection increased (17% vs 82%). Overall 5-year survival rate among patients with pulmonary metastases increased from 0 in group 1 to 41% (actuarial) in group 4. No clinical factor correlated significantly with outcome using univariate analysis, although there was a trend toward prolonged survival in those with longer disease-free intervals. Adjuvant chemotherapy and resection of pulmonary metastases have transformed a uniformly fatal condition into one with a reasonable expectation of long-term survival.


Analysis of β-amino alcohols as inhibitors of the potential anti-tubercular target N-acetyltransferase.
The synthesis and inhibitory potencies of a novel series of β-amino alcohols, based on the hit-compound 3-[3'-(4''-cyclopent-2'''-en-1'''-ylphenoxy)-2'-hydroxypropyl]-5,5 dimethylimidazolidine-2,4-dione as specific inhibitors of mycobacterial N-acetyltransferase (NAT) enzymes are reported. Effects of synthesised compounds on growth of Mycobacterium tuberculosis have been determined.


Empirically based comparisons of the reliability and validity of common quantification approaches for eyeblink startle potentiation in humans.
Startle potentiation is a well-validated translational measure of negative affect. Startle potentiation is widely used in clinical and affective science, and there are multiple approaches for its quantification. The three most commonly used approaches quantify startle potentiation as the increase in startle response from a neutral to threat condition based on (1) raw potentiation, (2) standardized potentiation, or (3) percent-change potentiation. These three quantification approaches may yield qualitatively different conclusions about effects of independent variables (IVs) on affect when within- or between-group differences exist for startle response in the neutral condition. Accordingly, we directly compared these quantification approaches in a shock-threat task using four IVs known to influence startle response in the no-threat condition: probe intensity, time (i.e., habituation), alcohol administration, and individual differences in general startle reactivity measured at baseline. We confirmed the expected effects of time, alcohol, and general startle reactivity on affect using self-reported fear/anxiety as a criterion. The percent-change approach displayed apparent artifact across all four IVs, which raises substantial concerns about its validity. Both raw and standardized potentiation approaches were stable across probe intensity and time, which supports their validity. However, only raw potentiation displayed effects that were consistent with a priori specifications and/or the self-report criterion for the effects of alcohol and general startle reactivity. Supplemental analyses of reliability and validity for each approach provided additional evidence in support of raw potentiation.


The composition-explicit distillation curve technique: Relating chemical analysis and physical properties of complex fluids.
The analysis of complex fluids such as crude oils, fuels, vegetable oils and mixed waste streams poses significant challenges arising primarily from the multiplicity of components, the different properties of the components (polarity, polarizability, etc.) and matrix properties. We have recently introduced an analytical strategy that simplifies many of these analyses, and provides the added potential of linking compositional information with physical property information. This aspect can be used to facilitate equation of state development for the complex fluids. In addition to chemical characterization, the approach provides the ability to calculate thermodynamic properties for such complex heterogeneous streams. The technique is based on the advanced distillation curve (ADC) metrology, which separates a complex fluid by distillation into fractions that are sampled, and for which thermodynamically consistent temperatures are measured at atmospheric pressure. The collected sample fractions can be analyzed by any method that is appropriate. The analytical methods we have applied include gas chromatography (with flame ionization, mass spectrometric and sulfur chemiluminescence detection), thin layer chromatography, FTIR, corrosivity analysis, neutron activation analysis and cold neutron prompt gamma activation analysis. By far, the most widely used analytical technique we have used with the ADC is gas chromatography. This has enabled us to study finished fuels (gasoline, diesel fuels, aviation fuels, rocket propellants), crude oils (including a crude oil made from swine manure) and waste oils streams (used automotive and transformer oils). In this special issue of the Journal of Chromatography, specifically dedicated to extraction technologies, we describe the essential features of the advanced distillation curve metrology as an analytical strategy for complex fluids.


Expansion of variant diversity associated with a high prevalence of pathogen strain superinfection under conditions of natural transmission.
Superinfection occurs when a second, genetically distinct pathogen strain infects a host that has already mounted an immune response to a primary strain. For antigenically variant pathogens, the primary strain itself expresses a broad diversity of variants over time. Thus, successful superinfection would require that the secondary strain express a unique set of variants. We tested this hypothesis under conditions of natural transmission in both temperate and tropical regions where, respectively, single-strain infections and strain superinfections of the tick-borne pathogen Anaplasma marginale predominate. Our conclusion that strain superinfection is associated with a significant increase in variant diversity is supported by progressive analysis of variant composition: (i) animals with naturally acquired superinfection had a statistically significantly greater number of unique variant sequences than animals either experimentally infected with single strains or infected with a single strain naturally, (ii) the greater number of unique sequences reflected a statistically significant increase in primary structural diversity in the superinfected animals, and (iii) the increase in primary structural diversity reflected increased combinations of the newly identified hypervariable microdomains. The role of population immunity in establishing temporal and spatial patterns of infection and disease has been well established. The results of the present study, which examined strain structure under conditions of natural transmission and population immunity, support that high levels of endemicity also drive pathogen divergence toward greater strain diversity.


Use of comparative data for integrated cancer services.
Comparative data are an important resource for management of integrated care. In 2001, the English Department of Health created 34 cancer networks, broadly serving populations of half to three million people, to coordinate cancer services across providers. We have investigated how national and regional routine data are used by the cancer network management teams. Telephone interviews using a standardised semi-structured questionnaire were conducted with 68 participants in 29 cancer network teams. Replies were analysed both quantitatively and qualitatively. While most network teams had a formal information strategy, data were used ad hoc more than regularly, and were not thought to be as influential in network decision making as other sources of information. Data collection was more prominent in information strategies than data use. Perceptions of data usefulness were mixed and there were worries over data quality, relevance, and potential misuse. Participants were receptive to the idea of a new limited dataset collating comparative data from currently available routine data sources. Few network structural factors were associated with data use, perceptions of current data, or receptivity to a new dataset. Comparative data are underused for managing integrated cancer services in England. Managers would welcome more comparative data, but also desired data to be relevant, quality assured and contextualised, and for the teams to be better resourced for data use.


Elevated pressure, a novel cancer therapeutic tool for sensitizing cisplatin-mediated apoptosis in A549.
Intensive cancer therapy strategies have thus far focused on sensitizing cancer cells to anticancer drug-mediated apoptosis to overcome drug resistance, and this strategy has led to more effective cancer therapeutics. Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is an effective anticancer drug used to treat many types of cancer, including non-small cell lung carcinoma (NSCLC), and can be used in combination with various chemicals to enhance cancer cell apoptosis. Here, we introduce the use of elevated pressure (EP) in combination with CDDP for cancer treatment and explore the effects of EP on CDDP-mediated apoptosis in NSCLC cells. Our findings demonstrate that preconditioning NSCLC cells with EP sensitizes cells for CDDP-induced apoptosis. Enhanced apoptosis was dependent on p53 and HO-1 expression, and was associated with increased DNA damage and down-regulation of genes involved in nucleotide excision repair. The transcriptional levels of transporter proteins indicated that the mechanism by which EP-induced CDDP sensitization was intracellular drug accumulation. The protein levels of some antioxidants, such as hemeoxygenase-1 (HO-1), glutathione (GSH) and glutathione peroxidase (Gpx), were decreased in A549 cells exposed to EP via the down-regulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Furthermore, normal human fibroblasts were resistant to EP treatment, with no elevated DNA damage or apoptosis. Collectively, these data show that administration of EP is a potential adjuvant tool for CDDP-based chemosensitivity of lung cancer cells that may reduce drug resistance.


