Enantioselective synthesis of boron-substituted quaternary carbons by NHC-Cu-catalyzed boronate conjugate additions to unsaturated carboxylic esters, ketones, or thioesters.
A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic alpha,beta-unsaturated carboxylic esters, ketones, and thioesters is disclosed. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C(1)-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired beta-boryl carbonyls in up to >98:2 enantiomer ratio (er). Processes involving unsaturated thioesters proceed with higher enantioselectivity (vs carboxylic esters or ketones), and the resulting products can be functionalized by Ag-mediated or Pd-catalyzed reactions that furnish the derived carboxylic ester or various ketones. Routine oxidation affords beta-hydroxy ketones or carboxylic esters, ketone aldol products that cannot be otherwise prepared efficiently by an alternative catalytic enantioselective protocol.


Magnitude knowledge: the common core of numerical development.
The integrated theory of numerical development posits that a central theme of numerical development from infancy to adulthood is progressive broadening of the types and ranges of numbers whose magnitudes are accurately represented. The process includes four overlapping trends: (1) representing increasingly precisely the magnitudes of non-symbolic numbers, (2) connecting small symbolic numbers to their non-symbolic referents, (3) extending understanding from smaller to larger whole numbers, and (4) accurately representing the magnitudes of rational numbers. The present review identifies substantial commonalities, as well as differences, in these four aspects of numerical development. With both whole and rational numbers, numerical magnitude knowledge is concurrently correlated with, longitudinally predictive of, and causally related to multiple aspects of mathematical understanding, including arithmetic and overall math achievement. Moreover, interventions focused on increasing numerical magnitude knowledge often generalize to other aspects of mathematics. The cognitive processes of association and analogy seem to play especially large roles in this development. Thus, acquisition of numerical magnitude knowledge can be seen as the common core of numerical development.


The effects of electrode placement upon EEG biofeedback training: the monopolar-bipolar controversy.
Roles of tradition, convenience, and noise or artifact rejection are discussed with regard to the monopolar versus bipolar electrode placement controversy in electroencephalography (EEG). Particular emphasis is placed on the relevance to biofeedback. The crucial interactions between the differential amplifier, brain waves, and monopolar/bipolar placements are discussed. Through logical analysis and empirical observation, it is demonstrated how the very nature of the EEG's differential amplifiers must destroy those elements of brain activity which are common to the recording electrodes. Controlled experiments further illustrate the critical importance of electrode placements. Various methods, including preferred electrode placements, are presented to help resolve recording problems that frequently arise. It is concluded that there are serious implications for researchers, EEG clinicians, biofeedback providers, and their clients in preferring one type of electrode placement technique over the other. EEG recording accuracy is affected by this choice.


Identification of novel protein-coding sequences in Eucalyptus grandis plants by high-resolution mass spectrometry.
Eucalyptus species are widely used in the forestry industry, and a significant increase in the number of sequences available in database repositories has been observed for these species. In proteomics, a protein is identified by correlating the theoretical fragmentation spectrum derived from genomic/transcriptomic data against the experimental fragmentation mass spectrum acquired from large-scale analysis of protein mixtures. Proteogenomics is an alternative approach that can identify novel proteins encoded by regions previously considered as non-coding. This study aimed to confidently identify and confirm the existence of previously unknown protein-coding sequences in the Eucalyptus grandis genome. To this end, we used a modified spectral correlation strategy and a dedicated de novo peptide sequencing pipeline. Upon the strategy used here, we confidently identified 41 novel peptide forms and six peptides containing at least one single amino acid substitution. The most representative genomic class of novel peptides was identified as originating from alternative reading frames. In contrast, no clear single amino acid substitution pattern was identified. Validation of the identifications was carried out using a parallel reaction monitoring approach that provided further mass spectrometry support for the existence of the novel peptide sequences. Data are available via ProteomeXchange with identifier PXD022110.


Fatal accidents and blood ethanol levels in adolescents and adults. The Wayne County experience, 1978-1988.
The files of 874 fatal traumatic accident victims, aged 12-25 years, examined at the Wayne County Medical Examiner's Office during the period 1978-1988 were reviewed. Postmortem blood alcohol results of individuals who died after less than 15 min of hospitalization were utilized to approximate alcohol levels at the time of the fatal injury. Relationships between types of accidents, sex, age, race, and time of accident were examined. White victims were far more likely to have been drinking than blacks, and the data indicated that underaged drinkers were involved in fatal accidents at lower levels of blood alcohol than their counterparts of legal drinking age. Consistent racial differences in average alcohol levels were not observed, however. Unlike female and black victims, who much less frequently tested positive for alcohol when underage, white male victims 16-21 years of age were just as likely to have been drinking as those aged 21-25. The results of the study show that postmortem blood alcohol level can be used to identify differences in alcohol consumption among groups of accident victims in a major metropolitan area.


Magnetic field effects of photocarrier generation in bulk heterojunctions at low temperature.
We report an experimental investigation of the magnetic field effect (MFE) in polymer bulk heterojunction devices at temperatures below 10 K using photocarrier extraction by linearly increasing voltages. The examined devices were composed of an active layer of poly(3-hexylthiophene) and [6,6]-phenyl-C61-butyric acid methyl ester. In the experiments, the delay time (td) dependence of the MFE was investigated in detail. For td < 80 μs, a positive MFE was observed in the field region B < 0.1 T and a negative MFE was observed for B > 0.2 T. For td > 8 ms, only a positive MFE proportional to B2 was observed. For the photocurrent pulse detected immediately after light irradiation, the MFE was negligibly small. In a high magnetic field of 15 T, a significant MFE exceeding 80% was observed at 1.8 K for td = 800 ms. We discuss the results based on a model of triplet-singlet (or singlet-triplet) conversion in the magnetic field and estimate the exchange integral for the charge-transfer exciton in this photovoltaic cell.


Comparison of pain levels in fusion prostate biopsy and standard TRUS-Guided biopsy.
Fusion prostate biopsy (FPB) has recently emerged as a popular and successful biopsy technique on diagnosis of prostate cancer. The aim of this study was to compare the pain levels in TRUS-guided standard 12-core prostate biopsy (SPB) and MpMRI-guided FPB. Patients detected with a PI-RADS (Prostate Imaging Reporting and Data System) ≥3 lesion on MpMRI underwent MpMRI-guided FPB (Group I) and the patients who had no suspected lesions or had a PI-RADS<3 lesion on MpMRI underwent TRUS-guided SPB (Group II). Pain assessment was performed using Visual Analog Scale (VAS) five minutes after the procedure. Following the procedure, the patients were asked to indicate the most painful biopsy step among the three steps. 252 patients were included in this study (Group I=159, Group II=93). The mean number of cores and the malignancy detection rate were significantly higher in Group I compared to Group II (p<0.001, p=0.043, respectively). No significant difference was found between the two groups with regard to VAS scores (p=0.070). The most painful part of the whole procedure was revealed to be the insertion of the probe into the rectum. However, no significant difference was found between the two groups with regard to the most painful biopsy step (p=0.140). FPB, with a relatively higher cancer detection rate, leads to the same pain level as SPB although it increases the number of biopsy cores and involves a more complex procedure compared to SPB. Further prospective studies with larger patient series are needed to substantiate our findings.


CMOS-Compatible Protonic Programmable Resistor Based on Phosphosilicate Glass Electrolyte for Analog Deep Learning.
Ion intercalation based programmable resistors have emerged as a potential next-generation technology for analog deep-learning applications. Proton, being the smallest ion, is a very promising candidate to enable devices with high modulation speed, low energy consumption, and enhanced endurance. In this work, we report on the first back-end CMOS-compatible nonvolatile protonic programmable resistor enabled by the integration of phosphosilicate glass (PSG) as the proton solid electrolyte layer. PSG is an outstanding solid electrolyte material that displays both excellent protonic conduction and electronic insulation characteristics. Moreover, it is a well-known material within conventional Si fabrication, which enables precise deposition control and scalability. Our scaled all-solid-state three-terminal devices show desirable modulation characteristics in terms of symmetry, retention, endurance, and energy efficiency. Protonic programmable resistors based on phosphosilicate glass, therefore, represent promising candidates to realize nanoscale analog crossbar processors for monolithic CMOS integration.


Pregnancy, alcohol intake, and intimate partner violence among men and women attending drinking establishments in a Cape Town, South Africa township.
The highest rates of fetal alcohol syndrome worldwide can be found in South Africa. Particularly in impoverished townships in the Western Cape, pregnant women live in environments where alcohol intake during pregnancy has become normalized and interpersonal violence (IPV) is reported at high rates. For the current study we sought to examine how pregnancy, for both men and women, is related to alcohol use behaviors and IPV. We surveyed 2,120 men and women attending drinking establishments in a township located in the Western Cape of South Africa. Among women 13.3% reported being pregnant, and among men 12.0% reported their partner pregnant. For pregnant women, 61% reported attending the bar that evening to drink alcohol and 26% reported both alcohol use and currently experiencing IPV. Daily or almost daily binge drinking was reported twice as often among pregnant women than non-pregnant women (8.4% vs. 4.2%). Men with pregnant partners reported the highest rates of hitting sex partners, forcing a partner to have sex, and being forced to have sex. High rates of alcohol frequency, consumption, binge drinking, consumption and binge drinking were reported across the entire sample. In general, experiencing and perpetrating IPV were associated with alcohol use among all participants except for men with pregnant partners. Alcohol use among pregnant women attending shebeens is alarmingly high. Moreover, alcohol use appears to be an important factor in understanding the relationship between IPV and pregnancy. Intensive, targeted, and effective interventions for both men and women are urgently needed to address high rates of drinking alcohol among pregnant women who attend drinking establishments.


Oxygen-induced retinopathy in the rat. Vitamins C and E as potential therapies.
Oxygen-induced retinopathy (OIR) was produced by subjecting newborn albino rats to a 60% oxygen atmosphere for 14 days before they were killed and retinal analysis was done. The extent of OIR was measured by estimating the severity of retinal vasoobliteration in ink-perfused flat-mounted retinas. This was done with the aid of a digitizing camera and an image-analysis system designed to create binary images of the retinal blood vessels. Retinal levels of several antioxidant molecules also were measured. Alpha-tocopherol and ascorbic acid were reduced in oxygen-exposed rats by 34% and 20%, respectively, compared with room air-raised control animals. Retinal glutathione reductase, S-transferase, and peroxidase showed no differences between oxygen-treated and -untreated rats. Attempts to increase the newborn rats' retinal ascorbic acid by administering daily subcutaneous injections (5 g/kg body weight) to the mother rats were unsuccessful. However, the level of retinal alpha-tocopherol of newborn rats could be altered by dietary manipulation of the mothers. The mothers were fed diets containing either 1 g alpha-tocopherol acetate/kg food or none, starting 21-25 days before the birth of their litters and lasting throughout the exposure period. This treatment resulted in three- to fourfold differences in the retinal alpha-tocopherol levels of the pups. The combination of dietary and oxygen treatments also resulted in significant differences in retinal glutathione peroxidase activity, with the vitamin E-deprived, oxygen-exposed group having highest levels. Newborn rats both supplemented with and deprived of alpha-tocopherol had less vasoobliteration than did those nursed by mothers fed rat chow.


The Impact of Social Pensions on Intergenerational Relationships: Comparative Evidence from China.
China launched a new rural pension scheme (hereafter NRPS) for rural residents in 2009, now covering almost all counties with over 400 million people enrolled. This implementation of the largest social pension program in the world offers a unique setting for studying the economics of intergenerational relationships during development, given the rapidity of China's population aging, traditions of filial piety and co-residence, decreasing number of children, and dearth of formal social security, at a relatively low income level. We draw on rich household surveys from two provinces at distinct development stages - impoverished Guizhou and relatively well-off Shandong - to better understand heterogeneity in the impact of pension benefits. Employing a fuzzy regression discontinuity design, we find that around the pension eligibility age cut-off, the NRPS significantly reduces intergenerational co-residence, especially between elderly parents and their adults sons; promotes pensioners' healthcare service consumption; and weakens (but does not supplant) non-pecuniary and pecuniary transfers across three generations. These effects are much larger in less developed Guizhou province.


Should junior doctors strike?
An impasse in negotiations between the Department of Health (DoH) and the British Medical Association in November this year led to an overwhelming vote for industrial action (IA) by junior doctors. At the time of writing, a last minute concession by DoH led to a deferment of IA to allow further negotiations mediated by the Advisory, Conciliation and Arbitration Service. However, IA by junior doctors remains a possibility if these negotiations stall again. Would the proposed action be ethically justifiable? Furthermore, is IA by doctors ever ethically defendable? Building on previous work, we explore important ethical considerations for doctors considering IA. The primary moral objection to doctors striking is often claimed to be risk of harm to patients. Other common arguments against IA by doctors include breaching their vocational responsibilities and possible damage to their relationship with patients and the public in general. These positions are in turn countered by claims of a greater long-term good and the legal and moral rights of employees to strike. Absolute restrictions appear to be hard to justify in the modern context, as does an unrestricted right to IA. We review these arguments, find that some common moral objections to doctors striking may be less relevant to the current situation, that a stronger contemporary objection to IA might be from a position of social justice and suggest criteria for ethically permissible doctor IA.


The detectivity of electron beam scanning types of image tubes.
A theoretical development has been applied to vidicon and orthicon types of image tubes which is similar to that used for ir photodetectors. In essence, a differential equation applicable to these image tubes has been used to obtain exact solutions for signal and noise. These expressions account for factors such as storage, frequency response, resolution, and efficiency. They can be inserted into the usual definitions of noise equivalent power, detectivity star, and detective quantum efficiency to provide exact expressions indicating the dependence of these quantities on basic factors governing tube generation. Experimental procedures are proposed for making signal and noise measurements which provide information directly comparable to those for photodetectors.


Endocytosis and recycling of varicella-zoster virus Fc receptor glycoprotein gE: internalization mediated by a YXXL motif in the cytoplasmic tail.
Varicella-zoster virus (VZV) encodes a cell surface Fc receptor, glycoprotein gE. VZV gE has previously been shown to display several features common to nonviral cell surface receptors. Most recently, VZV gE was reported to be tyrosine phosphorylated on a dimeric form (J. K. Olson, G. A. Bishop, and C. Grose, J. Virol. 71:110-119, 1997). Thereafter, attention focused on the ability of VZV gE to undergo receptor-mediated endocytosis. The current transient transfection studies demonstrated by confocal microscopy and internalization assays that VZV gE was endocytosed when expressed in HeLa cells. Endocytosis of gE was shown to be dependent on clathrin-coated vesicle formation within the cells. Subsequent colocalization studies showed that endocytosis of VZV gE closely mimicked endocytosis of the transferrin receptor. The gE cytoplasmic tail and more specifically tyrosine residue 582 were determined by mutagenesis studies to be important for efficient internalization of the protein; this tyrosine residue is part of a conserved YXXL motif. The amount of gE internalized at any given time reached a steady state of 32%. In addition, like the transferrin receptor, internalized gE recycled to the cell surface. The finding of gE endocytosis provided insight into earlier documentation of gE serine/threonine and tyrosine phosphorylation, since these phosphorylation events may serve as sorting signals for internalized receptors. Taken together with the previous discovery that both human and simian immunodeficiency virus envelope proteins can undergo endocytosis, the gE findings suggest that endocytosis of envelope components may be a posttranslational regulatory mechanism among divergent families of enveloped viruses.


Renal Function as a Predictor of Early Transmetatarsal Amputation Failure.
Chronic kidney disease (CKD) is a major concern in patients with foot disease because it is associated with high rates of neuropathy, peripheral vascular disease, and poor wound healing. The purpose of this study was to evaluate renal dysfunction as a risk factor for reamputation after initial transmetatarsal amputation (TMA). Patients who underwent a TMA were retrospectively identified in the American College of Surgeons National Surgical Quality Improvement Program database. Of 2018 patients, reamputation after TMA occurred in 4.4%. End-stage renal disease (ESRD) was associated with 100% increased odds of TMA failure (adjusted odds ratio [OR] = 2.00; 95% CI = 1.10, 3.52), 128% increased odds of major amputation (adjusted OR = 2.28; 95% CI = 1.27, 3.96), and 182% increased odds of 30-day mortality (adjusted OR = 2.82; 95% CI = 1.69, 4.64). In addition, white blood cell count >10 000/mm3 and deep infection at the time of surgery were independently associated with TMA failure. In conclusion, severe renal dysfunction is associated with TMA failure in the short-term, perioperative period. There was no incremental increase in risk of TMA failure with worsening level of renal function before ESRD. A multidisciplinary approach should be implemented in patients with CKD to prevent foot-related pathologies that may necessitate lower-extremity amputation. Levels of Evidence: Level III: Retrospective cohort study.


Judges' views of child sexual abuse: evaluating beliefs against research findings in a Finnish sample.
Beliefs impact our decision-making and different professionals have been shown to have beliefs about child sexual abuse (CSA) that do not coincide with scientific findings. In the present study, judges' beliefs regarding CSA were explored. Finnish judges (N = 104) answered a questionnaire about CSA related issues as well as questions regarding their professional experience of CSA cases. The judges held both correct and incorrect beliefs; while their CSA prevalence estimates were rather well in line with research findings, half of the participants estimated that no professionals use suggestive methods when interviewing children and more than 40% thought suggestive methods can be useful when trying to get a child to tell about real events. Judges correctly assumed symptoms cannot be used to assess a CSA case, however, the majority thought play observations were appropriate means for evaluating such suspicions. Experience seemed to lead to more confidence in their own expertise but not in an actual increase in knowledge, namely, judges thought themselves more expert when more experienced although their expertise as measured by the questionnaire did not improve. Overall, the judges had both correct and erroneous beliefs but while experience did not improve the situation, gaining information about CSA did. More research about the beliefs of judges and how such beliefs impact legal decision-making is needed.