Combining analytical frameworks to assess livelihood vulnerability to climate change and analyse adaptation options.
Experts working on behalf of international development organisations need better tools to assist land managers in developing countries maintain their livelihoods, as climate change puts pressure on the ecosystem services that they depend upon. However, current understanding of livelihood vulnerability to climate change is based on a fractured and disparate set of theories and methods. This review therefore combines theoretical insights from sustainable livelihoods analysis with other analytical frameworks (including the ecosystem services framework, diffusion theory, social learning, adaptive management and transitions management) to assess the vulnerability of rural livelihoods to climate change. This integrated analytical framework helps diagnose vulnerability to climate change, whilst identifying and comparing adaptation options that could reduce vulnerability, following four broad steps: i) determine likely level of exposure to climate change, and how climate change might interact with existing stresses and other future drivers of change; ii) determine the sensitivity of stocks of capital assets and flows of ecosystem services to climate change; iii) identify factors influencing decisions to develop and/or adopt different adaptation strategies, based on innovation or the use/substitution of existing assets; and iv) identify and evaluate potential trade-offs between adaptation options. The paper concludes by identifying interdisciplinary research needs for assessing the vulnerability of livelihoods to climate change.


Muscle metabolism during graded quadriceps exercise in man.
The aim of the study was to examine local muscle metabolism in response to graded exercise when the involved muscle mass is too small to elicit marked hormonal changes and local blood flow restriction. Nine healthy overnight fasted male subjects performed knee extension exercise with both thighs kicking at 25% of maximal power (Wmax) for 45 min (23+/-1% of pulmonary) followed by 35 min of kicking with one thigh at 65% and the other at 85% W(max) (40+/-1% ). Primed constant infusion of [U-13C] palmitate and [2H5]glycerol was carried out. Blood was sampled from a femoral artery and both femoral veins, and thigh blood flow was determined by thermodilution. Muscle biopsies were obtained from m. vastus lateralis of both thighs. From rest through exercise at 25, 65 and 85% Wmax the thigh blood flow (0.3+/-0.1, 2.5+/-0.2, 3.5+/-0.2, 4.1+/-0.3 l min(-1)) and oxygen uptake (0.02+/-0.01, 0.27+/-0.03, 0.48+/-0.04, 0.55+/-0.05 l min(-1)) increased (P<0.05). The plasma fatty acids oxidized in the thigh (5+/-1, 114+/-15, 162+/-30, 180+/-31 micromol min(-1)) increased (P<0.05) with exercise intensity, whereas the total thigh fat oxidation (19+/-6, 312+/-64, 356+/-93, 323+/-120 micromol min(-1)) increased (P<0.05) from rest, but remained unchanged through exercise. The thigh glycerol uptake (1+/-1, 16+/-4, 24+/-10, 39+/-8 micromol min(-1)) increased significantly from rest through exercise at 25-65 and 85% Wmax, respectively. Glucose uptake and glycogen breakdown always increased with exercise intensity. In conclusion, in the presence of a high blood flow and oxygen supply and only small hormonal changes, total fat oxidation in muscle increases from rest to light exercise, but then remains constant with exercise intensity up to heavy exercise. However, with increasing exercise intensity, oxidation of plasma free fatty acids increases and accordingly oxidation of other fat sources decreases. These findings are in contrast to whole body measurements performed during graded exercise involving a large muscle mass during which fat oxidation peaks at around 60% of .


Walking With a Robotic Exoskeleton Does Not Mimic Natural Gait: A Within-Subjects Study.
Robotic exoskeleton devices enable individuals with lower extremity weakness to stand up and walk over ground with full weight-bearing and reciprocal gait. Limited information is available on how a robotic exoskeleton affects gait characteristics. The purpose of this study was to examine whether wearing a robotic exoskeleton affects temporospatial parameters, kinematics, and muscle activity during gait. The study was completed by 15 healthy adults (mean age 26.2 [SD 8.3] years; 6 males, 9 females). Each participant performed walking under 2 conditions: with and without wearing a robotic exoskeleton (EKSO). A 10-camera motion analysis system synchronized with 6 force plates and a surface electromyography (EMG) system captured temporospatial and kinematic gait parameters and lower extremity muscle activity. For each condition, data for 5 walking trials were collected and included for analysis. Differences were observed between the 2 conditions in temporospatial gait parameters of speed, stride length, and double-limb support time. When wearing EKSO, hip and ankle range of motion (ROM) were reduced and knee ROM increased during the stance phase. However, during the swing phase, knee and ankle ROM were reduced when wearing the exoskeleton bionic suit. When wearing EKSO, EMG activity decreased bilaterally in the stance phase for all muscle groups of the lower extremities and in the swing phase for the distal muscle groups (tibialis anterior and soleus) as well as the left medial hamstrings. Wearing EKSO altered temporospatial gait parameters, lower extremity kinematics, and muscle activity during gait in healthy adults. EKSO appears to promote a type of gait that is disparate from normal gait in first-time users. More research is needed to determine the impact on gait training with EKSO in people with gait impairments.


Predictors of weight loss after bariatric surgery-a cross-disciplinary approach combining physiological, social, and psychological measures.
Bariatric surgery leads to a substantial weight loss (WL), however, a subset of patients undergoing surgery fails to achieve adequate WL. The reason for the individual variation in WL remains unexplained. Using an exploratory cross-disciplinary approach, we aimed to identify preoperative and early postoperative factors explaining the variation in WL after bariatric surgery. Sixty-one subjects were recruited. Eighteen subjects did not receive surgery and three subjects dropped out, leaving a total sample of 40 subjects. Physiological, social, and psychological data were collected before and 6 months after surgery. All variables were analyzed in combination using a least absolute shrinkage and selection operator (LASSO) regression to explain the variation in WL 18 months after Roux-en-Y gastric bypass (n = 30) and sleeve gastrectomy (n = 10). Mean WL was 31% (range: 10-52%). The following preoperative factors predicted 59% of the variation in WL: type of surgery (14%), diabetes status (12%), economic resources (9%), sex (7%), binge eating disorder (7%), degree of depression (5%), household type (3%), and physical activity (1%). Including information on early responses after surgery increased the ability to predict WL to 78% and was explained by early WL (47%), changes in energy density of food consumed from a buffet meal (9%), changes in glicentin (5%), degree of depression (5%), sex (5%), type of surgery (2%), economic resources (2%), and changes in drive for thinness (1%). Using a cross-disciplinary approach, a substantial part of the individual variation in WL was explained by a combination of basic patient characteristics, psychological profile, and social conditions as well as physiological, psychological and behavioral responses to surgery. These results suggest that patient characteristics collected in a cross-disciplinary approach may help determine predictors for less successful WL after bariatric surgery. If verified in larger cohorts this may form the basis for individualized postoperative support to optimize WL outcome.


Hyperthermia and Radiation Therapy in Locoregional Recurrent Breast Cancers: A Systematic Review and Meta-analysis.
To conduct a systematic review and meta-analysis to evaluate the outcome of hyperthermia (HT) and radiation therapy (RT) in locally recurrent breast cancers (LRBCs). A total of 708 abstracts were screened from 8 databases according to the PRISMA guidelines. Single-arm and 2-arm studies, treating LRBCs with HT and RT but without surgery (for local recurrence) or concurrent chemotherapy were considered. The evaluated endpoint was complete response (CR). Thirty-one full text articles, pertaining to 34 studies, were shortlisted for the meta-analysis. Eight were 2-arm (randomized, n=5; nonrandomized, n=3), whereas 26 were single-arm studies. In all, 627 patients were enrolled in 2-arm and 1483 in single-arm studies. Patients were treated with a median of 7 HT sessions, and an average temperature of 42.5°C was attained. Mean RT dose was 38.2 Gy (range, 26-60 Gy). Hyperthermia was most frequently applied after RT. In the 2-arm studies, a CR of 60.2% was achieved with RT + HT versus 38.1% with RT alone (odds ratio 2.64, 95% confidence interval [CI] 1.66-4.18, P<.0001). Risk ratio and risk difference were 1.57 (95% CI 1.25-1.96, P<.0001) and 0.22 (95% CI 0.11-0.33, P<.0001), respectively. In 26 single-arm studies, RT + HT attained a CR of 63.4% (event rate 0.62, 95% CI 0.57-0.66). Moreover, 779 patients had been previously irradiated (696 from single-arm and 83 from 2-arm studies). A CR of 66.6% (event rate 0.64, 95% CI 0.58-0.70) was achieved with HT and reirradiation (mean ± SD dose: 36.7 ± 7.7 Gy). Mean acute and late grade 3/4 toxicities with RT + HT were 14.4% and 5.2%, respectively. Thermoradiation therapy enhances the likelihood of CR rates in LRBCs over RT alone by 22% with minimal acute and late morbidities. For even those previously irradiated, reirradiation with HT provides locoregional control in two-thirds of the patients. Thermoradiation therapy could therefore be considered as an effective and safe palliative treatment option for LRBCs.


The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.


Emerging principles for the therapeutic exploitation of glycosylation.
Glycosylation plays a key role in a wide range of biological processes. Specific modification to a glycan's structure can directly modulate its biological function. Glycans are not only essential to glycoprotein folding, cellular homeostasis, and immune regulation but are involved in multiple disease conditions. An increased molecular and structural understanding of the mechanistic role that glycans play in these pathological processes has driven the development of therapeutics and illuminated novel targets for drug design. This knowledge has enabled the treatment of metabolic disorders and the development of antivirals and shaped cancer and viral vaccine strategies. Furthermore, an understanding of glycosylation has led to the development of specific drug glycoforms, for example, monoclonal antibodies, with enhanced potency.


Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care.
Patients with multiple myeloma (MM) experience significant delays in diagnosis due to non-specific symptomatology. The aim of this study was to characterise the frequency and timing of clinical features in the primary care setting prior to MM diagnosis. Population-based cohort study. Electronic health records data of approximately 17 million patients (2006-2016) within the UK Clinical Practice Research Datalink. Patients aged ≥18 years with newly diagnosed MM (NDMM), no history of solid tumours and ≥2 years registration in a primary care practice prior to MM diagnosis. Clinical features and symptoms including bone pain, skeletal-related events (SREs), investigation and confirmation of MM diagnostic CRAB criteria (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions) during the 2 years prior to MM diagnosis; time between symptom manifestation and/or relevant investigation and diagnosis of MM. Among 2646 patients with NDMM, 47.5% had a bone pain record during the 2-year period prior to MM diagnosis, mainly affecting the back. Regardless of baseline bone pain, investigations for serum calcium level were used in 36.4% of patients prior to MM diagnosis, followed by haemoglobin (65.6%) or renal function (74.1%). Median (Q1, Q3) time from first-recorded bone pain to MM diagnosis was 220 (80, 476) days. Median (Q1, Q3) time from first-recorded hypercalcaemia, renal impairment or anaemia to MM diagnosis was 23 (12, 46), 58 (17, 254) and 73 days (28, 232), respectively. An imaging investigation or referral for imaging was recorded for 60.0% of patients with bone pain/SRE and 32% without. Nearly half of patients diagnosed with NDMM presented with bone pain approximately 7 months prior to MM diagnosis. Investigations to evaluate all CRAB criteria, including targeted imaging, were underused. Early recognition of myeloma clinical features and optimised use of investigations in primary care may potentially expedite MM diagnosis.


Significance of orthopedic trauma specialists in trauma centers in Korea.
In 2012, the Korean central government selected trauma centers to provide effective treatment and reduce preventable mortality in severe trauma patients. General surgeons, thoracic surgeons, orthopedists, and neurosurgeons play pivotal roles in trauma centers, as most trauma patients require orthopedic procedures. This study aimed to underscore the importance of trauma orthopedic specialists (TOSs) by comparing treatment outcomes between a TOS and general orthopedists. Orthopedic trauma patients with injury severity scores > 15 points, admitted to level 1 trauma centers between March 2015 and December 2016, were divided into the TOS group (treated by 1 orthopedic trauma specialist who treats trauma patients with no limitation in the joint of specialization) and the general orthopedist group (GOG; treated by several general orthopedists who manage both trauma and disease but are each specialized in a certain joint). Emergency room response time, triage time, surgical preparation time, number of surgeries per patient, intensive care unit (ICU) duration, complications, and mortality were retrospectively analyzed. Among 272 patients, 52 were treated by a TOS and 220 were treated by several general orthopedists. For the TOS group and the GOG, the average emergency room response time was 8 and 32 min; average triage time, 27 and 162 min; average surgical preparation time, 141 and 350 min; average number of surgeries per patient, 1.9 and 2.7; and average ICU duration, 8.5 and 12.2 days, respectively. The TOS group saved $2700 per patient. No statistical differences were found in complications and mortality between the 2 groups. TOSs can provide rapid treatment to trauma patients and systemically participate in collaborative treatment with other specialists in a trauma center. As treatment provided by a TOS can also reduce the ICU duration, TOSs can play an important role in rapid rehabilitation and cost reduction for trauma patients.


Clinical unity and community empowerment: the use of smartphone technology to empower community management of chronic venous ulcers through the support of a tertiary unit.
Chronic ulcers affect roughly 60,000 Irish people, at a total cost of €600,000,000, or €10,000 per patient annually. By virtue of their chronicity, these ulcers also contribute a significant burden to tertiary outpatient vascular clinics. We propose utilizing mobile phone technology to decentralise care from tertiary centres to the community, improving efficiency and patient satisfaction, while maintaining patient safety. Bespoke mobile software was developed for Apples iPhone 4 platform. This allowed for the remote collection of patient images prospectively and their transmission with clinical queries, from the primary healthcare team to the tertiary centre. Training and iPhones were provided to five public health nurses in geographically remote areas of the region. Data were uploaded securely and user end software was developed allowing the review and manipulation of images, along with two way communication between the teams. Establishing reliability, patients were reviewed clinically as well as remotely, and concordance analysed. Qualitative data were collected through focus group discussion. From October to December 2011 eight patients (61-83 yrs, mean 75.3 yrs) with chronic venous ulceration and their five public health nurses were recruited. Data were transmitted using 3 G, Edge, GPRS and WiFi, at a mean speed of 69.03 kps. Concordance was 100% for wound bed assessment, 80% for skin integrity/colour and 60% for exudate assessment. Focus group analysis explored the concept, practicalities and future applications of the system. With an evolving national data network, the secure transmission of clinical images is a safe alternative to regular clinic appointments for patients with chronic venous ulceration. With further development, and packaged as a freely downloadable application, this has the potential to support the community care of chronic wounds.