Serum CYFRA 21-1 in advanced stage non-small cell lung cancer: an early measure of response.
Our objective was to test the prognostic importance of both the pretreatment level and change in serum CYFRA 21-1 after one cycle of chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and to compare these two CYFRA variables to routine clinical stage and response as measured by imaging. Our patients consisted of 58 with advanced NSCLC who were treated with chemotherapy. Fourteen were stage IIIa, 8 stage IIIb, and 36 stage IV, and none had received previous treatment. The choice of chemotherapy was left to the discretion of the treating physicians. We collected two serum samples, one before the first cycle of chemotherapy and the second before the second cycle, and analyzed these for serum CYFRA 21-1 using an electrochemiluminescence immunoassay and the ElecSys 2010 system (Roche Diagnostics Corp., Indianapolis, IN). We expressed changes in CYFRA in terms of the natural ratio logarithm of post-treatment to pretreatment CYFRA, and we used the Cox proportional hazards model to analyze survival time. Patients experienced an average drop of 27% in serum CYFRA after the first cycle of chemotherapy. Furthermore, the Cox model demonstrated that both the initial natural logarithm of serum CYFRA and presence of >27% drop in CYFRA were significantly related to subsequent survival (model P < 0.0006), but neither clinical stage nor clinical response related to survival (P > 0.1). In advanced stage NSCLC, the initial level of serum CYFRA appears to provide more prognostic information than clinical stage. Furthermore, a drop of >27% in CYFRA after one cycle of therapy adds prognostic information, so that this threshold appears to be an early measure of response to chemotherapy.


Prevalence and correlates of elder mistreatment in a community-dwelling population of U.S. Chinese older adults.
This study aimed to examine the prevalence and correlates of elder mistreatment among U.S. Chinese older adults. Data were drawn from the Population-Based Study of ChINese Elderly (PINE) study, a population-based epidemiological survey of 3,159 U.S. Chinese older adults in the Greater Chicago area. The study design was guided by a community-based participatory research approach. This study found a prevalence of 15.0% for elder mistreatment among community-dwelling Chinese older adults. In addition, higher levels of education (r = .16, p< .001), fewer children (r = .1, p< .001), lower health status (r = .11, p< .001), poorer quality of life (r = .05, p< .01), and worsening health over the past year (r = .08, p< .001) were positively correlated with any elder mistreatment. Elder mistreatment is prevalent among U.S. Chinese older adults. The findings point to a pressing need for researchers, community service workers, health care providers, and policy makers to increase efforts on reducing elder mistreatment in U.S. Chinese communities.


The diminishing returns of atovaquone-proguanil for elimination of Plasmodium falciparum malaria: modelling mass drug administration and treatment.
Artemisinin resistance is a major threat to current efforts to eliminate Plasmodium falciparum malaria which rely heavily on the continuing efficacy of artemisinin combination therapy (ACT). It has been suggested that ACT should not be used in mass drug administration (MDA) in areas where artemisinin-resistant P. falciparum is prevalent, and that atovaquone-proguanil (A-P) might be a preferable alternative. However, a single point mutation in the cytochrome b gene confers high level resistance to atovaquone, and such mutant parasites arise frequently during treatment making A-P a vulnerable tool for elimination. A deterministic, population level, mathematical model was developed based on data from Cambodia to explore the possible effects of large-scale use of A-P compared to dihydroartemisinin-piperaquine ACT for mass drug administration and/or treatment of P. falciparum malaria, with and without adjunctive primaquine (PQ) and long-lasting insecticide-treated bed nets (LLIN). The aim was local elimination. The model showed the initial efficacy of ACT and A-P for MDA to be similar. However, each round of A-P MDA resulted in rapid acquisition and spread of atovaquone resistance. Even a single round of MDA could compromise efficacy sufficient to preclude its use for treatment or prophylaxis. A switch to A-P for treatment of symptomatic episodes resulted in a complete loss of efficacy in the population within four to five years of its introduction. The impact of MDA was temporary and a combination of maintained high coverage with ACT treatment for symptomatic individuals and LLIN was necessary for elimination. For malaria elimination, A-P for MDA or treatment of symptomatic cases should be avoided. A combined strategy of high coverage with ACT for treatment of symptomatic episodes, LLIN and ACT + P MDA would be preferable.


[Development of utero-chorionic vascular resistance in early pregnancy].
The physiologic evolution of the utero-chorionic vascular resistances during the first trimester of pregnancy is described. With the use of pulsed Doppler, 25 normal pregnancies were followed weekly, performing 288 scans between the 6th and the 12th weeks of pregnancy. The detection of the FVW was done at the level of the uterine and retro-chorionic vessels. There is a progressive decrease of the vascular resistances to flow, with significant differences (p less than 0.001) between the values before and after the 9th week. The physiologic implications and its possible application to the study of the gestational pathology are commented.


The Global Network Maternal Newborn Health Registry: a multi-country, community-based registry of pregnancy outcomes.
The Global Network for Women's and Children's Health Research (Global Network) conducts clinical trials in resource-limited countries through partnerships among U.S. investigators, international investigators based in in low and middle-income countries (LMICs) and a central data coordinating center. The Global Network's objectives include evaluating low-cost, sustainable interventions to improve women's and children's health in LMICs. Accurate reporting of births, stillbirths, neonatal deaths, maternal mortality, and measures of obstetric and neonatal care is critical to determine strategies for improving pregnancy outcomes. In response to this need, the Global Network developed the Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnant women, fetuses and neonates receiving care in defined catchment areas at the Global Network sites. This publication describes the MNHR, including participating sites, data management and quality and changes over time. Pregnant women who reside in or receive healthcare in select communities are enrolled in the MNHR of the Global Network. For each woman and her offspring, sociodemographic, health care, and the major outcomes through 42-days post-delivery are recorded. Study visits occur at enrollment during pregnancy, at delivery and at 42 days postpartum. From 2010 through 2018, the Global Network MNHR sites were located in Guatemala, Belagavi and Nagpur, India, Pakistan, Democratic Republic of Congo, Kenya, and Zambia. During this period at these sites, 579,140 pregnant women were consented and enrolled in the MNHR, nearly 99% of all eligible women. Delivery data were collected for 99% of enrolled women and 42-day follow-up data for 99% of those delivered. In this supplement, the trends over time and assessment of differences across geographic regions are analyzed in a series of 18 manuscripts utilizing the MNHR data. Improving maternal, fetal and newborn health in countries with poor outcomes requires an understanding of the characteristics of the population, quality of health care and outcomes. Because the worst pregnancy outcomes typically occur in countries with limited health registration systems and vital records, alternative registration systems may prove to be highly valuable in providing data. The MNHR, an international, multicenter, population-based registry, assesses pregnancy outcomes over time in support of efforts to develop improved perinatal healthcare in resource-limited areas. Trial Registration The Maternal Newborn Health Registry is registered at Clinicaltrials.gov (ID# NCT01073475). Registered February 23, 2019. https://clinicaltrials.gov/ct2/show/NCT01073475.


Peripheral gangrene in children with atypical hemolytic uremic syndrome.
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe clinical manifestation, frequent recurrence, and poor long-term prognosis. It is usually caused by abnormalities in complement regulation. We report 2 cases of children affected by a catastrophic extrarenal complication. A 4-year-old Indian girl developed gangrene of the finger tips 2 days after initial presentation of aHUS. Factor H autoantibodies were identified. Renal function continued to decline despite daily plasma exchanges, and she was started on peritoneal dialysis 5 days after admission. The distal tips of the left hand remained gangrenous with a line of demarcation. Three weeks later, she did not return for follow-up and died at home because of dialysis-related complications. An Arabic girl developed end-stage renal disease due to aHUS in the fourth month after birth. A de novo activating C3 mutation was found. At age 9 months, she suddenly developed ischemic changes in fingers of both hands and several toes. The lesions progressed, and several finger tips became gangrenous despite intense plasma exchange therapy. The decision was made to administer complement blocking therapy with the C5 antibody eculizumab. All nonnecrotic digits rapidly regained perfusion. The 3 already gangrenous fingers healed with loss of the end phalanges. During maintenance, eculizumab aHUS activity subsided completely and some late recovery of renal function was observed. aHUS may present by thrombotic macroangiopathy of small peripheral arteries. Eculizumab appears effective in preserving tissue viability if administered before gangrene occurs and should be considered as first-line rescue therapy in such cases.


The multilocus sequence typing network: mlst.net.
The unambiguous characterization of strains of a pathogen is crucial for addressing questions relating to its epidemiology, population and evolutionary biology. Multilocus sequence typing (MLST), which defines strains from the sequences at seven house-keeping loci, has become the method of choice for molecular typing of many bacterial and fungal pathogens (and non-pathogens), and MLST schemes and strain databases are available for a growing number of prokaryotic and eukaryotic organisms. Sequence data are ideal for strain characterization as they are unambiguous, meaning strains can readily be compared between laboratories via the Internet. Laboratories undertaking MLST can quickly progress from sequencing the seven gene fragments to characterizing their strains and relating them to those submitted by others and to the population as a whole. We provide the gateway to a number of MLST schemes, each of which contain a set of tools for the initial characterization of strains, and methods for relating query strains to other strains of the species, including clustering based on differences in allelic profiles, phylogenetic trees based on concatenated sequences, and a recently developed method (eBURST) for identifying clonal complexes within a species and displaying the overall structure of the population. This network of MLST websites is available at http://www.mlst.net.


Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis using UK Biobank data: population based cohort study.
To evaluate the benefit of combining polygenic risk scores with the QCancer-10 (colorectal cancer) prediction model for non-genetic risk to identify people at highest risk of colorectal cancer. Population based cohort study. Data from the UK Biobank study, collected between March 2006 and July 2010. 434 587 individuals with complete data for genetics and QCancer-10 predictions were included in the QCancer-10 plus polygenic risk score modelling and validation cohorts. Prediction of colorectal cancer diagnosis by genetic, non-genetic, and combined risk models. Using data from UK Biobank, six different polygenic risk scores for colorectal cancer were developed using LDpred2 polygenic risk score software, clumping, and thresholding approaches, and a model based on genome-wide significant polymorphisms. The top performing genome-wide polygenic risk score and the score containing genome-wide significant polymorphisms were combined with QCancer-10 and performance was compared with QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. Polygenic risk scores derived using the LDpred2 program performed best, with an odds ratio per standard deviation of 1.584 (95% confidence interval 1.536 to 1.633), and top age and sex adjusted C statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10 plus polygenic risk score models out-performed QCancer-10 alone. In men, the integrated LDpred2 model produced a C statistic of 0.730 (0.720 to 0.741) and explained variation of 28.2% (26.3 to 30.1), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9 to 23.1) for QCancer-10 alone. In women, the C statistic for the integrated LDpred2 model was 0.687 (0.673 to 0.702) and explained variation was 21.0% (18.7 to 23.7), compared with 0.645 (0.631 to 0.659) and 12.4% (10.3 to 14.6) for QCancer-10 alone. In the top 20% of individuals at highest absolute risk, the sensitivity and specificity of the integrated LDpred2 models for predicting colorectal cancer diagnosis was 47.8% and 80.3% respectively in men, and 42.7% and 80.1% respectively in women, with increases in absolute risk in the top 5% of risk in men of 3.47-fold and in women of 2.77-fold compared with the median. Illustrative decision curve analysis indicated a small incremental improvement in net benefit with QCancer-10 plus polygenic risk score models compared with QCancer-10 alone. Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population.


Anticipatory planning and control of grasp positions and forces for dexterous two-digit manipulation.
Dexterous object manipulation requires anticipatory control of digit positions and forces. Despite extensive studies on sensorimotor learning of digit forces, how humans learn to coordinate digit positions and forces has never been addressed. Furthermore, the functional role of anticipatory modulation of digit placement to object properties remains to be investigated. We addressed these questions by asking human subjects (12 females, 12 males) to grasp and lift an inverted T-shaped object using precision grip at constrained or self-chosen locations. The task requirement was to minimize object roll during lift. When digit position was not constrained, subjects could have implemented many equally valid digit position-force coordination patterns. However, choice of digit placement might also have resulted in large trial-to-trial variability of digit position, hence challenging the extent to which the CNS could have relied on sensorimotor memories for anticipatory control of digit forces. We hypothesized that subjects would modulate digit placement for optimal force distribution and digit forces as a function of variable digit positions. All subjects learned to minimize object roll within the first three trials, and the unconstrained device was associated with significantly smaller grip forces but larger variability of digit positions. Importantly, however, digit load force modulation compensated for position variability, thus ensuring consistent object roll minimization on each trial. This indicates that subjects learned object manipulation by integrating sensorimotor memories with sensory feedback about digit positions. These results are discussed in the context of motor equivalence and sensorimotor integration of grasp kinematics and kinetics.


Do Moral Communities Play a Role in Criminal Sentencing? Evidence From Pennsylvania.
Religion and social control have been a sociological concern since Durkheim and Weber, and the relationship between religion and punishment has long been the subject of speculation. However, surprisingly little empirical research exists on the role of religion or religious context in criminal justice, and almost no research on the role of religious context on actual sentencing practices. We conceptualize the potential relationships between religious context and sentencing severity by drawing from the focal concerns and court community perspectives in the sentencing literature and moral communities theory developed by Rodney Stark. We suspect that Christian moral communities might shape notions of perceived blameworthiness for court community actors. Such moral communities might also affect notions of community protection - affecting perceptions of dangerousness, or perhaps rehabilitation, and might influence practical constraints/consequences (e.g., local political ramifications of harsh or lenient sentences). We examine these questions using a set of hierarchical models using sentencing data from Pennsylvania county courts and data on the religious composition of Pennsylvania counties from the Associated Religion Data Archives. We find that county Christian religious homogeneity increases the likelihood of incarceration. In addition, Christian homogeneity as well as the prevalence of civically engaged denominations in a county condition the effects of important legally relevant determinants of incarceration. Furthermore, we find evidence that Christian homogeneity activates the effect of local Republican electoral dominance on incarceration. We argue that Christian homogeneity effects sentencing practices primarily through local political processes that shape the election of judges and prosecutors.


Toxic exposures and psychiatric disease--lessons from the epidemiology of cancer.
Toxic chemicals such as lead, methyl mercury, organic solvents, manganese, kepone, and the organophosphates are recognized to cause psychiatric disease. Whether such associations are exceptional, or if in fact a high proportion of all psychiatric illnesses are of toxic environmental etiology, and therefore potentially avoidable, is not known. Epidemiologic studies of cancer, particularly analyses of geographic variations in mortality, of variations in incidence in migrant populations, of trends over time, and of induction by environmental agents suggest that extragenetic environmental factors (tobacco, alcohol, drugs, diet, radiation, air pollution, and industrial chemicals) may account for the majority of all human cancers. Similar application of epidemiologic techniques to the study of psychiatric illnesses might yield etiologic clues in relation to toxic environmental exposures and may also suggest approaches to disease prevention.


Reverse engineering of metabolic networks, a critical assessment.
Inferring metabolic networks from metabolite concentration data is a central topic in systems biology. Mathematical techniques to extract information about the network from data have been proposed in the literature. This paper presents a critical assessment of the feasibility of reverse engineering of metabolic networks, illustrated with a selection of methods. Appropriate data are simulated to study the performance of four representative methods. An overview of sampling and measurement methods currently in use for generating time-resolved metabolomics data is given and contrasted with the needs of the discussed reverse engineering methods. The results of this assessment show that if full inference of a real-world metabolic network is the goal there is a large discrepancy between the requirements of reverse engineering of metabolic networks and contemporary measurement practice. Recommendations for improved time-resolved experimental designs are given.


Outbreak of West Nile virus causing severe neurological involvement in children, Nuba Mountains, Sudan, 2002.
An atypical outbreak of West Nile virus (WNV) occurred in Ngorban County, South Kordophan, Sudan, from May to August 2002. We investigated the epidemic and conducted a case-control study in the village of Limon. Blood samples were obtained for cases and controls. Patients with obvious sequelae underwent cerebrospinal fluid (CSF) sampling as well. We used enzyme-linked immunosorbent assay (ELISA) and neutralization tests for laboratory diagnosis and identified 31 cases with encephalitis, four of whom died. Median age was 36 months. Bivariate analysis did not reveal any significant association with the risk factors investigated. Laboratory analysis confirmed presence of IgM antibodies caused by WNV in eight of 13 cases, indicative of recent viral infection. The unique aspects of the WNW outbreak in Sudan, i.e. disease occurrence solely among children and the clinical domination of encephalitis, involving severe neurological sequelae, demonstrate the continuing evolution of WNV virulence. The spread of such a virus to other countries or continents cannot be excluded.


Functional evidence that intercellular adhesion molecule-1 (ICAM-1) is a ligand for LFA-1-dependent adhesion in T cell-mediated cytotoxicity.
Although intercellular adhesion molecule-1 (ICAM-1) has been implicated as a ligand in some LFA-1-dependent adhesion, its importance to T cell function has not been established. The present studies investigate the importance of ICAM-1 for human cytotoxic T lymphocytes (CTL), both in their formation of antigen-independent conjugates (AIC) and in their lysis of targets. Analysis of monoclonal antibody (mAb) inhibition of AIC formation indicate that ICAM-1 mAb 1 blocks (a) AIC formation with some but not all targets; (b) the LFA-1 pathway but not the CD2/LFA-3 pathway of adhesion; (c) by binding to the target cell, not the T cell. In studies of cell-mediated lysis (CML) ICAM-1 mAb inhibited lysis of some targets, such as U-937, that use ICAM-1 predominantly in AIC formation; CML on some other targets is not inhibited by ICAM-1 mAb. These data indicate that ICAM-1 is a ligand for AIC formation, antigen-specific CTL recognition and cytolysis of particular target cells. The data also indicate that ICAM-1 is not used in LFA-1-dependent CTL interactions with all kinds of target cells, suggesting the existence of alternative ligands for LFA-1.


Effect of phase of stimulation on acute damage caused by eccentric contractions in mouse soleus muscle.
Eccentric contractions (activation during muscle lengthening) can cause muscle damage. The effect of phase of stimulation on the extent of muscle damage was studied by using the work-loop method. For the work-loop method, the muscle was subjected to sinusoidal length changes at 2 Hz. The muscle was activated at different times during the imposed length-change cycle; this time is called the phase of stimulation. Work was calculated from the loop formed when force was plotted against length. Work done was positive when the muscle was shortening and was negative when the muscle was lengthening; net work was the difference. One complete length-change cycle was 100 (i.e., given as a percentage of the cycle); shortening occurred from 25 to 75. The muscle did the most net work when stimulated at phase 20, that is, when activation started just before shortening. Damage was defined as a decrease in work. Significant damage occurred after a single trial of three consecutive eccentric contractions; the muscle did less positive and less net work because of the damage. Maximal damage occurred at phases 90 and 0, the center of the lengthening part of the length-change cycle (work decreased 10%). Negligible damage occurred at phases 20-40. Negative work (work required to lengthen the muscle) also decreased because of the damage. Eccentric contractions caused much more damage than concentric contractions during oscillatory work.


Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate.
In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0-3) with the recommended DMF dosage (240 mg twice daily). Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks. The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing and related symptoms was 5% in the placebo group and 37% in the DMF group. Most GI and flushing events were of mild or moderate severity and resolved during the study. The events were temporally associated with the use of diverse symptomatic therapies (efficacy not assessed) and infrequently led to DMF discontinuation. This integrated analysis indicates that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.


Meningioangiomatosis in young dogs: a case series and literature review.
Meningioangiomatosis (MA) is a proliferative disorder of the central nervous system (CNS) that has been reported rarely in humans and sporadically in dogs. Meningioangiomatosis may occur in the brainstem or cervical spinal cord of young dogs and can be identified tentatively by magnetic resonance imaging. The histopathologic hallmark of MA is a leptomeningeal plaque that extends along the CNS microvasculature and invades the adjacent neural parenchyma. This case series describes the neurologic signs, clinical progression, diagnostic imaging, and neuropathology of 4 dogs with MA. The 4 dogs with MA are compared and contrasted with 4 previously reported cases in dogs as well as with their human counterpart.


From molecular to colloidal manganese vanadium oxides for water oxidation catalysis.
The spontaneous, sonication-driven conversion of a molecular manganese vanadium oxide water oxidation catalyst, (n-Bu4N)3[Mn4V4O17(OAc)3] × 3H2O, into colloidal manganese vanadium oxide particles (average particle size ca. 70 nm) together with their stability and chemical water oxidation activity is reported. The nanoparticulate metal oxide colloid (approximate composition: VMn5O10·ca. 6H2O·ca. 0.2nBu4N+) is formed spontaneously when the molecular precursor is sonicated in water. The particles show water oxidation activity when combined with CeIV as the oxidant, are stable even under highly acidic reaction conditions and can be recovered and reused.


High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis.
To define whether the high sensitivity cardiac troponin T (hs-cTnT) assay in patients with immunoglobulin light chain amyloidosis (AL) improves risk prediction. Cardiac involvement is the major cause of death in patients with AL amyloidosis. Risk stratification is facilitated by cardiac biomarkers such as cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Stored serum from patients with newly diagnosed AL was used to measure hs-cTnT, cTnT, and NT-proBNP. Survival modelling was performed. The direct numeric result from hs-cTnT measurement cannot merely be substituted for a cTnT measurement in the Mayo AL staging system. The performance of the receiver operator curve derived an hs-cTnT cut-point of 54 ng/L which improves on the value of 35 ng/L validated with the prior iteration of the assay. An alternate staging option using hs-cTnT alone-using the two thresholds 14 ng/L and 54 ng/L-performs as well as either the original Mayo AL staging system or other systems incorporating hs-cTnT. On multivariate analysis, an hs-cTnT alone staging system was independent of period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models were explored, but none performed better than the original system or the new hs-cTnT system. Thus, hs-cTnT can be used alone for the staging of disease prognosis. A survival model based on hs-cTnT improves the prognostic staging of patients with AL amyloidosis, relegating NT-proBNP to a measure of cardiac response.


Ear Mite Removal in the Santa Catalina Island Fox (Urocyon littoralis catalinae): Controlling Risk Factors for Cancer Development.
Ear mites (Otodectes cynotis) and ear canal tumors are highly prevalent among federally endangered Island foxes (Urocyon littoralis catalinae) living on Santa Catalina Island off the coast of Southern California. Since studies began in the 1990s, nearly all foxes examined were found to be infected with ear mites, and ceruminous gland tumors (carcinomas and adenomas) were detected in approximately half of all foxes ≥ 4 years of age. We hypothesized that reduction of ear mite infection would reduce otitis externa and ceruminous gland hyperplasia, a risk factor for tumor development. In this study, we conducted a randomized field trial to assess the impact of acaricide treatment on ear mite prevalence and intensity of infection, otitis externa, ceruminous gland hyperplasia, and mite-specific IgG and IgE antibody levels. Treatment was highly effective at eliminating mites and reducing otitis externa and ceruminous gland hyperplasia, and mite-specific IgG antibody levels were significantly lower among uninfected foxes. Ceruminous gland hyperplasia increased in the chronically infected, untreated foxes during the six month study. Our results provide compelling evidence that acaricide treatment is an effective means of reducing ear mites, and that mite removal in turn reduces ear lesions and mite-specific IgG antibody levels in Santa Catalina Island foxes. This study has advanced our understanding of the underlying pathogenesis which results in ceruminous gland tumors, and has helped inform management decisions that impact species conservation.


LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects.
A recently published study showed the safety and efficacy of LSD-assisted psychotherapy in patients with anxiety associated with life-threatening diseases. Participants of this study were included in a prospective follow-up. 12 months after finishing LSD psychotherapy, 10 participants were tested for anxiety (STAI) and participated in a semi-structured interview. A Qualitative Content Analysis (QCA) was carried out on the interviews to elaborate about LSD effects and lasting psychological changes. None of the participants reported lasting adverse reactions. The significant benefits as measured with the STAI were sustained over a 12-month period. In the QCA participants consistently reported insightful, cathartic and interpersonal experiences, accompanied by a reduction in anxiety (77.8%) and a rise in quality of life (66.7%). Evaluations of subjective experiences suggest facilitated access to emotions, confrontation of previously unknown anxieties, worries, resources and intense emotional peak experiences à la Maslow as major psychological working mechanisms. The experiences created led to a restructuring of the person's emotional trust, situational understanding, habits and world view. LSD administered in a medically supervised psychotherapeutic setting can be safe and generate lasting benefits in patients with a life-threatening disease. Explanatory models for the therapeutic effects of LSD warrant further study.


An update on the management of urinary tract infections in the era of antimicrobial resistance.
Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growing concern due to limited therapeutic options. Gram-negative bacteria, specifically Enterobacteriaceae, are common causes of both community-acquired and hospital acquired UTIs. These organisms can acquire genes that encode for multiple antibiotic resistance mechanisms, including extended-spectrum-lactamases (ESBLs), AmpC- β -lactamase, and carbapenemases. The assessment of suspected UTI includes identification of characteristic symptoms or signs, urinalysis, dipstick or microscopic tests, and urine culture if indicated. UTIs are categorized according to location (upper versus lower urinary tract) and severity (uncomplicated versus complicated). Increasing rates of antibiotic resistance necessitate judicious use of antibiotics through the application of antimicrobial stewardship principles. Knowledge of the common causative pathogens of UTIs including local susceptibility patterns are essential in determining appropriate empiric therapy. The recommended first-line empiric therapies for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-day course of nitrofurantion or a 3-g single dose of fosfomycin tromethamine. Second-line options include fluoroquinolones and β-lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs due to AmpC- β -lactamase-producing organisms include fosfomycin, nitrofurantion, fluoroquinolones, cefepime, piperacillin-tazobactam and carbapenems. In addition, treatment options for UTIs due to ESBLs-producing Enterobacteriaceae include nitrofurantion, fosfomycin, fluoroquinolones, cefoxitin, piperacillin-tazobactam, carbapenems, ceftazidime-avibactam, ceftolozane-tazobactam, and aminoglycosides. Based on identification and susceptibility results, alternatives to carbapenems may be used to treat mild-moderate UTIs caused by ESBL-producing Enterobacteriaceae. Ceftazidime-avibactam, colistin, polymixin B, fosfomycin, aztreonam, aminoglycosides, and tigecycline are treatment options for UTIs caused by carbapenem-resistant Enterobacteriaceae (CRE). Treatment options for UTIs caused by multidrug resistant (MDR)-Pseudomonas spp. include fluoroquinolones, ceftazidime, cefepime, piperacillin-tazobactam, carbapenems, aminoglycosides, colistin, ceftazidime-avibactam, and ceftolozane-tazobactam. The use of fluoroquinolones for empiric treatment of UTIs should be restricted due to increased rates of resistance. Aminoglycosides, colistin, and tigecycline are considered alternatives in the setting of MDR Gram-negative infections in patients with limited therapeutic options.


Estimation of monthly surface air temperatures from MODIS LST time series data: application to the deserts in the Sultanate of Oman.
Air temperature records in remote deserts and inaccessible mountainous regions rely upon data acquired from the nearest meteorological stations, which could be at tens of kilometers apart. The present study provides a reliable approach to extract air temperatures for any distant region using thermal data of satellite images. The study postulates that if there is a strong correlation between land surface temperatures (LST) from satellite images and air temperature records from ground meteorological stations, hence, air temperatures (day/night) could be directly extrapolated from regression equations with high confidence results. Data utilized in this study were obtained from 12 meteorological stations settled and distributed upon different physiographic units of Oman. Satellite images were acquired from the Moderate Resolution Imaging Spectroradiometer (MODIS) LST product. Regression analysis of max and min air temperatures from weather stations was conducted versus day and night LST from MODIS Aqua LST (MYD11A2) images. Results showed that the regression coefficients for the selected locations are strong for the night/min (R2 = 0.81-0.94) and day/max (R2 = 0.72-0.92) correlations of the 12 stations. The root mean square errors (RMSE) of the statistical models are 0.97 and 1.98 for the night and day temperatures, respectively. Moreover, the association between each pair of the data is significant at the 99% level (p < 0.01). As MODIS data cover large geographic extents, it was possible to produce national diurnal and annual air temperature maps of accurate records with considering the variation of the physiographic setting.