Detection of redundant fusion transcripts as biomarkers or disease-specific therapeutic targets in breast cancer.
Fusion genes and fusion gene products are widely employed as biomarkers and therapeutic targets in hematopoietic cancers, but their applications have yet to be appreciated in solid tumors. Here, we report the use of SnowShoes-FTD, a powerful new analytic pipeline that can identify fusion transcripts and assess their redundancy and tumor subtype-specific distribution in primary tumors. In a study of primary breast tumors, SnowShoes-FTD was used to analyze paired-end mRNA-Seq data from a panel of estrogen receptor (ER)(+), HER2(+), and triple-negative primary breast tumors, identifying tumor-specific fusion transcripts by comparison with mRNA-Seq data from nontransformed human mammary epithelial cell cultures plus the Illumina Body Map data from normal tissues. We found that every primary breast tumor that was analyzed expressed one or more fusion transcripts. Of the 131 tumor-specific fusion transcripts identified, 86 were "private" (restricted to a single tumor) and 45 were "redundant" (distributed among multiple tumors). Among the redundant fusion transcripts, 7 were unique to ER(+) tumors and 8 were unique to triple-negative tumors. In contrast, none of the redundant fusion transcripts were unique to HER2(+) tumors. Both private and redundant fusion transcripts were widely expressed in primary breast tumors, with many mapping to genomic loci implicated in breast carcinogenesis and/or risk. Our finding that some fusion transcripts are tumor subtype-specific suggests that these entities may be critical determinants in the etiology of breast cancer subtypes, useful as biomarkers for tumor stratification, or exploitable as cancer-specific therapeutic targets.


Fahr's disease: an incidental finding in a patient of tubercular meningitis.
Fahr's disease, also known as idiopathic basal ganglia calcification, is a rare clinical entity characterised by bilaterally symmetric calcification of the basal ganglia. Most of the patients present with extrapyramidal symptoms, but the natural history, progression and treatment still remain unknown. We report a case of tubercular meningitis diagnosed by a cerebrospinal fluid examination with incidental findings of an extensive basal ganglia calcification on CT. CT of sibling, done to evaluate an episode of seizure, revealed strikingly similar calcification. Both these calcifications were due to Fahr's disease. The patient was treated with antitubercular and antiepileptic drugs. The patient fully recovered clinically and currently is seizure-free on antiepileptic treatment.


Cardiac tamponade as a complication of parenteral nutrition.
Complications arising from the use of central venous catheters are numerous, but cardiac tamponade is a complication well defined, very rare and often fatal. The mortality rate is 47-77% in the literature. We report a case of successful diagnosis and treatment of cardiac tamponade by parenteral nutrition in a 31-year-old female. There are only few cases of cardiac tamponade reported in the world literature since 1958. The true incidence is unclear and the most cases occur in children. Despite the rarity of this condition, it has a high mortality rate. The clinical findings are pain and discomfort in the epigastrium and chest region, nausea, dyspnea, tachycardia, distended jugular veins, paradoxical pulse, hypotension, electrocardiographic tracing signals with low voltage and enlargement of cardiac area. The immediate diagnosis and the treatment of cardiac tamponade are capital for patient survival. Cardiac tamponade should be suspected among patients with sudden onset of shock in use of parenteral nutrition, and therefore immediately treated.


A Differential Electrochemical Readout ASIC With Heterogeneous Integration of Bio-Nano Sensors for Amperometric Sensing.
A monolithic biosensing platform is presented for miniaturized amperometric electrochemical sensing in CMOS. The system consists of a fully integrated current readout circuit for differential current measurement as well as on-die sensors developed by growing platinum nanostructures (Pt-nanoS) on top of electrodes implemented with the top metal layer. The circuit is based on the switch-capacitor technique and includes pseudodifferential integrators for concurrent sampling of the differential sensor currents. The circuit further includes a differential to single converter and a programmable gain amplifier prior to an ADC. The system is fabricated in [Formula: see text] technology and measures current within [Formula: see text] with minimum input-referred noise of [Formula: see text] and consumes [Formula: see text] from a [Formula: see text] supply. Differential sensing for nanostructured sensors is proposed to build highly sensitive and offset-free sensors for metabolite detection. This is successfully tested for bio-nano-sensors for the measurement of glucose in submilli molar concentrations with the proposed readout IC. The on-die electrodes are nanostructured and cyclic voltammetry run successfully through the readout IC to demonstrate detection of [Formula: see text].


Correlation between Ovarian Reserve and Incidence of Ectopic Pregnancy after In Vitro Fertilization and Embryo Transfer.
To elucidate the correlation between ovarian reserve and the incidence of ectopic pregnancy (EP) following in vitro fertilization and embryo transfer (IVF/ET) cycles. In this observational study, 430 fresh IVF/ET cycles were examined from patient data of two university hospital infertility clinics. All included patients were positive for β-human chorionic gonadotropin (hCG) at 2 weeks after oocyte retrieval via controlled ovarian stimulation. For each cycle, information on age, duration of infertility, basal follicle stimulating hormone (FSH), anti-Müllerian hormone (AMH), days of ovarian stimulation, numbers of retrieved oocytes and transferred embryos, and pregnancy outcomes was collected. Patients with AMH lower than 1.0 ng/dL or basal FSH higher than 10 mIU/mL were classified into the decreased ovarian reserve (DOR) group, and the remaining patients were classified into the normal ovarian reserve (NOR) group. In total, 355 cycles showed NOR, and 75 cycles DOR. There were no significant differences between the DOR and NOR groups regarding intrauterine (74.7% vs. 83.4%, respectively) or chemical (14.7% vs. 14.1%, respectively) pregnancies. The DOR group had a higher EP than that of NOR group [10.7% (8/75) vs. 2.5% (9/355), p=0.004]. In both univariate [odds ratio (OR) 5.6, 95% confidence interval (CI) 1.4-9.6, p=0.011] and multivariate (adjusted OR 5.1, 95 % CI 1.1-18.7, p=0.012) analysis, DOR was associated with a higher risk of EP. DOR may be associated with a higher risk of EP in IVF/ET cycles with controlled ovarian stimulation. More careful monitoring may be necessary for pregnant women with DOR.


Contraceptive knowledge and attitudes among women seeking induced abortion in Kathmandu, Nepal.
To map the knowledge about and attitudes toward birth control methods among women in Kathmandu, Nepal, and to compare the results between women seeking an induced abortion and a control group. This was a cross-sectional cohort study with matched controls. Women aged 15-49 years seeking medical care at the Department of Gynecology and Obstetrics at Kathmandu Medical College were included and interviewed. A case was defined as a woman who sought an elective medical or surgical abortion. A control was defined as a woman who sought medical care at the outpatient department or had already been admitted to the ward for reasons other than elective abortion. A questionnaire developed for the study - dealing with different demographic characteristics as well as knowledge about and attitudes toward contraceptives - was filled out based on the interview. A total of 153 women were included: 64 women seeking an abortion and 89 controls. Women seeking an abortion had been pregnant more times than the control group and were more likely to have been informed about contraceptives. Women with higher education were less likely to seek an abortion than women with lower education. There was no significant difference in knowledge about and attitudes toward contraceptives between cases and controls. The women considered highest possible effectiveness to be the most important feature when deciding on a birth control method. Women seeking abortion in Kathmandu had shorter education and a history of more pregnancies and deliveries than women in the control group. Education and counseling on sex and reproduction as well as on contraceptive methods probably need to be improved in Nepal to avoid unwanted pregnancies. Attitudes about contraceptives need to be further investigated to develop better and more effective methods to educate women about family planning in order to increase reproductive health.


Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials.
To compare the safety and efficacy of antibiotic treatment versus appendicectomy for the primary treatment of uncomplicated acute appendicitis. Meta-analysis of randomised controlled trials. Randomised controlled trials of adult patients presenting with uncomplicated acute appendicitis, diagnosed by haematological and radiological investigations. Antibiotic treatment versus appendicectomy. The primary outcome measure was complications. The secondary outcome measures were efficacy of treatment, length of stay, and incidence of complicated appendicitis and readmissions. Four randomised controlled trials with a total of 900 patients (470 antibiotic treatment, 430 appendicectomy) met the inclusion criteria. Antibiotic treatment was associated with a 63% (277/438) success rate at one year. Meta-analysis of complications showed a relative risk reduction of 31% for antibiotic treatment compared with appendicectomy (risk ratio (Mantel-Haenszel, fixed) 0.69 (95% confidence interval 0.54 to 0.89); I(2)=0%; P=0.004). A secondary analysis, excluding the study with crossover of patients between the two interventions after randomisation, showed a significant relative risk reduction of 39% for antibiotic therapy (risk ratio 0.61 (0.40 to 0.92); I(2)=0%; P=0.02). Of the 65 (20%) patients who had appendicectomy after readmission, nine had perforated appendicitis and four had gangrenous appendicitis. No significant differences were seen for treatment efficacy, length of stay, or risk of developing complicated appendicitis. Antibiotics are both effective and safe as primary treatment for patients with uncomplicated acute appendicitis. Initial antibiotic treatment merits consideration as a primary treatment option for early uncomplicated appendicitis.


Targeted inversion of a polar silencer within the HoxD complex re-allocates domains of enhancer sharing.
Mammalian Hox genes are clustered at four genomic loci. During development, neighbouring genes are coordinately regulated by global enhancer sequences, which control multiple genes at once, as exemplified by the expression of series of contiguous Hoxd genes in either limbs or gut. The link between vertebrate Hox gene transcription and their clustered distribution is poorly understood. Experimental and comparative approaches have revealed that various mechanisms, such as gene clustering or global enhancer sequences, might have constrained this genomic organization and stabilized it throughout evolution. To understand what restricts the effect of a particular enhancer to a precise set of genes, we generated a loxP/Cre-mediated targeted inversion within the HoxD cluster. Mice carrying the inversion showed a reciprocal re-assignment of the limb versus gut regulatory specificities, suggesting the presence of a silencer element with a unidirectional property. This polar silencer appears to limit the number of genes that respond to one type of regulation and thus indicates how separate regulatory domains may be implemented within intricate gene clusters.


Azole and fungicide resistance in clinical and environmental Aspergillus fumigatus isolates.
Aspergillus fumigatus is a human pathogen but it is also a widespread filamentous fungus in the environment. A. fumigatus can therefore be exposed to antifungals used in medical and agricultural environments. Only the class of azoles is used in both of these environments (i.e. voriconazole and itraconazole in medicine; prochloraz, propiconazole or imazalil in agriculture). Exposure to azoles provides the potential for the development of resistance. Several clinical itraconazole-resistant isolates have been reported in A. fumigatus and their resistance mechanisms have been partially resolved. Since limited data exist on the susceptibility of A. fumigatus to both medical and agricultural antifungals, we undertook a drug susceptibility study including clinical (400) and agricultural (150) A. fumigatus isolates (Swiss origin). We tested azoles and also compounds of major antifungal classes used in agriculture (i.e. azoxystrobin, iprodione, benalaxyl or cyprodinil). The results showed that all A. fumigatus isolates were intrinsically resistant to iprodione, benalaxyl or cyprodinil (MIC90 > 32 microg x ml(-1)) and that azoxystrobin minimal inhibitory concentrations (MICs) showed a wide range (0.06 to 32 microg x ml(-1)). MIC ranges of azoles were compound-dependent. MIC90 for voriconazole, itraconazole, imazalil and prochloraz were within a range of 0.13 to 1 microg x ml(-1) and similar between clinical and environmental isolates, whereas propiconazole was the least active compound (MIC90: 4-8 microg x ml(-1)). Ten clinical and 36 environmental isolates with high itraconazole MIC ( > or = 2 microg x ml(-1)) were detected. In clinical isolates, no cross-resistance was observed between itraconazole and all others azoles tested. Several patterns of azole MICs were, however, observed in the environmental isolates. Unexpectedly, a single environmental isolate was voriconazole-resistant (MIC of 16 microg x ml(-1)) but still susceptible to itraconazole (MIC of 2 microg x ml(-1)). Taken together, our results demonstrate the absence of susceptibility of A. fumigatus isolates to non-azole agricultural agents and that there is little impact of azole resistance in both clinical and environmental isolates. When detected, azole resistance was compound-specific.


A clear solution: semiconductor nanocrystals as photoinitiators in solvent free polymerization.
Semiconductor nanocrystals have been shown to have unique advantages over traditional organic photoinitiators for polymerization in solution. However, efficient photoinitiation with such nanoparticles in solvent-free and additive-free formulations so far has not been achieved. Herein, the ability to use semiconductor nanocrystals for efficient bulk polymerization as sole initiators is reported, operating under modern UV-blue-LED light sources found in 3D printers and other photocuring applications. Hybrid semiconductor-metal nanorods exhibit superior photoinitiation capability to their pristine semiconductor counterparts, attributed to the enhanced charge separation and oxygen consumption in such systems. Moreover, photoinitiation by semiconductor nanocrystals overcoated by inorganic ligands is reported, thus increasing the scope of possible applications and shedding light on the photoinitiation mechanism; in light of the results, two possible pathways are discussed - ligand-mediated and cation-coordinated oxidation. A demonstration of the unique attributes of the quantum photoinitiators is reported in their use for high-resolution two-photon printing of optically fluorescing microstructures, demonstrating a multi-functionality capability. The bulk polymerization demonstrated here can be advantageous over solvent based methods as it alleviates the need of post-polymerization drying and reduces waste and exposure to toxic solvents, as well as broadens the possible use of quantum photoinitiators for industrial and research uses.