Post-traumatic stress disorder (PTSD) after childbirth.
There has been discussion about the possible occurrence of post-traumatic stress disorder (PTSD) in mothers after difficult childbirth. Four cases with a symptom profile suggestive of PTSD commencing within 48 hours of childbirth are presented. The PTSD was in each case associated with the delivery. In each case, there was an associated depressive illness. All four had persistent disorders, and two had difficulties with mother/infant attachment. As confirmed by other reports, the prevalence of PTSD associated with childbirth is a matter of concern.


PTSD in those who care for the injured.
Post Traumatic Stress Disorder (PTSD) has become a focus for the care of trauma victims, but the incidence of PTSD in those who care for injured patients has not been well studied. Our hypothesis was that a significant proportion of health care providers involved with trauma care are at risk of developing PTSD. A system-wide survey was applied using a modified version of the Primary Care PTSD Screen [PC-PTSD], a validated PTSD screening tool currently being used by the VA to screen veterans for PTSD. Pre-hospital and in-hospital care providers including paramedics, nurses, trauma surgeons, emergency medicine physicians, and residents were invited to participate in the survey. The survey questionnaire was anonymously and voluntarily performed online using the Qualtrix system. Providers screened positive if they affirmatively answered any three or more of the four screening questions and negative if they answered less than three questions with a positive answer. Respondents were grouped by age, gender, region, and profession. 546 providers answered all of the survey questions. The screening was positive in 180 (33%) and negative in 366 (67%) of the responders. There were no differences observed in screen positivity for gender, region, or age. Pre-hospital providers were significantly more likely to screen positive for PTSD compared to the in-hospital providers (42% vs. 21%, P<0.001). Only 55% of respondents had ever received any information or education about PTSD and only 13% of respondents ever sought treatment for PTSD. The results of this survey are alarming, with high proportions of healthcare workers at risk for PTSD across all professional groups. PTSD is a vastly underreported entity in those who care for the injured and could potentially represent a major problem for both pre-hospital and in-hospital providers. A larger, national study is warranted to verify these regional results.


Leptin increases mitotic index and regeneration ratio in hepatectomized rats.
The aim of this study was to evaluate the potential effect of intraperitoneal administration of leptin on the hepatic regeneration and the mitotic index. 56 Sprague-Dawley rats were divided into 7 groups each containing 8 rats. Group 1 was evaluated as the sham group and no surgical procedure was performed on animals. The rats in groups 2, 3, and 4 (named C24, C48, C72, respectively) were given intraperitoneal injection of 2 ml/kg normal saline 60 minutes before the surgical procedure consisting of laparotomy and 70% hepatectomy. These groups were used as controls at 24, 48, and 72 hours. The rats in groups 5, 6, and 7 (named L24, L48, and L72, respectively) were given intraperitoneal injection of 20 µg/kg doses of recombinant mouse leptin 60 minutes before the same surgical procedure. These groups were evaluated as the experiment groups at 24, 48, and 72 hours. Blood samples were collected for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and the remaining tissue samples were obtained for liver histopathology, regeneration rate, and mitotic index (MI). The weights of the remaining livers were also noted. The values of AST and ALT were higher in the groups that were administered leptin and they had significantly higher mitotic index than the other groups. Leptin also significantly increased the regeneration ratio as compared to the control group. The weights of the remaining livers were also higher in the leptin groups. Intraperitoneal administration of leptin was observed to increase liver regeneration and mitotic rate in 70% hepatectomized rats.


UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination.
Ubiquitination of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitination, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. We have previously shown that mice lacking the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, are infertile associated with meiotic arrest at prophase I. We here show that UBR2 localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates transcriptional silencing via the ubiquitination of histone H2A. UBR2 interacts with the ubiquitin conjugating enzyme HR6B and its substrate H2A and promotes the HR6B-H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in chromosome-wide transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. Our findings suggest that insufficiency in UBR2-dependent histone ubiquitination triggers a pachytene checkpoint system, providing a new insight into chromatin remodeling and gene expression regulation.


The pathophysiology of hyperventilation syndrome.
Hyperventilation is defined as breathing in excess of the metabolic needs of the body, eliminating more carbon dioxide than is produced, and, consequently, resulting in respiratory alkalosis and an elevated blood pH. The traditional definition of hyperventilation syndrome describes "a syndrome, characterized by a variety of somatic symptoms induced by physiologically inappropriate hyperventilation and usually reproduced by voluntary hyperventilation". The spectrum of symptoms ascribed to hyperventilation syndrome is extremely broad, aspecific and varying. They stem from virtually every tract, and can be caused by physiological mechanisms such as low Pa,CO2, or the increased sympathetic adrenergic tone. Psychological mechanisms also contribute to the symptomatology, or even generate some of the symptoms. Taking the traditional definition of hyperventilation syndrome as a starting point, there should be three elements to the diagnostic criterion: 1) the patient should hyperventilate and have low Pa,CO2, 2) somatic diseases causing hyperventilation should have been excluded, and 3) the patient should have a number of complaints which are, or have been, related to the hypocapnia. Recent studies have questioned the tight relationship between hypocapnia and complaints. However, the latter can be maintained and/or elicited when situations in the absence of hypocapnia in which the first hyperventilation and hypocapnia was present recur. Thus, the main approach to diagnosis is the detection of signs of (possible) dysregulation of breathing leading to hypocapnia. The therapeutic approach to hyperventilation syndrome has several stages and/or degrees of intervention: psychological counselling, physiotherapy and relaxation, and finally drug therapy. Depending on the severity of the problem, one or more therapeutic strategies can be chosen.


Nanoplasmonic Sensor Detects Preferential Binding of IRSp53 to Negative Membrane Curvature.
Biosensors based on plasmonic nanostructures are widely used in various applications and benefit from numerous operational advantages. One type of application where nanostructured sensors provide unique value in comparison with, for instance, conventional surface plasmon resonance, is investigations of the influence of nanoscale geometry on biomolecular binding events. In this study, we show that plasmonic "nanowells" conformally coated with a continuous lipid bilayer can be used to detect the preferential binding of the insulin receptor tyrosine kinase substrate protein (IRSp53) I-BAR domain to regions of negative surface curvature, i.e., the interior of the nanowells. Two different sensor architectures with and without an additional niobium oxide layer are compared for this purpose. In both cases, curvature preferential binding of IRSp53 (at around 0.025 nm-1 and higher) can be detected qualitatively. The high refractive index niobium oxide influences the near field distribution and makes the signature for bilayer formation less clear, but the contrast for accumulation at regions of negative curvature is slightly higher. This work shows the first example of analyzing preferential binding of an average-sized and biologically important protein to negative membrane curvature in a label-free manner and in real-time, illustrating a unique application for nanoplasmonic sensors.


Comparative Proteomic Analysis of Rana chensinensis Oviduct.
As one of most important traditional Chinese medicine resources, the oviduct of female Rana chensinensis (Chinese brown frog) was widely used in the treatment of asthenia after sickness or delivery, deficiency in vigor, palpitation, and insomnia. Unlike other vertebrates, the oviduct of Rana chensinensis oviduct significantly expands during prehibernation, in contrast to the breeding period. To explain this phenomenon at the molecular level, the protein expression profiles of Rana chensinensis oviduct during the breeding period and prehibernation were observed using isobaric tags for relative and absolute quantitation (iTRAQ) technique. Then, all identified proteins were used to obtain gene ontology (GO) annotation. Ultimately, KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis was performed to predict the pathway on differentially expressed proteins (DEPs). A total of 4479 proteins were identified, and 312 of them presented different expression profiling between prehibernation and breeding period. Compared with prehibernation group, 86 proteins were upregulated, and 226 proteins were downregulated in breeding period. After KEGG enrichment analysis, 163 DEPs were involved in 6 pathways, which were lysosome, RNA transport, glycosaminoglycan degradation, extracellular matrix (ECM)⁻receptor interaction, metabolic pathways and focal adhesion. This is the first report on the protein profiling of Rana chensinensis oviduct during the breeding period and prehibernation. Results show that this distinctive physiological phenomenon of Rana chensinensis oviduct was mainly involved in ECM⁻receptor interaction, metabolic pathways, and focal adhesion.


Insulin inhibits glucocorticoid-stimulated L-type 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression by activation of the c-Jun N-terminal kinase pathway.
The hepatic isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PF2K/Fru-2,6-BPase) is transcriptionally stimulated by glucocorticoids, whereas insulin blocks this stimulatory effect. Although this inhibitory effect has been extensively reported, nothing is known about the signalling pathway responsible. We have used well-characterized inhibitors for proteins involved in different signalling cascades to assess the involvement of these pathways on the transcriptional regulation of glucocorticoid-stimulated PF2K/Fru-2,6-BPase by insulin. Our results demonstrate that the phosphoinositide 3-kinase, p70/p85 ribosomal S6 kinase, extracellular signal-regulated protein kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase pathways are not involved in the inhibitory effect of insulin on glucocorticoid-stimulated PF2K/Fru-2,6-BPase. To evaluate the implication of the MAP kinase/ERK kinase (MEK)-4-stress-activated protein kinase-c-Jun-N-terminal protein kinase ('JNK-SAPK') pathway we overexpressed the N-terminal JNK-binding domain of the JNK-interacting protein 1 ('JIP-1'), demonstrating that activation of JNK is necessary for the insulin inhibitory effect. Moreover, overexpression of MEK kinase 1 and JNK-haemagglutinin resulted in the inhibition of the glucocorticoid-stimulated PF2K/Fru-2,6-BPase. These results provide clear and specific evidence for the role of JNK in the insulin inhibition of glucocorticoid-stimulated PF2K/Fru-2,6-BPase gene expression. In addition, we performed experiments with a mutant of the glucocorticoid receptor in which the JNK phosphorylation target Ser-246 had been mutated to Ala. Our results demonstrate that the phosphorylation of the glucocorticoid receptor on Ser-246 is not responsible for the JNK repression of glucocorticoid-stimulated PF2K/Fru-2,6-BPase gene expression.