Yogurt Is a Low-Glycemic Index Food.
High yogurt intake is associated with a reduced risk of type 2 diabetes (T2DM). Although several mechanisms could explain this association, this paper addresses the glycemic and insulinemic impact of yogurt. There is evidence that low-glycemic index (GI) and low-glycemic load (GL) diets are associated with a reduced risk of T2DM. The 93 GI values for yogurt in the University of Sydney's GI database have a mean ± SD of 34 ± 13, and 92% of the yogurts are low-GI (≤55). The 43 plain yogurts in the database have a lower GI than the 50 sweetened yogurts, 27 ± 11 compared with 41 ± 11 (P < 0.0001). This difference is not explained by sugar, per se, but rather by the higher protein-to-carbohydrate ratio in plain yogurt. Although yogurt has a low GI, its insulinemic index (II) is higher than its GI. High insulin responses may be deleterious because hyperinsulinemia is associated with an increased risk of T2DM. Nevertheless, this may not be a concern for yogurt because, although its II is higher than its GI, the II of yogurt is within the range of II values for nondairy low-GI foods. In addition, mixed meals containing dairy protein elicit insulin responses similar to those elicited by mixed meals of similar composition containing nondairy protein. Because the GI of yogurt is lower than that of most other carbohydrate foods, exchanging yogurt for other protein and carbohydrate sources can reduce the GI and GL of the diet, and is in line with recommended dietary patterns, which include whole grains, fruits, vegetables, nuts, legumes, fish, vegetable oils, and yogurt.


Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells.
Natural killer (NK) cells play a key role in inflammation and tumor regression through their ability to migrate into tissues. CXCL12 is a chemokine that promotes lymphocyte invasion and migration into tissues; however, the mechanism for this process remains incompletely understood. In this study, we show that CXCL12 significantly enhanced CD16(+)CD56(+) human peripheral NK-cell invasion into type I collagen by the catalytic activity of matrix metalloproteinase-1 (MMP-1). Confocal immunofluorescence and co-immunoprecipitation studies suggest that MMP-1 colocalized with alpha(2)beta(1) integrin on CXCL-12-stimulated NK-cell surface. The binding of pro-MMP-1 with alpha(2)beta(1) integrin required activation of G(i)-coupled pathway. However, the production of MMP-1 from CXCL12-stimulated NK cells was mediated by p38 and mitogen-activated or extracellular signal-regulation protein kinase kinase 1/2 in a manner independent of the G(i)-coupled pathway. These results suggest that CXCL12/CXCR4 interaction transduces the two signaling pathways to promote NK-cell invasion, which stimulates pericellular degradation of extracellular matrix proteins by membrane-associated MMP-1. The mechanisms would thus play a role in facilitating lymphocyte trafficking and accumulation in tissues during physiological and pathological processes.


A systematic review on the effectiveness of complementary and alternative medicine for chronic non-specific low-back pain.
The purpose of this systematic review was to assess the effects of spinal manipulative therapy (SMT), acupuncture and herbal medicine for chronic non-specific LBP. A comprehensive search was conducted by an experienced librarian from the Cochrane Back Review Group (CBRG) in multiple databases up to December 22, 2008. Randomised controlled trials (RCTs) of adults with chronic non-specific LBP, which evaluated at least one clinically relevant, patient-centred outcome measure were included. Two authors working independently from one another assessed the risk of bias using the criteria recommended by the CBRG and extracted the data. The data were pooled when clinically homogeneous and statistically possible or were otherwise qualitatively described. GRADE was used to determine the quality of the evidence. In total, 35 RCTs (8 SMT, 20 acupuncture, 7 herbal medicine), which examined 8,298 patients, fulfilled the inclusion criteria. Approximately half of these (2 SMT, 8 acupuncture, 7 herbal medicine) were thought to have a low risk of bias. In general, the pooled effects for the studied interventions demonstrated short-term relief or improvement only. The lack of studies with a low-risk of bias, especially in regard to SMT precludes any strong conclusions; however, the principal findings, which are based upon low- to very-low-quality evidence, suggest that SMT does not provide a more clinically beneficial effect compared with sham, passive modalities or any other intervention for treatment of chronic low-back pain. There is evidence, however, that acupuncture provides a short-term clinically relevant effect when compared with a waiting list control or when acupuncture is added to another intervention. Although there are some good results for individual herbal medicines in short-term individual trials, the lack of homogeneity across studies did not allow for a pooled estimate of the effect. In general, these results are in agreement with other recent systematic reviews on SMT, but in contrast with others. These results are also in agreement with recent reviews on acupuncture and herbal medicine. Randomized trials with a low risk of bias and adequate sample sizes are directly needed.


Recent results using CAMPATH-1 antibodies to control GVHD and graft rejection.
Recent data from the CAMPATH users group are reported. Different protocols have been tested using the CD52 antibodies Campath-1M and Campath-1G for prevention of GVHD and graft rejection in allogeneic transplants from both sibling and volunteer unrelated donors. Leukaemia relapse remains a significant problem for patients with CML, but in other diseases the recent results using T cell depletion appear to be as good as, or better than, published data with conventional GVHD prophylaxis. In addition, the morbidity and mortality associated with chronic GVHD are substantially reduced. Future collaborative studies to consolidate these findings include a randomised trial of the humanised antibody Campath-1H organised under the auspices of the EBMT. There are also plans to carry out experimental studies using Campath-1 antibodies to deplete T cells from peripheral blood stem cell harvests.


Effect of chemically defined diets on antral and serum gastrin levels in rats.
When rats were fed isocaloric amounts of chemically defined diets with variable amounts of protein (8-60%) or fat (0-30%) over a 10-day period, their serum and antral gastrin concentrations were, respectively, 60 and 40% lower than the levels of chow-fed rats. It was also determined that neither the low bulk content of these diets nor their inability to adequately buffer the gastric pH contributed to this response. The time course of this dietary-induced reduction in gastrin levels was investigated and it was found that the serum hormone levels were significantly reduced as early as 1-2 h after chow-fed rats were placed on these chemically defined diets. Antral gastrin levels were maintained at normal levels for 4-5 days after rats started consuming these synthetic diets and fell thereafter. With all of the chemically defined diets tested, the gastrin secretory response to a meal was significantly reduced. It therefore appears that synthetic diets lack some undefined food constituent present in chow that is required for the normal postprandial release of gastrin or, alternatively, that they contain an inhibitory factor which blocks the normal secretory response.


Quantitation of hemodynamic function during developmental vascular regression in the mouse eye.
Ultrasound biomicroscopy (UBM) utilizes frequencies higher than conventional diagnostic ultrasound and can noninvasively provide anatomic and functional information about mouse ocular structures in vivo at high resolution. Vascular development can also be assessed with high-frequency Doppler imaging, which permits detection and characterization of ocular blood flow not detectable at lower, conventional Doppler frequencies. The eyes of CD-1 mice were examined daily from the day of birth to postnatal day (P)16. Hyaloid vascular system anatomy was imaged with UBM and microcomputed tomography (microCT). Blood flow velocity was also measured with Doppler UBM imaging in the hyaloid artery, vasa hyaloidea propria, tunica vasculosa lentis, and retina. In the mouse, the hyaloid vasculature degenerated from a well-defined structure at birth by progressive loss of branches. Hyaloid regression coincided with a progressive decrease in blood velocity detected in the hyaloid vascular structures, which is thought to be one of the major triggering factors of the regression in these vessels. At P13, no further blood flow was detected in the CD-1 mouse hyaloid vasculature. An inverse relationship was also shown between peak blood velocity in the lens and retina. UBM imaging provides a valuable means of rapidly and noninvasively characterizing ocular development in vivo. MicroCT scans have also provided intralumenal images of hyaloid vascular structure. This is the first study of vascular structure and function during the dynamic process of hyaloid vascular regression during mouse neonatal eye development and the first three-dimensional images of the complex hyaloid vascular structure.


Journal Club: incidental thyroid nodules detected at imaging: can diagnostic workup be reduced by use of the Society of Radiologists in Ultrasound recommendations and the three-tiered system?
The purpose of this study was to determine the number of thyroid nodule workups that could be eliminated and the number of malignant tumors that would be missed if the Society of Radiologists in Ultrasound (SRU) recommendations and the three-tiered system were applied to incidental thyroid nodules (ITN) detected at imaging. This retrospective study included ITN in 390 consecutively registered patients who underwent ultrasound-guided fine-needle aspiration of one or more thyroid nodules from July 2010 to June 2011. Images were reviewed, and nodules were categorized according to two workup criteria: ITN seen on ultrasound images were categorized according to SRU recommendations, and those seen on CT, MR, or PET/CT images were classified according to the three-tiered risk-categorization system. In this study 114 of 390 (29%) patients had nodules first detected incidentally during imaging studies, and 107 patients met the inclusion criteria. These patients had 47 ITN seen at ultrasound and 60 ITN seen at either CT, MRI, or PET/CT. If the SRU recommendations had been applied, 14 of 47 (30%) patients with ITN on ultrasound images would not have received fine-needle aspiration and one of four cases of cancer would have been missed. The missed malignant tumor was a 14-mm localized papillary carcinoma. If the three-tiered system had been applied, 21 of 60 (35%) patients with ITN on CT, MR, or PET/CT images would not have received fine-needle aspiration, but none of the three malignancies would have been missed. Overall, 35 of 107 (33%) of patients with ITN did not meet the SRU recommendations or the three-tiered criteria. Use of the SRU recommendations and three-tiered system can reduce the workup of ITN by one third compared with current practice without specific guidelines. One case of localized papillary carcinoma was missed when the SRU recommendations were used.


Equivalence of several generalized percolation models on networks.
In recent years, many variants of percolation have been used to study network structure and the behavior of processes spreading on networks. These include bond percolation, site percolation, k-core percolation, bootstrap percolation, the generalized epidemic process, and the Watts threshold model (WTM). We show that-except for bond percolation-each of these processes arises as a special case of the WTM, and bond percolation arises from a small modification. In fact "heterogeneous k-core percolation," a corresponding "heterogeneous bootstrap percolation" model, and the generalized epidemic process are completely equivalent to one another and the WTM. We further show that a natural generalization of the WTM in which individuals "transmit" or "send a message" to their neighbors with some probability less than 1 can be reformulated in terms of the WTM, and so this apparent generalization is in fact not more general. Finally, we show that in bond percolation, finding the set of nodes in the component containing a given node is equivalent to finding the set of nodes activated if that node is initially activated and the node thresholds are chosen from the appropriate distribution. A consequence of these results is that mathematical techniques developed for the WTM apply to these other models as well, and techniques that were developed for some particular case may in fact apply much more generally.


Arm Pain Versus Neck Pain: A Novel Ratio as a Predictor of Post-Operative Clinical Outcomes in Cervical Radiculopathy Patients.
Informed patient selection and counseling is key in improving surgical outcomes. Understanding the impact that certain baseline variables can have on postoperative outcomes is essential in optimizing treatment for certain symptoms, such as radiculopathy from cervical spine pathologies. The aim was to identify baseline characteristics that were related to improved or worsened postoperative outcomes for patients undergoing surgery for cervical spine radiculopathic pain. Retrospective review of prospectively collected data. Patient Sample: Surgical cervical spine patients with a diagnosis classification of "degenerative." Diagnoses included in the "degenerative" category were those that caused radiculopathy: cervical disc herniation, cervical stenosis, and cervical spondylosis without myelopathy. Baseline variables considered as predictors were: (1) age, (2) body mass index (BMI), (3) gender, (4) history of cervical spine surgery, (5) baseline Neck Disability Index (NDI) score, (6) baseline SF-36 Physical Component Summary (PCS) scores, (7) baseline SF-36 Mental Component Summary (MCS) scores, (8) Visual Analog Scale (VAS) Arm score, and (9) VAS Neck. Outcome Measures: Improvement in NDI (≥50%), VAS Arm/Neck (≥50%), SF-36 PCS/MCS (≥10%) scores at 2-years postoperative. An arm-to-neck ratio (ANR) was also generated from baseline VAS scores. Univariate and multivariate analyses evaluated predictors for 2-year postoperative outcome improvements, controlling for surgical complications and technique. Three hundred ninety-eight patients were included. Patients with ANR ≤ 1 (n = 214) were less likely to reach improvements in 2-year NDI (30.0% vs 39.2%, P = .050) and SF-36 PCS (42.4% vs 53.5%, P = .025). Multivariate analysis for neck disability revealed higher baseline SF-36 PCS (odds ratio [OR] 1.053) and MCS (OR 1.028) were associated with over 50% improvements. Higher baseline NDI were reduced odds of postoperative neck pain improvement (OR 0.958). Arm pain greater than neck pain at baseline was associated with both increased odds of postoperative arm pain improvement (OR 1.707) and SF36 PCS improvement (OR 1.495). This study identified specific symptom locations and health-related quality of life (HRQL) scores, which were associated with postoperative pain and disability improvement. In particular, baseline arm pain greater than neck pain was determined to have the greatest impact on whether patients met at least 50% improvement in their upper body pain score. These findings are important for clinicians to optimize patient outcomes through effective preoperative counseling.


Letting the cat out of the bag: athletes, coaches and physiotherapists share their perspectives on injury prevention in elite sports.
To explore how sports injury prevention takes place in elite sport practice and to describe the perspectives of athletes, coaches and physiotherapists regarding the most critical factors that help prevent injury in the elite sports context. Qualitative study. Semistructured interviews with 19 international level athletes, coaches and physiotherapists, from different Olympic sports. Interviews were transcribed verbatim and analysed using comparative data analysis based on Grounded Theory. The participants perceived injury risk as an inherent part of elite sports, because athletes try to enhance performance by pushing their limits. Participants described injury prevention as a learning process that changed over time, based on their sports experience and the injuries that they had sustained along their career. Communication among the athletes, coaches and physiotherapists was described as a key component of the injury prevention process. Study participants emphasised the relevance of teamwork and shared responsibility. Performance was presented as the core of the athlete's daily practice, indicating that injury prevention can be a means to that end but is not a goal in itself for this community. Participants perceive injury prevention as part of elite sports and thus embrace the need for injury prevention. Injury prevention strategies in elite sports were described as a learning process, following the dynamic nature of training for maximal performance. Performance is the participants' main goal.