Enzymic characteristics of fat globule membranes from bovine colostrum and bovine milk.
Fat globule membranes have been isolated from bovine colostrum and bovine milk by the dispersion of the fat in sucrose solutions at 4 degrees C and fractionation by centrifugation through discontinuous sucrose gradients. The morphology and enzymic characteristics of the separated fractions were examined. Fractions comprising a large proportion of the total extracted membrane were thus obtained having high levels of the Golgi marker enzymes UDP-galactose N-acetylglucosamine beta-4-galactosyltransferase and thiamine pyrophosphatase. A membrane-derived form of the galactosyltransferase has been solubilized from fat and purified to homogeneity. This enzyme is larger in molecular weight than previously studied soluble galactosyltransferases, but resembles in size the galactosyltransferase of lactating mammary Golgi membranes. In contrast, when fat globule membranes were prepared by traditional procedures, which involved washing the fat at higher temperatures, before extraction, galactosyltransferase was not present in the membranes, having been released into supernatant fractions, When the enzyme released by this procedure was partially purified and examined by gel filtration, it was found to be of a degraded form resembling in size the soluble galactosyltransferase of milk. The release is therefore attributed to the action of proteolytic enzymes. Our observations contrast with previous biochemical studies which suggested that Golgi membranes do not contribute to the milk fat globule membrane. They are, however, consistent with electron microscope studies of the fat secretion process, which indicate that secretory vesicle membranes, derived from the Golgi apparatus, may provide a large proportion of the fat globule membrane.


Optimization strategies for DNA microarray-based detection of bacteria with 16S rRNA-targeting oligonucleotide probes.
The usability of the DNA microarray format for the specific detection of bacteria based on their 16S rRNA genes was systematically evaluated with a model system composed of six environmental strains and 20 oligonucleotide probes. Parameters such as secondary structures of the target molecules and steric hindrance were investigated to better understand the mechanisms underlying a microarray hybridization reaction, with focus on their influence on the specificity of hybridization. With adequate hybridization conditions, false-positive signals could be almost completely prevented, resulting in clear data interpretation. Among 199 potential nonspecific hybridization events, only 1 false-positive signal was observed, whereas false-negative results were more common (17 of 41). Subsequent parameter analysis revealed that this was mainly an effect of reduced accessibility of probe binding sites caused by the secondary structures of the target molecules. False-negative results could be prevented and the overall signal intensities could be adjusted by introducing a new optimization strategy called directed application of capture oligonucleotides. The small number of false-positive signals in our data set is discussed, and a general optimization approach is suggested. Our results show that, compared to standard hybridization formats such as fluorescence in situ hybridization, a large number of oligonucleotide probes with different characteristics can be applied in parallel in a highly specific way without extensive experimental effort.


Nicotinamide Nucleotide Transhydrogenase as a Novel Treatment Target in Adrenocortical Carcinoma.
Adrenocortical carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. In this study, we evaluated a potential new treatment target for ACC, focusing on the mitochondrial reduced form of NAD phosphate (NADPH) generator nicotinamide nucleotide transhydrogenase (NNT). NNT has a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating human NNT mutations result in congenital adrenal insufficiency. We hypothesized that NNT silencing in ACC cells will induce toxic levels of oxidative stress. To explore this, we transiently knocked down NNT in NCI-H295R ACC cells. As predicted, this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress. Steroidogenesis was paradoxically stimulated by NNT loss, as demonstrated by mass spectrometry-based steroid profiling. Next, we generated a stable NNT knockdown model in the same cell line to investigate the longer lasting effects of NNT silencing. After long-term culture, cells adapted metabolically to chronic NNT knockdown, restoring their redox balance and resilience to oxidative stress, although their proliferation remained suppressed. This was associated with higher rates of oxygen consumption. The molecular pathways underpinning these responses were explored in detail by RNA sequencing and nontargeted metabolome analysis, revealing major alterations in nucleotide synthesis, protein folding, and polyamine metabolism. This study provides preclinical evidence of the therapeutic merit of antioxidant targeting in ACC as well as illuminating the long-term adaptive response of cells to oxidative stress.


Prevalence and factors associated with sleep disorders among children with cerebral palsy in Uganda; a cross-sectional study.
Sleep plays a prominent role in the growth and development of children. Children with cerebral palsy (CP) are more prone to sleep disorders (SDs) than their peers. Children with CP, have a higher prevalence of disorders involving; initiation and maintenance of sleep, sleep-wake transition, excessive sleepiness and arousal. These sleep disorders impact on the quality of life of these children. Despite, having a high prevalence of CP in Uganda, there is a paucity of data that focuses on sleep disorders in CP, including a lack of prevalence estimates of sleep breathing disorder (SBD) in CP. Understanding the prevalence and disorders of sleep within this population would help advise on the development of tailored interventions to address the needs of these children and improve their quality of life. This study determined the prevalence and associated factors of sleep disorders among children aged 2 - 12 years with cerebral palsy in Uganda. This was a cross sectional study. All participants had a physical examination and screening with the Sleep Disturbances Scale for Children (SDSC) questionnaire to determine the prevalence of sleeps disorders. A total score (TS) ≥ 51 on the Sleep Disturbances Scale for Children was regarded as abnormal. A total of 135 participants were recruited. The prevalence of sleep disorders was 43/135 (32%) with 95% CI: (24.0-39.7). The most common type of sleep disorders was a disorder of initiating and maintaining sleep 37(27%). The factors associated with sleep disorders among children with cerebral palsy were bilateral spasticity (p = 0.004); OR:(95%CI), 11.193: (2.1 - 59.0), lowest levels of gross motor function V (p = < 0.001); OR:(95%CI), 13.182: (3.7 - 47.0) or IV (p = 0.007); OR:(95%CI), 12.921: (2.0 - 82.3), lowest level of manual ability V (p = 0.004); OR:(95%CI), 11.162: (2.2 - 56.4) and presence of epilepsy (p = 0.011); OR:(95%CI), 3.865: (1.4 - 10.9). The prevalence of sleep disorders among children with cerebral palsy in Uganda is high. Severe disability and presence of epilepsy were associated with sleep disorders among children with cerebral palsy.


Placement of central venous lines for sepsis in the elderly has markedly increased-Evidence from a cohort of New Jersey (USA) emergency departments.
Early goal directed therapy for sepsis patients requires placement of central lines (CVPL) to measure central pressure. We hypothesized that the percentage of CVPL placed for sepsis has increased over time, whereas the frequency of lines placed for other conditions has not changed. This was a retrospective cohort study. Investigators analyzed records from consecutive ED patients in nine hospitals over a 10-year period. Patients >65 years identified with CVPL by CPT codes and diagnoses established by ICD-9 codes.We computed the annual number of patients that had a CVPL placed for sepsis and other conditions. We calculated the change from 2005 and 2014 in the normalized number of patients >65 with sepsis and other conditions and the 95% confidence intervals (CIs).We normalized the annual number of CVPLs by the average number of total annual visits for those >65 years as the annual visits in the >65 years cohort increased by > 25% over the course of the study. We then plotted the annual number of normalized CVPLs for sepsis and other conditions placed versus year and computed the linear regression coefficients (R2). Alpha was set at 0.05. Of the 3,772520 visits in the data base there were 711,435 visits by patients >65 years; 3184 (0.45%) had CVPL placed and 784 of those patients were treated for sepsis. The percent of patients with CVPL for sepsis increased 212% (95% CI: 115% to 356%) from 2005 to 2014, but there was no statistically significant annual change in percent of CVPL placed for other conditions (10% decrease, 95% CI: -26% to 9%). The linear regression coefficient for the plot of annual normalized number of CVPLs vs. year (See table and plot) was statistically significant for sepsis (R2 = 0.94, p < 0.001) but not for other conditions (R2 = 0.09, p = 0.80). We found that CVPL placed for sepsis tripled from 2004 to 2011, whereas CVPL placed for other conditions did not change significantly.


Terahertz pulsed imaging of freshly excised human colonic tissues.
We present the results from a feasibility study which measures properties in the terahertz frequency range of excised cancerous, dysplastic and healthy colonic tissues from 30 patients. We compare their absorption and refractive index spectra to identify trends which may enable different tissue types to be distinguished. In addition, we present statistical models based on variations between up to 17 parameters calculated from the reflected time and frequency domain signals of all the measured tissues. These models produce a sensitivity of 82% and a specificity of 77% in distinguishing between healthy and all diseased tissues and a sensitivity of 89% and a specificity of 71% in distinguishing between dysplastic and healthy tissues. The contrast between the tissue types was supported by histological staining studies which showed an increased vascularity in regions of increased terahertz absorption.


Prenatal alcohol exposure and long-term developmental consequences.
Fetal alcohol syndrome (FAS) is a leading cause of congenital mental retardation but little is known about the long-term development and adolescent outcome of children with FAS. In a 10-year follow-up study of 60 patients diagnosed as having FAS in infancy and childhood, we investigated the long-term sequelae of intrauterine alcohol exposure. We found that the characteristic craniofacial malformations of FAS diminish with time, but microcephaly and, to a lesser degree, short stature and underweight (in boys) persist; in female adolescents body weight normalises. Persistent mental retardation is the major sequela of intrauterine alcohol exposure in many cases, and environmental and educational factors do not have strong compensatory effects on the intellectual development of affected children.


Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer.
Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer. We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies. In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone. These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.


Evolutionary drivers of kype size in Atlantic salmon (Salmo salar): domestication, age and genetics.
The diversity of reproduction and associated mating patterns in Atlantic salmon (Salmo salar) has long captivated evolutionary biologists. Salmo salar exhibit strategies involving migration, bold mating behaviours and radical morphological and physiological change. One such radical change is the elongation and curvature of the lower jaw in sexually mature males into a hook-like appendage called the kype. The kype is a secondary sexual characteristic used in mating hierarchies and a prime candidate for sexual selection. As one of the core global aquaculture fish species, however, mate choice, and thus sexual selection, has been replaced by industrial artificial fertilization seeking to develop more commercially viable strains. Removal of mate choice provides a unique opportunity to examine the kype over successive generations in the absence of sexual selection. Here we use a large-scale common-garden experiment, incorporating six experimental strains (wild, farmed and wild × farmed hybrids), experiencing one to three sea winters, to assess the impact of age and genetic background. After controlling for allometry, fork length-adjusted kype height (AKH) was significantly reduced in the domesticated strain in comparison to two wild strains. Furthermore, genetic variation at a locus on linkage group SSA1 was associated with kype height, and a locus on linkage group SSA23 was associated with fork length-adjusted kype length (AKL). The reduction in fork length-AKH in domesticated salmon suggests that the kype is of importance in mate choice and that it has decreased due to relaxation of sexual selection. Fork length-AKL showed an increase in domesticated individuals, highlighting that it may not be an important cue in mate choice. These results give us insight into the evolutionary significance of the kype, as well as implications of genetic induced phenotypic change caused by domesticated individuals escaping into the natural environment.


Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.
Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.


Fatigue before and after mild traumatic brain injury: pre-post-injury comparisons in relation to Apolipoprotein E.
To assess the incidence of fatigue for persons following a mild traumatic brain injury (MTBI) and to evaluate the relationship between fatigue and APOE genotype. As fatigue is often found to be influenced by anxiety, depression and sleep disturbance, these factors were also measured. Thirty-one persons who sustained a MTBI were drawn from a population-based longitudinal study. Each person who sustained a MTBI was matched by age, gender, education and APOE genotype with two non-head injury controls. Self-reported pre- and post-injury incidence of fatigue, anxiety, depression and sleep disturbance was compared within-group and between groups. For the MTBI group, incidence of fatigue was almost twice as common post- than pre-injury, whereas there was no corresponding change in a non-injured control group. Within the MTBI-group, post-injury fatigue was particularly common for carriers of the APOE epsilon4 allele. Fatigue is common sequela after a MTBI and especially pronounced for carriers of the APOE epsilon4 allele.


Atrazine molecular imprinted polymers: comparative analysis by far-infrared and ultraviolet induced polymerization.
Atrazine molecular imprinted polymers (MIPs) were comparatively synthesized using identical polymer formulation by far-infrared (FIR) radiation and ultraviolet (UV)-induced polymerization, respectively. Equilibrium binding experiments were carried out with the prepared MIPs; the results showed that MIP(uv) possessed specific binding to atrazine compared with their MIP(FIR) radiation counterparts. Scatchard plot's of both MIPs indicated that the affinities of the binding sites in MIPs are heterogeneous and can be approximated by two dissociation-constants corresponding to the high- and low-affinity binding sites. Moreover, several common pesticides including atrazine, cyromazine, metamitron, simazine, ametryn, terbutryn were tested to determine their specificity, similar imprinting factor (IF) and different selectivity index (SI) for both MIPs. Physical characterization of the polymers revealed that the different polymerization methods led to slight differences in polymer structures and performance by scanning electron microscope (SEM), Fourier transform infrared absorption (FT-IR), and mercury analyzer (MA). Finally, both MIPs were used as selective sorbents for solid phase extraction (SPE) of atrazine from lake water, followed by high performance liquid chromatography (HPLC) analysis. Compared with commercial C18 SPE sorbent (86.4%-94.8%), higher recoveries of atrazine in spiked lake water were obtained in the range of 90.1%-97.1% and 94.4%-101.9%, for both MIPs, respectively.


Participation in Activities Associated With Quality of Life for Long-Term Survivors of Rectal Cancer.
Cancer patients' participation in social, recreational, and civic activities is strongly associated with quality of life (QOL), but these activities are not well integrated into cancer survivorship research or interventions. Test the hypothesis that for long-term (≥ 5 years) survivors of rectal cancer, clinical factors (type of surgery and bowel function) are associated with long-term participation in activities and that participation in activities is associated with long-term QOL. Observational study with longitudinal and cross-sectional components. Participation in activities and QOL. Tumor registry records were used to identify patients and obtain clinical data; surveys assessed participation and QOL. Using general linear models, we analyzed participation in activities in relation to type of surgery and bowel function after adjustment for potential confounders. We analyzed overall QOL relative to participation in activities after adjustment. A total of 567 rectal cancer survivors completed a mailed questionnaire. Overall response rate was 61%. The type of operation (p < 0.0001), receipt of radiation therapy (p = 0.002), and bowel function (p < 0.0001) were associated with participation in activities. Participation in activities was the strongest predictor of QOL (p < 0.0001), explaining 20% of the variance (R2) in QOL, with all other variables together accounting for another 18% of the variance. The importance of participation in activities on rectal cancer survivors' QOL is underappreciated. We recommend revising QOL instruments used in cancer care and research to include questions about participation in activities. Interventions should address maintenance of preferred activities and adoption of new, fulfilling activities.


First trimester biochemical screening for Down syndrome: free beta hCG versus intact hCG.
To compare free beta hCG versus intact hCG in first trimester Down syndrome screening we analysed 63 cases of Down syndrome and 400 unaffected control pregnancies between 10 and 13 weeks' gestation. The Down syndrome median multiple of the median (MoM) was significantly higher (p=0.001) for free beta hCG (1.89 MoM) than for intact hCG (1.37 MoM). Although distributions for free beta hCG (unaffected, 0.2157; DS, 0.2322) are wider than for intact hCG (unaffected, 0.1697; DS, 0.2158), overall 27% of Down syndrome cases were above the 95th percentile for free beta hCG compared to 19% for intact hCG. Combined with maternal age, free beta hCG detected 45% of Down syndrome pregnancies at a 5% false positive rate. Intact hCG combined with maternal age demonstrated a detection efficiency comparable to maternal age alone (35% versus 32%). In contrast, a recent study (Haddow et al., 1998-NEJM 338: 955-961) indicated that intact hCG yielded a higher first trimester Down syndrome detection efficiency than free beta hCG (29% versus 25% respectively). Re-analysis of distribution parameters in the Haddow et al. study, however, show that free beta hCG was actually the better marker (23% detection for intact hCG versus 29% for free beta hCG).


Glycemic index, glycemic load, and chronic disease risk--a meta-analysis of observational studies.
Inconsistent findings from observational studies have prolonged the controversy over the effects of dietary glycemic index (GI) and glycemic load (GL) on the risk of certain chronic diseases. The objective was to evaluate the association between GI, GL, and chronic disease risk with the use of meta-analysis techniques. A systematic review of published reports identified a total of 37 prospective cohort studies of GI and GL and chronic disease risk. Studies were stratified further according to the validity of the tools used to assess dietary intake. Rate ratios (RRs) were estimated in a Cox proportional hazards model and combined by using a random-effects model. From 4 to 20 y of follow-up across studies, a total of 40 129 incident cases were identified. For the comparison between the highest and lowest quantiles of GI and GL, significant positive associations were found in fully adjusted models of validated studies for type 2 diabetes (GI RR = 1.40, 95% CI: 1.23, 1.59; GL RR = 1.27, 95% CI: 1.12, 1.45), coronary heart disease (GI RR = 1.25, 95% CI: 1.00, 1.56), gallbladder disease (GI RR = 1.26, 95% CI: 1.13, 1.40; GL RR = 1.41, 95% CI: 1.25, 1.60), breast cancer (GI RR = 1.08, 95% CI: 1.02, 1.16), and all diseases combined (GI RR = 1.14, 95% CI: 1.09, 1.19; GL RR = 1.09, 95% CI: 1.04, 1.15). Low-GI and/or low-GL diets are independently associated with a reduced risk of certain chronic diseases. In diabetes and heart disease, the protection is comparable with that seen for whole grain and high fiber intakes. The findings support the hypothesis that higher postprandial glycemia is a universal mechanism for disease progression.