Perioperative cerebral ischemia promote infiltrative recurrence in glioblastoma.
Hypoxia is a key driver for infiltrative growth in experimental gliomas. It has remained elusive whether tumor hypoxia in glioblastoma patients contributes to distant or diffuse recurrences. We therefore investigated the influence of perioperative cerebral ischemia on patterns of progression in glioblastoma patients. We retrospectively screened MRI scans of 245 patients with newly diagnosed glioblastoma undergoing resection for perioperative ischemia near the resection cavity. 46 showed relevant ischemia nearby the resection cavity. A control cohort without perioperative ischemia was generated by a 1:1 matching using an algorithm based on gender, age and adjuvant treatment. Both cohorts were analyzed for patterns of progression by a blinded neuroradiologist. The percentage of diffuse or distant recurrences at first relapse was significantly higher in the cohort with perioperative ischemia (61.1%) compared to the control cohort (19.4%). The results of the control cohort matched well with historical data. The change in patterns of progression was not associated with a difference in survival. This study reveals an unrecognized association of perioperative cerebral ischemia with distant or diffuse recurrence in glioblastoma. It is the first clinical study supporting the concept that hypoxia is a key driver of infiltrative tumor growth in glioblastoma patients.


The dual roles of homeobox genes in vascularization and wound healing.
Homeobox genes represent a family of highly conserved transcription factors originally discovered to regulate organ patterning during development. More recently, several homeobox genes were shown to affect processes in adult tissue, including angiogenesis and wound healing. Whereas a subset of members of the Hox-family of homeobox genes activate growth and migration to promote angiogenesis or wound healing, other Hox genes function to restore or maintain quiescent, differentiated tissue function. Pathological tissue remodeling is linked to differential expression of activating or stabilizing Hox genes and dysregulation of Hox expression can contribute to disease progression. Studies aimed at understanding the role and regulation of Hox genes have provided insight into how these potent morphoregulatory genes can be applied to enhance tissue engineering or limit cancer progression.


Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint.
Cdc7 kinase is evolutionarily conserved and is involved in initiation and progression of DNA replication. However, roles of Cdc7 in checkpoint responses remain largely unknown. In this study, we show that deletion of the Cdc7 genes in mouse embryonic stem (ES) cells abrogates hydroxyurea (HU)- or UV-induced activation of Chk1. HU-induced Chk1 activation is also impaired in human cancer cell lines in which Cdc7 is depleted by siRNA, and Cdc7-depleted cells are more sensitive to HU treatment. In contrast, ATR and Rad17 are relocated to chromatin in these cells following HU treatment, indicating that stalled DNA replication forks are detected normally. Cdc7-depleted cells exhibit defects in chromatin association and phosphorylation of Claspin, suggesting that Cdc7 exerts its effect at least partially through Claspin. Consistent with this prediction, Cdc7 interacts with and phosphorylates Claspin. We propose that Cdc7 is required for activation of the ATR-Chk1 checkpoint pathway through regulation of Claspin.


Mechanism and consequences for avoidance of superparasitism in the solitary parasitoid Cotesia vestalis.
A parasitoid's decision to reject or accept a potential host is fundamental to its fitness. Superparasitism, in which more than one egg of a given parasitoid species can deposit in a single host, is usually considered sub-optimal in systems where the host is able to support the development of only a single parasitoid. It follows that selection pressure may drive the capacity for parasitoids to recognize parasitized hosts, especially if there is a fitness cost of superparasitism. Here, we used microsatellite studies of two distinct populations of Cotesia vestalis to demonstrate that an egg laid into a diamondback moth (Plutella xylostella) larva that was parasitized by a conspecific parasitoid 10 min, 2 or 6 h previously was as likely to develop and emerge successfully as was the first-laid egg. Consistent with this, a naive parasitoid encountering its first host was equally likely to accept a healthy larva as one parasitized 10 min prior, though handling time of parasitized hosts was extended. For second and third host encounters, parasitized hosts were less readily accepted than healthy larvae. If 12 h elapsed between parasitism events, the second-laid egg was much less likely to develop. Discrimination between parasitized and healthy hosts was evident when females were allowed physical contact with hosts, and healthy hosts were rendered less acceptable by manual injection of parasitoid venom into their hemolymph. Collectively, these results show a limited capacity to discriminate parasitized from healthy larvae despite a viability cost associated with failing to avoid superparasitism.


Risk factors for pressure injuries among critical care patients: A systematic review.
To identify risk factors independently predictive of pressure injury (also known as pressure ulcer) development among critical-care patients. We undertook a systematic review of primary research based on standardized criteria set forth by the Institute of Medicine. We searched the following databases: CINAHL (EBSCOhost), the Cochrane Library (Wilson), Dissertations & Theses Global (ProQuest), PubMed (National Library of Medicine), and Scopus. There was no language restriction. A research librarian coordinated the search strategy. Articles that potentially met inclusion criteria were screened by two investigators. Among the articles that met selection criteria, one investigator extracted data and a second investigator reviewed the data for accuracy. Based on a literature search, we developed a tool for assessing study quality using a combination of currently available tools and expert input. We used the method developed by Coleman et al. in 2014 to generate evidence tables and a summary narrative synthesis by domain and subdomain. Of 1753 abstracts reviewed, 158 were identified as potentially eligible and 18 fulfilled eligibility criteria. Five studies were classified as high quality, two were moderate quality, nine were low quality, and two were of very low quality. Age, mobility/activity, perfusion, and vasopressor infusion emerged as important risk factors for pressure injury development, whereas results for risk categories that are theoretically important, including nutrition, and skin/pressure injury status, were mixed. Methodological limitations across studies limited the generalizability of the results, and future research is needed, particularly to evaluate risk conferred by altered nutrition and skin/pressure injury status, and to further elucidate the effects of perfusion-related variables. Results underscore the importance of avoiding overinterpretation of a single study, and the importance of taking study quality into consideration when reviewing risk factors. Maximal pressure injury prevention efforts are particularly important among critical-care patients who are older, have altered mobility, experience poor perfusion, or who are receiving a vasopressor infusion.


Thioredoxin is a potential therapy for light-induced photoreceptor degeneration in diabetic mice.
Retina degeneration is a set of disease that can be characterized by progressive loss of rod or cone photoreceptors that can experience higher light exposure compared with other parts of our body. To investigate in diabetic mice the effects of different light on retinal photoreceptor and its related mechanisms, 4-6 weeks male Balb/c mices were randomly divided into control group, light treatment group (light 1 and light 2), light treatment with filter membrane group (LFM1 and LFM2), light treatment filter blue light group (LFB), diabetic group (DM), diabetic with light treatment group (DM+Light), diabetic light treatment with filter membrane group (DM+LFM1 and DM+LFM2), diabetic light treatment with filter blue light group (DM+LFB). Electroretinography (ERG) was used to assess retinal function. H&E staining was used to observe the morphology and measure the outer nuclear layer thickness in the retina. The related gene expression was detected by Real-time PCR. Light can significantly reduce the retinal function, outer nuclear layer thickness, and Trx expression. After different kinds of membranes and blue light filter treatments, the outer nuclear layer thickness, Nrf2, Trx expression can be improved in diabetic mice. However, the expression of Txnip and ASK1 was decreased. Light can increase the photoreceptor damage in diabetic mice. The reduction of light intensity and change in the visible light components can reduce the light-induced damage in diabetic mice, and the mechanism may be related to up-regulation the antioxidant protein Trx expression.


Shock-Driven Endotheliopathy in Trauma Patients Is Associated with Leucocyte Derived Extracellular Vesicles.
Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock.