Effect of intravenously administered tetrathiomolybdate on plasma copper concentrations of copper-loaded sheep.
Chronic copper toxicity was induced in 14 ewes in two groups by oral dosing with CuSO4. Copper dosing was stopped in sheep of groups 1 and 2 at the first rise of serum acid phosphatase activity and on the first day of haemolysis, respectively. Thiomolybdate was administered intravenously (i.v.) to sheep of group 2 at the rate of 100 mg on the first day of haemolysis and at 24-h intervals, with a maximum of 3 doses during haemolysis. Thiomolybdate was also given intravenously at a dose of 50 mg twice weekly for 11 weeks to four sheep of group 1 after the cessation of copper dosing (group 1B) and to five sheep of group 2 at the end of haemolysis. Plasma copper concentration was determined before and 24 h after each injection of 50 mg thiomolybdate and "elevations" of plasma copper concentration were seen after each injection of thiomolybdate. The differences between plasma copper concentrations observed before and after each thiomolybdate injection for doses 1 to 11 were significantly higher than those seen for doses 12 to 22. Following thiomolybdate administration, the copper content of the liver of sheep in groups 1B and 2 was reduced much more than in sheep of group 1A, in which copper dosing also ceased but which did not receive thiomolybdate. It was concluded that the high plasma copper response to thiomolybdate doses 1 to 11 was due to an influx of copper into the bloodstream from the heavily copper-loaded liver cells. The lower plasma copper response during the latter part of thiomolybdate administration was due to a gradual reduction in the amount of copper entering the bloodstream from the liver cells, as these cells became depleted of copper. Some of this copper may become part of the glomerular filtrate and be taken up by the cells of the proximal convoluted tubules of the kidney or may be excreted in the urine.


The joint associations of multiple risk factors with the occurrence of nosocomial infection.
To compare nosocomial infection rates estimated in different time periods or in different hospitals, it is necessary to control for differences in the distribution of factors that substantially influence a patient's susceptibility to infection. To evaluate the associations of multiple risk factors with the occurrence of infection at each of four major sites and to develop composite measures for use in controlling for differences in the distribution of risk among groups of patients, we used a multivariate categorical data analysis technique to study the infection experience of 169,518 patients admitted in 1970 to the 338 hospitals studied in the Study on the Efficacy of Nosocomial Infection Control (SENIC, Project). The relative importance of risk factors and their complex interactions varied by site. The factors found to be highly important for one or more sites were duration of urinary catheterization, the patients' intrinsic risk as reflected in their diagnoses and types of surgical procedures, duration of preoperative hospitalization, duration of operation, anatomic location of surgical procedure, previous infection and steroid or immunosuppressive therapy. Site-specific risk strata and estimates of each patient's probability of acquiring infection were developed from these data for use in future SENIC analyses.


YouDo - we help! - An Open Information and Training Platform for Informal Caregivers.
The number of people in need of care increases constantly, and in the coming few years many seniors will depend on their close relatives for their care needs. These relatives very often need support to fulfill their role as informal caregivers. The YouDo prototype presented in this paper aims to provide special training programs for informal caregivers in order to help them to improve the quality of their nursing. This work illustrates first development concepts, used methods and techniques towards a modular, extensible and user adaptable multimodal information and training platform.


Work-arounds slow electronic health record use.
The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, and birthing centers, as well as some abortion facilities, must file information on medical errors.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu.


Differential distribution patterns of CRABP I and CRABP II transcripts during mouse embryogenesis.
We have compared the transcript distribution of cellular retinoic acid binding protein (CRABP) I and II genes in mouse embryos at various stages of development. Both CRABP transcripts are present in embryonic structures from the earliest stages studied and exhibit specific patterns of distribution, suggesting that the two retinoic acid (RA) binding proteins perform different functions during mouse embryogenesis. The CRABP I transcript distribution correlates well with structures known to be targets of excess retinoid-induced teratogenesis (e.g. neural crest cells and hindbrain), suggesting that cells expressing CRABP I are those that cannot tolerate high levels of RA for their normal developmental function. The embryonic structures expressing CRABP II transcripts include those structures that have been shown to be adversely affected by excess of retinoids, such as limbs and hindbrain, but CRABP II transcripts are also found in structures not known to be specifically vulnerable to raised RA levels. The CRABP II gene is coexpressed with retinoic acid receptor (RAR)-beta and cellular retinol binding protein (CRBP) I genes in a number of tissues such as the gut endoderm, hypophysis and interdigital mesenchyme, all of which are devoid of CRABP I transcripts. Interestingly, the expression of the three genes, RAR-beta, CRABP II and CRBP I, is induced by retinoic acid, which suggests a link between the synthesis of RA from retinol and the control of expression of subsets of RA-responsive genes. The transcript distribution of CRABP I and II is discussed in relation to the teratogenic effects of RA, and compared to the RA-sensitive pattern of expression of other important developmental genes.


Iloprost reduces colitis induced oxidative stress: An experimental study in rats.
Reactive oxygen species have a known potent role in the pathogenesis of ulcerative colitis. Iloprost, a pharmaceutical, is a chemically stable derivative of a naturally- occurring human prostacyclin. Several studies have demonstrated protective effects of iloprost via its antioxidant and its anti-inflammatory activity. The aim of this study is to evaluate the effects of iloprost on oxidant/antioxidant status, as well as the large bowel histopathology in experimental colitis. Forty adult male Wistar-albino rats were randomly divided in to four equal weight-matched groups: sham group (n=10), iloprost administered sham group (n=10), colitis group (n=10), iloprost administered colitis group (n=10). Acetic acid (1 ml of 4% solution) was used to induce colonic inflammation in the rats. Colonic tissue and plasma malondialdehyde levels were significantly lower in the iloprost administered colitis group than the colitis group (p<0.01). Tissue glutathione levels of the iloprost administered colitis group were significantly higher than the colitis group (p<0.001). We have demonstrated in this study iloprost to be an antioxidant, as well as iloprost demonstrating protective activity against colitis induced oxidative stress.


Is there a reliable association between patient-reported limb claudication and vascular imaging methods in Takayasu arteritis?
Vessel imaging in Takayasu arteritis (TAK) is often performed in clinical practice following laboratory test abnormalities or clinical symptoms, such as limb claudication. Conversely, the association between limb claudication and vessel imaging manifestations has not been assessed. This observational, cross-sectional study analyzed 139 adult TAK patients from 2000 to 2018. Their arterial vessel imaging information (especially significant stenosis and occlusion data) was registered and crosschecked with clinical and laboratory data. When vessel imaging was performed, the median age and disease duration of the patients were 38 (27.3-47.0) and 5.0 (1.0-12.0) years, respectively. There was no association between arterial abnormalities and demographic data, constitutional symptoms or laboratory parameters. Limb claudication was reported in 42 patients (30.2%): 17.3% reported it in the upper left limb (ULL), 12.2% reported it in the upper right limb (URL), 12.9% reported it in the lower left limb (LLL), and 12.2% reported it in the lower right limb (LRL). When crossmatched with imaging, both ULL and URL were associated with left vertebral artery stenosis/occlusion, and URL was associated with right iliac artery stenosis/occlusion, but no other association was found. In contrast, both LLL and LRL claudication were associated with infrarenal aortic, left iliac and right iliac artery stenosis/ occlusion (p<0.05). Moreover, the ULL and URL claudication symptoms were significantly associated with each other (p<0.001). Upper limb claudication was associated only with left vertebral artery stenosis/occlusion, whereas the subclavian arteries were not, suggesting that the symptom might not be fully explained by limb ischemia. In contrast, lower limb claudication was associated especially with infrarenal aortic and/or iliac arteries stenosis/occlusion.


The public health risk posed by Listeria monocytogenes in frozen fruit and vegetables including herbs, blanched during processing.
A multi-country outbreak of Listeria monocytogenes ST6 linked to blanched frozen vegetables (bfV) took place in the EU (2015-2018). Evidence of food-borne outbreaks shows that L. monocytogenes is the most relevant pathogen associated with bfV. The probability of illness per serving of uncooked bfV, for the elderly (65-74 years old) population, is up to 3,600 times greater than cooked bfV and very likely lower than any of the evaluated ready-to-eat food categories. The main factors affecting contamination and growth of L. monocytogenes in bfV during processing are the hygiene of the raw materials and process water; the hygienic conditions of the food processing environment (FPE); and the time/Temperature (t/T) combinations used for storage and processing (e.g. blanching, cooling). Relevant factors after processing are the intrinsic characteristics of the bfV, the t/T combinations used for thawing and storage and subsequent cooking conditions, unless eaten uncooked. Analysis of the possible control options suggests that application of a complete HACCP plan is either not possible or would not further enhance food safety. Instead, specific prerequisite programmes (PRP) and operational PRP activities should be applied such as cleaning and disinfection of the FPE, water control, t/T control and product information and consumer awareness. The occurrence of low levels of L. monocytogenes at the end of the production process (e.g. < 10 CFU/g) would be compatible with the limit of 100 CFU/g at the moment of consumption if any labelling recommendations are strictly followed (i.e. 24 h at 5°C). Under reasonably foreseeable conditions of use (i.e. 48 h at 12°C), L. monocytogenes levels need to be considerably lower (not detected in 25 g). Routine monitoring programmes for L. monocytogenes should be designed following a risk-based approach and regularly revised based on trend analysis, being FPE monitoring a key activity in the frozen vegetable industry.


Practicing physiotherapy in Danish private practice: an ethical perspective.
Despite an increasingly growth of professional guidelines, textbooks and research about ethics in health care, awareness about ethics in Danish physiotherapy private practice seen vague. This article explores how physiotherapists in Danish private practice, from an ethical perspective, perceive to practice physiotherapy. The empirical data consists of interviews with twenty-one physiotherapists. The interviews are analysed from a hermeneutic approach, inspired by Ricoeur's textual interpretation of distanciation. The analysis follows three phases: naïve reading, structural analysis and comprehensive analysis. Four main themes are constructed: Beneficence as the driving force; Disciplining the patient through the course of physiotherapy; Balancing between being a trustworthy professional and a businessperson; The dream of a code of practice. Private practice physiotherapy is embedded in a structural frame directed by both political and economical conditions that shape the conditions for practicing physiotherapy. It means that beneficence in practice is a balance between the patient, the physiotherapists themselves and the business. Beneficence towards the patient is expressed as an implicit demand. Physiotherapeutic practice is expressed as being an integration of professionalism and personality which implies that the physiotherapists also have to benefit themselves. Private practice seems to be driven by a paternalistic approach towards the patient, where disciplining the patient is a crucial element of practice, in order to optimise profit. Physiotherapists wish for a more beneficent practice in the future by aiming at bridging 'to be' and 'ought to be'.


Automated percutaneous lumbar discectomy for the contained herniated lumbar disc: a systematic assessment of evidence.
Lumbar disc prolapse, protrusion, and extrusion account for less than 5% of all low back problems, but are the most common causes of nerve root pain and surgical interventions. The typical rationale for traditional surgery is an effort to provide more rapid relief of pain and disability. It should be noted that the majority of patients will recover with conservative management. The primary rationale for any form of surgery for disc prolapse associated with radicular pain is to relieve nerve root irritation or compression due to herniated disc material. The primary modality of treatment continues to be either open or microdiscectomy, but several alternative techniques including automated percutaneous lumbar discectomy (APLD) have been described. However, there is a paucity of evidence for all decompression techniques, specifically alternative techniques including automated and laser discectomy. A systematic review of the literature. To determine the effectiveness of APLD. A comprehensive evaluation of the literature relating to automated lumbar disc decompression was performed. The literature was evaluated according to Cochrane review criteria for randomized controlled trials (RCTs), and Agency for Healthcare Research and Quality (AHRQ) criteria was utilized for observational studies. A literature search was conducted of English language literature through PubMed, EMBASE, the Cochrane library, systematic reviews, and cross references from reviews and systematic reviews. The level of evidence was classified as Level I, II, or III with 3 subcategories in Level II based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF). Pain relief was the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, opioid intake, and return to work. Short-term effectiveness was defined as one year or less, whereas, long-term effectiveness was defined as greater than one year. Based on USPSTF criteria, the indicated evidence for APLD is Level II-2 for short- and long-term relief. Paucity of RCTs in the literature. This systematic review indicated Level II-2 evidence for APLD. APLD may provide appropriate relief in properly selected patients with contained lumbar disc prolapse.


The association of visual impairment and 3-year mortality among the elderly in Taiwan: the Shihpai Eye Study.
The association between visual impairment and mortality has been controversial. Moreover, literature on the relationship was very limited in the Asian population. The purpose of this study was to investigate whether visual impairment increases the 3-year risk of mortality in a cohort of urban Chinese elderly individuals. Participants in the Shihpai Eye Study, who were aged ≥65 years, with a baseline examination conducted between July 1, 1999 and December 31, 2000, were recruited for the current study. The total number of possible participants identified was 4750. Of those, 3746 persons were eligible, and 2045 persons were randomly selected to be invited to participate in the study. Of those 2045 individuals, 1361 (66.6%) participated in both the questionnaire and eye examination. A follow-up of a fixed cohort was also conducted after 3 years. The death of any participants was confirmed through the household registration system. Of the 1361 participants included at baseline, 54 (3.97%) died before the 3-year follow-up. Multiple logistic regression analysis showed that mortality was significantly associated with a fall history [relative risk (RR): 2.12; 95% confidence intervals (CI): 1.08-3.98] and a history of diabetes (RR: 2.06; 95% CI: 1.03-3.95). Visual impairment was not a significant predictor of mortality after adjustment for confounders. After adjustments were made for age, sex, education, marital status, lifestyle factors, depression symptoms, fall history, and history of systemic diseases, visual impairment was not a significant predictor of 3-year mortality in elderly persons.


Dads at the dinner table. A cross-sectional study of Australian fathers' child feeding perceptions and practices.
Maternal perceptions and practices regarding child feeding have been extensively studied in the context of childhood overweight and obesity. To date, there is scant evidence on the role of fathers in child feeding. This cross-sectional study aimed to identify whether characteristics of fathers and their concerns about their children's risk of overweight were associated with child feeding perceptions and practices. Questionnaires were used to collect data from 436 Australian fathers (mean age = 37 years, SD = 6) of a child (53% boys) aged between 2 and 5 years (M = 3.5 years, SD = 0.9). These data included a range of demographic variables and selected subscales from the Child Feeding Questionnaire on concern about child weight, perceived responsibility for child feeding and controlling practices (pressure to eat and restriction). Multivariable linear regression was used to examine associations between demographic variables and fathers' feeding perceptions and practices. Results indicated that fathers' who were more concerned about their child becoming overweight reported higher perceived responsibility for child feeding and were more controlling of what and how much their child eats. Greater time commitment to paid work, possessing a health care card (indicative of socioeconomic disadvantage) and younger child age were associated with fathers' perceiving less responsibility for feeding. Factors such as paternal BMI and education level, as well as child gender were not associated with feeding perceptions or practices. This study contributes to the extant literature on fathers' role in child feeding, revealing several implications for research and interventions in the child feeding field.


Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors.
Novel piperidine-based bivalent ligands were prepared in enantiomerically pure form and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes). In this study, we have succeeded in using (1) the length of the linking chain connecting the two piperidine-based monomer units and (2) the absolute configuration of the piperidine monomer as a means to tailor activity and selectivity at the three monoamine transporters tested. In this series, the bivalent ligand 16, comprised of two (+)-trans-piperidine units linked by a pentamethylene spacer, exhibits a combination of high DA transporter (DAT) and 5-HT transporter (SERT) activity (K(i) = 39 nM and 7 nM, respectively). Piperidine 16 is capable of reducing cocaine's locomotor effects in mice while not having any effect on locomotion when tested alone. Additionally, compound 16 (1-10 mg/kg) does not substitute for cocaine in drug discrimination studies in rats. However, the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as lead candidates in the discovery of new therapeutics to treat a range of neurological disorders including cocaine addiction.


Multiple protective functions of sigma1 receptor.
The Sigma Receptor 1 (sig-1R) is a protein present in numerous normal tissues, such as brain, retina, lens, liver, lung, heart, but also in many tumor lines. Its amino acid sequence is homologous to fungal C-8,7 sterol isomerase, but it has no known homology with mammalian proteins and does not possess sterol isomerase activity. It is localized in plasma and ER membranes, and its exact function is not clarified as of yet. Last reports point to its participation in regulation of ionic channels activity, particularly calcium channels. Application of numerous synthetic ligands of sigma1 receptor provided means to study its protective effects and metabolic functions in different tissues. This review describes influence of sigma1 receptor on various aspects of cellular metabolism, such as calcium signalling, mitochondrial functions, oxidative stress, survival and apoptotic pathways, and tumor cells proliferation.


Biomechanical assessment of a PEEK rod system for semi-rigid fixation of lumbar fusion constructs.
The concept of semi-rigid fixation (SRF) has driven the development of spinal implants that utilize nonmetallic materials and novel rod geometries in an effort to promote fusion via a balance of stability, intra- and inter-level load sharing, and durability. The purpose of this study was to characterize the mechanical and biomechanical properties of a pedicle screw-based polyetheretherketone (PEEK) SRF system for the lumbar spine to compare its kinematic, structural, and durability performance profile against that of traditional lumbar fusion systems. Performance of the SRF system was characterized using a validated spectrum of experimental, computational, and in vitro testing. Finite element models were first used to optimize the size and shape of the polymeric rods and bound their performance parameters. Subsequently, benchtop tests determined the static and dynamic performance threshold of PEEK rods in relevant loading modes (flexion-extension (F/E), axial rotation (AR), and lateral bending (LB)). Numerical analyses evaluated the amount of anteroposterior column load sharing provided by both metallic and PEEK rods. Finally, a cadaveric spine simulator was used to determine the level of stability that PEEK rods provide. Under physiological loading conditions, a 6.35 mm nominal diameter oval PEEK rod construct unloads the bone-screw interface and increases anterior column load (approx. 75% anterior, 25% posterior) when compared to titanium (Ti) rod constructs. The PEEK construct's stiffness demonstrated a value lower than that of all the metallic rod systems, regardless of diameter or metallic composition (78% < 5.5 mm Ti; 66% < 4.5 mm Ti; 38% < 3.6 mm Ti). The endurance limit of the PEEK construct was comparable to that of clinically successful metallic rod systems (135N at 5 × 10(6) cycles). Compared to the intact state, cadaveric spines implanted with PEEK constructs demonstrated a significant reduction of range of motion in all three loading directions (> 80% reduction in F/E, p < 0.001; > 70% reduction in LB, p < 0.001; > 54% reduction in AR, p < 0.001). There was no statistically significant difference in the stability provided by the PEEK rods and titanium rods in any mode (p = 0.769 for F/E; p = 0.085 for LB; p = 0.633 for AR). The CD HORIZON(®) LEGACY(™) PEEK Rod System provided intervertebral stability comparable to currently marketed titanium lumbar fusion constructs. PEEK rods also more closely approximated the physiologic anteroposterior column load sharing compared to results with titanium rods. The durability, stability, strength, and biomechanical profile of PEEK rods were demonstrated and the potential advantages of SRF were highlighted.


Hip Arthroscopy Successfully Treats Femoroacetabular Impingement in Adolescent Athletes.
There is evidence that femoroacetabular impingement (FAI) is increasingly prevalent among adolescent athletes. Abnormal contact forces across the hip and alterations in bony morphology characteristic of FAI may be especially detrimental in this group, given their young age and active lifestyle. The purpose of this study was to report the findings, outcomes, and return to sport percentage among adolescent athletes with FAI treated with hip arthroscopy. A retrospective review of all patients younger than 18 years who underwent hip arthroscopy for FAI at a single institution was performed. All athletes who were attempting to return to sport and underwent hip arthroscopy were included. Patients with previous hip surgery and/or hip conditions were excluded. Arthroscopic procedures and an assessment of intra-articular findings were recorded. Patient-reported outcome measures were recorded at 3 months, 1 year, and 2 years postoperatively, and included the modified Harris hip score, the nonarthritic hip score, hip outcome score-sports subscale, visual analogue scale for pain, and patient satisfaction. Return to sport percentage and ability levels were also noted. There were 96 eligible cases of adolescent athletes treated with hip arthroscopy; 81 (84.4%) hips in 69 patients had 2-year follow-up. Running/track and field was the most common sport (25), followed by soccer (12), dance (10), baseball/softball (9), and basketball (6). There were 61 females and 20 males, whose average age was 15.9±1.2 y (range: 13.1 to 18.0 y). The most common procedures were labral repair (81.5%), iliopsoas fractional lengthening (72.8%), femoroplasty (69.1%), and acetabuloplasty (66.7%). Capsular repair or plication was performed in most patients (81.5%). Cartilage damage was more common on the acetabulum than the femur, with Outerbridge grade 2 or higher occurring in 23.5% and 4.9% of hips, respectively. Statistically significant improvements were seen in all patient-reported outcomes from preoperative to minimum 2-year follow-up. A total of 84.0% of patients had returned to their sport at latest follow-up. There were 6 (7.4%) patients who underwent revision arthroscopy at a mean of 37.3 months postoperatively. Symptomatic FAI in adolescent athletes can be successfully treated with hip arthroscopy, with a higher return to sport rate and low complications and reoperation rate at minimum 2-year follow-up.


Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer.
Diaphragm involvement by ovarian cancer is often considered to be a major obstacle to successful cytoreductive surgery. Lack of evidence of survival benefit, concerns over safety and lack of experience are common justifications for this belief. In this study, we sought to evaluate the therapeutic value of diaphragmatic surgery in advanced ovarian cancer. Relevant data from all consecutive patients with stage IIIC and IV epithelial ovarian cancer, primarily operated at Mayo Clinic from 1994 through 1998, were collected and analyzed. Statistical analyses were performed using chi(2) test, Cox regression model and Kaplan-Meier curves including log rank test. For comparison of trends in performing procedures, an additional 91 consecutive patients undergoing surgery from August 1, 2002 and August 31, 2004 were analyzed. 244 eligible patients were identified. Mean age was 64 years (range: 24-87), and 5-year overall survival (OS) was 31.5%. For the entire cohort, residual disease (RD) was the only independent prognostic factor in multivariate analysis (P < 0.0001) when considering other factors including demographic, intraoperative findings and procedures performed. For the subgroup of patients with tumor involving the diaphragm (N = 181), patients who underwent diaphragm surgery (stripping of the diaphragmatic peritoneum, full or partial thickness diaphragm resection, excision of nodules or CUSA) had improved 5-year OS relative to those that did not (53% vs. 15%; P < 0.0001). Furthermore, in multivariate analysis of patients with diaphragm disease, both RD and performance of diaphragm surgery were independent predictors of outcome (P < 0.001). Considering the subgroup of patients with RD < 1 cm, we noted a strong survival advantage for those patients who underwent diaphragm surgical procedures (5-year survival: 55% vs. 28%; P = 0.0005). Over time, we noted a statistically significant increase in the rate of diaphragm procedures for patients with diaphragm involvement from 1994-98 relative to 2002-3 (22.5% vs. 40%: P = 0.022). Surgical procedures to treat diaphragm disease increase the rate of complete and optimal debulking and correlate with improved survival even compared to patients optimally debulked without diaphragm surgery performed.


Evolution in intergenerational exchanges between elderly people and their grandchildren in Taiwan; data from a multiple round cross-sectional study from 1993 to 2007.
This study aimed to evaluate social evolution in Taiwan in recent decades using the changing pattern of care provided by grandparents for their grandchildren as an indicator. Data from the second, fourth and sixth wave surveys of the Study of Health and Living Status of the Middle-Aged and Elderly in Taiwan were used for the analysis. This survey collected individual characteristics, including age, gender, education, ethnicity, dwelling place, living with partners, co-resident with children, employment status, self-reported health status and their provision of care for their grandchildren. Information about the attitudes toward National Health Insurance (NHI) was further collected in a questionnaire of 1999 following the implementation of NHI in 1995. By elders, we mean persons 60 or more years old. By grandchildren, we mean persons under 16 years of age. First, changes in individual characteristics were compared during these study periods (chi-square test). Then the logistic regression was performed to determine how significantly elders' grandchild-care behavior was associated with their individual characteristics. The percentage of elders providing grandchild care increased from 7.7% in 1993 to 13.6% in 1999, and then to 19.4% in 2007. By analysis, significant association was found between behavior in taking care of grandchildren and individuals of lower age, grandmothers, those living with partners or co-residing with children, those unemployed and those with better self-reported health status. And the effect of year was confirmed in the multivariable analysis. This study pointed out the changing pattern of elders' behavior in taking care of their grandchildren as the main indicator and their related individual characteristics. We argue the need for improving social security policies in an ageing society. We suggest that the interaction between population policies and those of social welfare, including policies for health care and childcare, should be carefully evaluated.


SMAD signaling promotes melanoma metastasis independently of phenotype switching.
The development of metastatic melanoma is thought to require the dynamic shifting of neoplastic cells between proliferative and invasive phenotypes. Contrary to this conventional "phenotype switching" model, we now show that disease progression can involve malignant melanoma cells simultaneously displaying proliferative and invasive properties. Using a genetic mouse model of melanoma in combination with in vitro analyses of melanoma cell lines, we found that conditional deletion of the downstream signaling molecule Smad4, which abrogates all canonical TGF-β signaling, indeed inhibits both tumor growth and metastasis. Conditional deletion of the inhibitory signaling factor Smad7, however, generated cells that are both highly invasive and proliferative, indicating that invasiveness is compatible with a high proliferation rate. In fact, conditional Smad7 deletion led to sustained melanoma growth and at the same time promoted massive metastasis formation, a result consistent with data indicating that low SMAD7 levels in patient tumors are associated with a poor survival. Our findings reveal that modulation of SMAD7 levels can overcome the need for phenotype switching during tumor progression and may thus represent a novel therapeutic target in metastatic disease.


A novel mitochondrial MAVS/Caspase-8 platform links RNA virus-induced innate antiviral signaling to Bax/Bak-independent apoptosis.
Semliki Forest virus (SFV) requires RNA replication and Bax/Bak for efficient apoptosis induction. However, cells lacking Bax/Bak continue to die in a caspase-dependent manner. In this study, we show in both mouse and human cells that this Bax/Bak-independent pathway involves dsRNA-induced innate immune signaling via mitochondrial antiviral signaling (MAVS) and caspase-8. Bax/Bak-deficient or Bcl-2- or Bcl-xL-overexpressing cells lacking MAVS or caspase-8 expression are resistant to SFV-induced apoptosis. The signaling pathway triggered by SFV does neither involve death receptors nor the classical MAVS effectors TNFR-associated factor-2, IRF-3/7, or IFN-β but the physical interaction of MAVS with caspase-8 on mitochondria in a FADD-independent manner. Consistently, caspase-8 and -3 activation are reduced in MAVS-deficient cells. Thus, after RNA virus infection MAVS does not only elicit a type I antiviral response but also recruits caspase-8 to mitochondria to mediate caspase-3 activation and apoptosis in a Bax/Bak-independent manner.


A minimal contouring approach to the computation of the Reeb graph.
Given a manifold surface {\cal M} and a continuous scalar function f:{\cal M}\rightarrow {\hbox{\rlap{I}\kern 2.0pt{\hbox{R}}}}, the Reeb graph of ({\cal M},f) is a widely used high-level descriptor of {\cal M} and its usefulness has been demonstrated for a variety of applications, which range from shape parameterization and abstraction to deformation and comparison. In this context, we propose a novel contouring algorithm for the construction of a discrete Reeb graph with a minimal number of nodes, which correspond to the critical points of f (i.e., minima, maxima, and saddle points) and its level sets passing through the saddle points. In this way, we do not need to sample, sweep, or increasingly sort the f-values. Since most of the computation uses only local information on the mesh connectivity, equipped with the f-values at the surface vertices, the proposed approach is insensitive to noise and requires a small-memory footprint and temporary data structures. Furthermore, we maintain the parametric nature of the Reeb graph with respect to the input scalar function and we efficiently extract the Reeb graph of time-varying maps. Indicating with n and s the number of vertices of {\cal M} and saddle points of f, the overall computational cost O(sn) is competitive with respect to the O(n\,\log \,n) cost of previous work. This cost becomes optimal if {\cal M} is highly sampled or s\le \log n, as it happens for Laplacian eigenfunctions, harmonic maps, and one-forms.


Outcome of unilateral ankle arthrodesis and total ankle replacement in terms of bilateral gait mechanics.
Previous studies assessed the outcome of ankle arthrodesis (AA) and total ankle replacement (TAR) surgeries; however, the extent of postoperative recovery towards bilateral gait mechanics (BGM) is unknown. We evaluated the outcome of the two surgeries at least 2 years post rehabilitation, focusing on BGM. 36 participants, including 12 AA patients, 12 TAR patients, and 12 controls were included. Gait assessment over 50 m distance was performed utilizing pressure insoles and 3D inertial sensors, following which an intraindividual comparison was performed. Most spatiotemporal and kinematic parameters in the TAR group were indicative of good gait symmetry, while the AA group presented significant differences. Plantar pressure symmetry among the AA group was also significantly distorted. Abnormality in biomechanical behavior of the AA unoperated, contralateral foot was observed. In summary, our results indicate an altered BGM in AA patients, whereas a relatively fully recovered BGM is observed in TAR patients, despite the quantitative differences in several parameters when compared to a healthy population. Our study supports a biomechanical assessment and rehabilitation of both operated and unoperated sides after major surgeries for ankle osteoarthrosis.


Computational heterogeneity in the human mesencephalic dopamine system.
Recent evidence in animals has indicated that the mesencephalic dopamine system is heterogeneous anatomically, molecularly, and functionally, and it has been suggested that the dopamine system comprises distinct functional systems. Identifying and characterizing these systems in humans will have widespread ramifications for understanding drug addiction and mental health disorders. Model-based studies in humans have suggested an analogous computational heterogeneity, in which dopaminergic targets in striatum encode both experience-based learning signals and counterfactual learning signals that are based on hypothetical information. We used brainstem-tailored fMRI to identify mesencephalic sources of experiential and counterfactual learning signals. Participants completed a decision-making task based on investing in markets. This sequential investment task generated experience-based learning signals, in the form of temporal difference (TD) reward prediction errors, and counterfactual learning signals, in the form of "fictive errors." Fictive errors are reinforcement learning signals based on hypothetical information about "what could have been." An additional learning signal was constructed to be relatable to a motivational salience signal. Blood oxygenation level dependent responses in regions of substantia nigra (SN) and ventral tegmental area (VTA), where dopamine neurons are located, coded for TD and fictive errors, and additionally were related to the motivational salience signal. These results are highly consistent with animal electrophysiology and provide direct evidence that human SN and VTA heterogeneously handle important reward-harvesting computations.


Efficacy of tricaine methanesulfonate (MS-222) as an anesthetic agent for blocking sensory-motor responses in Xenopus laevis tadpoles.
Anesthetics are drugs that reversibly relieve pain, decrease body movements and suppress neuronal activity. Most drugs only cover one of these effects; for instance, analgesics relieve pain but fail to block primary fiber responses to noxious stimuli. Alternately, paralytic drugs block synaptic transmission at neuromuscular junctions, thereby effectively paralyzing skeletal muscles. Thus, both analgesics and paralytics each accomplish one effect, but fail to singularly account for all three. Tricaine methanesulfonate (MS-222) is structurally similar to benzocaine, a typical anesthetic for anamniote vertebrates, but contains a sulfate moiety rendering this drug more hydrophilic. MS-222 is used as anesthetic in poikilothermic animals such as fish and amphibians. However, it is often argued that MS-222 is only a hypnotic drug and its ability to block neural activity has been questioned. This prompted us to evaluate the potency and dynamics of MS-222-induced effects on neuronal firing of sensory and motor nerves alongside a defined motor behavior in semi-intact in vitro preparations of Xenopus laevis tadpoles. Electrophysiological recordings of extraocular motor discharge and both spontaneous and evoked mechanosensory nerve activity were measured before, during and after administration of MS-222, then compared to benzocaine and a known paralytic, pancuronium. Both MS-222 and benzocaine, but not pancuronium caused a dose-dependent, reversible blockade of extraocular motor and sensory nerve activity. These results indicate that MS-222 as benzocaine blocks the activity of both sensory and motor nerves compatible with the mechanistic action of effective anesthetics, indicating that both caine-derivates are effective as single-drug anesthetics for surgical interventions in anamniotes.


Incipient microphase separation in short chain perfluoropolyether-block-poly(ethylene oxide) copolymers.
Incipient microphase separation is observed by wide angle X-ray scattering (WAXS) in short chain multiblock copolymers consisting of perfluoropolyether (PFPE) and poly(ethylene oxide) (PEO) segments. Two PFPE-PEO block copolymers were studied; one with dihydroxyl end groups and one with dimethyl carbonate end groups. Despite having a low degree of polymerization (N ∼ 10), these materials exhibited significant scattering intensity, due to disordered concentration fluctuations between their PFPE-rich and PEO-rich domains. The disordered scattering intensity was fit to a model based on a multicomponent random phase approximation to determine the value of the interaction parameter, χ, and the radius of gyration, Rg. Over the temperature range 30-90 °C, the values of χ were determined to be very large (∼2-2.5), indicating a high degree of immiscibility between the PFPE and PEO blocks. In PFPE-PEO, due to the large electron density contrast between the fluorinated and non-fluorinated block and the high value of χ, disordered scattering was detected at intermediate scattering angles, (q ∼ 2 nm-1) for relatively small polymer chains. Our ability to detect concentration fluctuations was enabled by both a relatively large value of χ and significant scattering contrast.


Characteristics of misreporters of dietary intake and physical activity.
To characterise misreporters of energy intake (EI) and energy expenditure (EE). Cross-sectional study, using a validated position and motion instrument, ActiReg, as the reference method to study misreporters of EI and of EE. EI was measured using a dietary record and EE using a physical activity questionnaire (PAQ). Misreporters were defined as subjects outside the 95% confidence limits of agreement between EI or EE reported/EE measured. Free-living Danish volunteers. One hundred and thirty-eight volunteers aged between 20 and 59 years. Body mass index, smoking, 'try to eat healthily' and worries about weight were related to degree of under-reported EI. The percentage energy from added sugar was lowest (P < 0.001) and the percentage energy from protein (P < 0.001) highest in under-reporters compared with acceptable reporters. Subjects who reported being very physically active at work or in leisure time reported a higher EE than measured EE compared with less physically active subjects (P < 0.05). Likewise, subjects who regard themselves as fit or very fit reported a higher EE than subjects who regard themselves as moderately fit (P < 0.05). Possible over-reporters reported less time as very light activity (P = 0.007), more time as moderate activity (P = 0.01) and more time as vigorous activity (P = 0.02) than acceptable reporters. Under-reporting of EI should always be taken into consideration; however, only a few characteristics of under-reporters are consistent among studies. Misreporting of EI was more prevalent than misreporting of EE. The level of physical activity more than the time spent involved in various activities was misreported.


A complete BAC-based physical map of the Arabidopsis thaliana genome.
Arabidopsis thaliana is a small flowering plant that serves as the major model system in plant molecular genetics. The efforts of many scientists have produced genetic maps that provide extensive coverage of the genome (http://genome-www. stanford.edu/Arabidopsis/maps.html). Recently, detailed YAC, BAC, P1 and cosmid-based physical maps (that is, representations of genomic regions as sets of overlapping clones of corresponding libraries) have been established that extend over wide genomic areas ranging from several hundreds of kilobases to entire chromosomes. These maps provide an entry to gain deeper insight into the A. thaliana genome structure. A. thaliana has been chosen as the subject of the first large-scale project intended to determine the full genome sequence of a plant. This sequencing project, together with the increasing interest in map-based gene cloning, has highlighted the requirement for a complete and accurate physical map of this plant species. To supply the scientific community with a high-quality resource, we present here a complete physical map of A. thaliana using essentially the IGF BAC library. The map consists of 27 contigs that cover the entire genome, except for the presumptive centromeric regions, nucleolar organization regions (NOR) and telomeric areas. This is the first reported map of a complex organism based entirely on BAC clones and it represents the most homogeneous and complete physical map established to date for any plant genome. Furthermore, the analysis performed here serves as a model for an efficient physical mapping procedure using BAC clones that can be applied to other complex genomes.


Assessing the privacy risks of data sharing in genomics.
The protection of identity of participants in medical research has traditionally been guaranteed by the maintenance of the confidentiality of health information through mechanisms such as only releasing data in an aggregated form or after identifying variables have been removed. This protection of privacy is regarded as a fundamental principle of research ethics, through which the support of research participants and the public is maintained. Whilst this traditional model was adopted for genetics and genomics research, and was generally considered broadly fit for purpose, we argue that this approach is increasingly untenable in genomics. Privacy risk assessments need to have regard to the whole data environment, not merely the quality of the dataset to be released in isolation. As sources of data proliferate, issues of privacy protection are increasingly problematic in relation to the release of genomic data. However, we conclude that, by paying careful attention to potential pitfalls, scientific funders and researchers can take an important part in attempts to safeguard the public and ensure the continuation of potentially important scientific research.


Associations between Community Environmental-Level Factors and Diet Quality in Geographically Isolated Australian Communities.
Remote Indigenous Australians experience disproportionately poor cardio-metabolic health, which is largely underpinned by adverse dietary intake related to social determinants. Little evidence exists about the community environmental-level factors that shape diet quality in this geographically isolated population group. This study aimed to explore the modifiable environmental-level factors associated with the features of dietary intake that underpin cardio-metabolic disease risk in this population group. Community-level dietary intake data were estimated from weekly store sales data collected throughout 2012 and linked with concurrent social, built, and physical environmental dimension data for 13 remote Indigenous Australian communities in the Northern Territory. Statistical analyses were performed to investigate associations. At the community level, store sales of discretionary foods were lower in communities with greater distance to a neighbouring store (r = -0.45 (p < 0.05)). Sales of sugar-sweetened beverages were lower in communities with higher levels of household crowding (r = -0.55 (p < 0.05)), higher levels of Indigenous unemployment (r = -0.62 (p = 0.02)), and greater distance to neighbouring stores (r = -0.61 (p = 0.004)). Modifiable environmental-level factors may be associated with adverse diet quality in remote Indigenous Australian communities and further investigations of these factors should be considered when developing policies to improve dietary intake quality in geographically isolated populations.


Isolation by elevation: genetic structure at neutral and putatively non-neutral loci in a dominant tree of subtropical forests, Castanopsis eyrei.
The distribution of genetic diversity among plant populations growing along elevational gradients can be affected by neutral as well as selective processes. Molecular markers used to study these patterns usually target neutral processes only, but may also be affected by selection. In this study, the effects of elevation and successional stage on genetic diversity of a dominant tree species were investigated controlling for neutrality of the microsatellite loci used. Diversity and differentiation among 24 populations of Castanopsis eyrei from different elevations (251-920 m) and successional stages were analysed by eight microsatellite loci. We found that one of the loci (Ccu97H18) strongly deviated from a neutral model of differentiation among populations due to either divergent selection or hitchhiking with an unknown selected locus. The analysis showed that C. eyrei populations had a high level of genetic diversity within populations (A(R) = 7.6, H(E) = 0.82). Genetic variation increased with elevation for both the putatively selected locus Ccu97H18 and the neutral loci. At locus Ccu97H18 one allele was dominant at low elevations, which was replaced at higher elevations by an increasing number of other alleles. The level of genetic differentiation at neutral loci was similar to that of other Fagaceae species (F(ST) = 0.032, = 0.15). Population differentiation followed a model of isolation by distance but additionally, strongly significant isolation by elevation was found, both for neutral loci and the putatively selected locus. The results indicate higher gene flow among similar elevational levels than across different elevational levels and suggest a selective influence of elevation on the distribution of genetic diversity in C. eyrei. The study underlines the importance to check the selective neutrality of marker loci in analyses of population structure.


Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation.
Nuclear import receptors of the KPNA family recognize the nuclear localization signal in proteins and together with importin-β mediate translocation into the nucleus. Accordingly, KPNA family members have a highly conserved architecture with domains that contact the nuclear localization signal and bind to importin-β. Here, we describe autosomal recessive mutations in KPNA7 found by whole exome sequencing in a sibling pair with severe developmental disability, infantile spasms, subsequent intractable epilepsy consistent with Lennox-Gastaut syndrome, partial agenesis of the corpus callosum, and cerebellar vermis hypoplasia. The mutations mapped to exon 7 in KPNA7 result in two amino-acid substitutions, Pro339Ala and Glu344Gln. On the basis of the crystal structure of the paralog KPNA2 bound to a bipartite nuclear localization signal from the retinoblastoma protein, the amino-acid substitutions in the affected subjects were predicted to occur within the seventh armadillo repeat that forms one of the two nuclear localization signal-binding sites in KPNA family members. Glu344 is conserved in all seven KPNA proteins, and we found that the Glu354Gln mutation in KPNA2 is sufficient to reduce binding to the retinoblastoma nuclear localization signal to approximately one-half that of wild-type protein. Our data show that compound heterozygous mutations in KPNA7 are associated with a human neurodevelopmental disease, and provide the first example of a human disease associated with mutation of a nuclear transport receptor.


Pathogenesis of Fistulating Crohn's Disease: A Review.
Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.


Gestational age at birth and child special educational needs: a UK representative birth cohort study.
To examine the association between gestational age at birth across the entire gestational age spectrum and special educational needs (SENs) in UK children at 11 years of age. The Millennium Cohort Study is a nationally representative longitudinal sample of children born in the UK during 2000-2002. Information about the child's birth, health and sociodemographic factors was collected when children were 9 months old. Information about presence and reasons for SEN was collected from parents at age 11. Adjusted relative risks (aRRs) were estimated using modified Poisson regression, accounting for confounders. The sample included 12 081 children with data at both time points. The overall prevalence of SEN was 11.2%, and it was inversely associated with gestational age. Among children born <32 weeks of gestation, the prevalence of SEN was 27.4%, three times higher than among those born at 40 weeks (aRR=2.89; 95% CI 2.02 to 4.13). Children born early term (37-38 weeks) were also at increased risk for SEN (aRR=1.33; 95% CI 1.11 to 1.59); this was the same when the analysis was restricted to births after labour with spontaneous onset. Birth before full term was more strongly associated with having a formal statement of SEN or SEN for multiple reasons. Children born at earlier gestational ages are more likely to experience SEN, have more complex SEN and require support in multiple facets of learning. This association was observed even among children born early-term and when labour began spontaneously.


Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells.
In pluripotent stem cells, DNA damage triggers loss of pluripotency and apoptosis as a safeguard to exclude damaged DNA from the lineage. An intricate DNA damage response (DDR) signaling network ensures that the response is proportional to the severity of the damage. We combined an RNA interference screen targeting all kinases, phosphatases, and transcription factors with global transcriptomics and phosphoproteomics to map the DDR in mouse embryonic stem cells treated with the DNA cross-linker cisplatin. Networks derived from canonical pathways shared in all three data sets were implicated in DNA damage repair, cell cycle and survival, and differentiation. Experimental probing of these networks identified a mode of DNA damage-induced Wnt signaling that limited apoptosis. Silencing or deleting the p53 gene demonstrated that genotoxic stress elicited Wnt signaling in a p53-independent manner. Instead, this response occurred through reduced abundance of Csnk1a1 (CK1α), a kinase that inhibits β-catenin. Together, our findings reveal a balance between p53-mediated elimination of stem cells (through loss of pluripotency and apoptosis) and Wnt signaling that attenuates this response to tune the outcome of the DDR.


Ultrafast stimulated emission of nitrophenolates in organic and aqueous solutions.
Early-time dynamics of nitroaromatics and its coressponding bases can give valuable insights into photo-induced reactions relevant to atmospheric and environmental processes. In this work, femtosecond broadband absorption spectroscopy between 350 and 700 nm has been applied to explore the ultrafast dynamics of o-, p- and m-nitrophenol anions (NP-) in basic organic and aqueous solution. Excitation at 400 nm promotes these compounds into the first bright electronic singlet state, which is a charge-transfer state. A surprising finding for all nitrophenolates was a characteristic, spectrally broad stimulated emission (SE) from the electronically excited state into the ground state. The corresponding lifetime was on the order of a few hundred femtoseconds for o- and p-NP- while it was roughly ten times larger for m-NP-. In line with earlier observations, the SE is governed by an out-of-plane torsional motion of the nitro group, leading to a close energetic approach of the relevant electronically excited singlet and ground states. Subsequent dynamics can be assigned to excited state absorption and ground state relaxation due to energy dissipation of the vibrational modes to the solvent that occur for up to several tens of picoseconds. No longer-lasting transient absorption (TA) was found; instead, a complete recovery of the ground state bleaching was observed indicating that triplet state relaxation is either not significantly involved in this spectral part or shifted to other regions. In the aqueous system, time constants for all processes are much smaller than in organic solution, a fact that can be explained by the larger dipole moment of the solvent and the correspondingly stronger intermolecular coupling between NP- and the aqueous solvent.


Multidisciplinary cancer team meeting structure and treatment decisions: a prospective correlational study.
Anecdotally, organizational factors appear to have an effect on the quality of decision-making in the multidisciplinary team (MDT) meeting. We assess the effect of the number of team-members present, number and order of cases, and the timing of meetings on the process of decision-making in MDT meetings. Between December 2009 and January 2010, data were prospectively collected on treatment decisions, meeting characteristics, quality of information, and teamworking for all cases discussed at a London-based MDT meeting. Variables measured using a validated assessment tool (MDT MODe) and correlational analyses were performed. Treatment decisions were reached in 254 of 298 (85%) cases. Cases toward the end of meetings were associated with lower rates of decision-making, information quality, and teamworking (r = -0.15 to -0.37). Increased number of cases per meeting and team members in attendance were associated with better information and teamworking (r = 0.29-0.43). More time per case was associated with improved teamworking (r = 0.16). A positive correlation was obtained between ability to reach decisions and improved information and teamworking (r = 0.36-0.54; all P ≤ 0.001). Organizational factors related to the structure of the MDT meeting are associated with variation in the likelihood of reaching a treatment decision. Further research is required to establish causation and to modify such factors in order to improve the quality of cancer care.


Predictors of supplementation for breastfed babies in a Baby-Friendly hospital.
Supplementation of breastfed babies is common during the hospital stay. The Baby Friendly Hospital Initiative (BFHI) optimises practices to support exclusive breastfeeding, yet supplementation is still prevalent. To determine predictors for supplementation in a cohort of breastfed babies in a Baby-Friendly hospital. Electronic hospital records of 1530 healthy term or near term singleton infants and their mothers were examined retrospectively and analysed to identify factors associated with in-hospital supplementation using Poisson regression (unadjusted and adjusted). Fifteen percent of breastfed infants were supplemented during their hospital stay. Analysis by multivariable Poisson regression found that supplementation was independently associated with overweight (reference normal weight) (aRR [adjusted relative risk]=1.46; 95% CI: 1.11-1.93); primiparity (aRR=1.40; 95% CI: 1.09-1.80); early term gestation (37-376 weeks, aRR=2.79; 95% CI: 1.88-4.15; 38-386 weeks, aRR=2.03, 95%CI: 1.46-2.82); birthweight less than 2500 grams (reference 3000-3499 grams) (aRR=3.60; 95% CI: 2.32-5.60) and use of postpartum uterotonic (aRR=2.47; 95% CI: 1.09-5.55). Greater than 65 minutes of skin-to-skin contact at birth reduced the risk of supplementation (aRR=0.66; 95% CI; 0.48-0.92). These identified predictors for supplementation, can inform the development of interventions for mother-infant pairs antenatally or in the early postpartum period around increased breastfeeding education and support to reduce supplementation. It may also be possible to reduce supplementation through judicious use of postpartum uterotonics and facilitation of mother-infant skin-to-skin contact at birth for greater than one hour duration.


Differential tinnitus-related neuroplastic alterations of cortical thickness and surface area.
Structural neuroimaging techniques have been used to identify cortical and subcortical regions constituting the neuroarchitecture of tinnitus. One recent investigation used voxel-based morphometry (VBM) to analyze a sample of tinnitus patients (TI, n = 257) (Schecklmann et al., 2013). A negative relationship between individual distress and cortical volume (CV) in bilateral auditory regions was observed. However, CV has meanwhile been identified as a neuroanatomical measurement that confounds genetically distinct neuroanatomical traits, namely cortical thickness (CT) and cortical surface area (CSA). We performed a re-analysis of the identical sample using the automated FreeSurfer surface-based morphometry (SBM) approach (Fischl, 2012). First, we replicated the negative correlation between tinnitus distress and bilateral supratemporal gray matter volume. Second, we observed a negative correlation for CSA in the left periauditory cortex and anterior insula. Furthermore, we noted a positive correlation between tinnitus duration and CT in the left periauditory cortex as well as a negative correlation in the subcallosal anterior cingulate, a region collated to the serotonergic circuit and germane to inhibitory functions. In short, the results elucidate differential neuroanatomical alterations of CSA and CT for the two independent tinnitus-related psychological traits distress and duration. Beyond this, the study provides further evidence for the distinction and specific susceptibility of CSA and CT within the context of neuroplasticity of the human brain.


Factors related to changes in CD4+ T-cell counts over time in patients living with HIV/AIDS: a multilevel analysis.
The measurement of CD4+ T-cell (CD4) counts is a strong predictor of progression to AIDS and a means of monitoring antiviral therapy (ART). The success or failure of controlling virus levels in untreated patients or those taking ART may be associated with treatment adherence, habits, correlated infections unrelated to HIV, cancer, immunosuppressive drugs; as well as socio-economic and psychosocial aspects and access to healthcare. The aim of the present study was to identify, using a multilevel model, the factors related to the variations of CD4 counts over time, in patients living with HIV. A cohort study was conducted with patients living with HIV, selected from July 2007 to December 2010. Patients were monitored from records of their first CD4 count after being diagnosed with HIV. A multilevel model with 3 levels of aggregation was applied to analyze the associations of predictor variables and the behavior of CD4 over time. A total of 1870 patients were enrolled. The mean number of CD4 at the beginning of the cohort was 393.1 cells/mm³, and there was a mean increase of 1.529 cells/mm³ per month. Patient's age, smoking, use of illicit drugs, hospital treatment, changing doctors and the use of ART, were factors that affected the kinetics of the CD4 count during the follow-up period. The results of this study indicated increased levels of CD4 over time in a cohort of patients living with HIV/AIDS and identified factors that may influence this increase and are liable to intervention.


Proteolytic Systems in Milk: Perspectives on the Evolutionary Function within the Mammary Gland and the Infant.
Milk contains elements of numerous proteolytic systems (zymogens, active proteases, protease inhibitors and protease activators) produced in part from blood, in part by mammary epithelial cells and in part by immune cell secretion. Researchers have examined milk proteases for decades, as they can cause major defects in milk quality and cheese production. Most previous research has examined these proteases with the aim to eliminate or control their actions. However, our recent peptidomics research demonstrates that these milk proteases produce specific peptides in healthy milk and continue to function within the infant's gastrointestinal tract. These findings suggest that milk proteases have an evolutionary function in aiding the infant's digestion or releasing functional peptides. In other words, the mother provides the infant with not only dietary proteins but also the means to digest them. However, proteolysis in the milk is controlled by a balance of protease inhibitors and protease activators so that only a small portion of milk proteins are digested within the mammary gland. This regulation presents a question: If proteolysis is beneficial to the infant, what benefits are gained by preventing complete proteolysis through the presence of protease inhibitors? In addition to summarizing what is known about milk proteolytic systems, we explore possible evolutionary explanations for this proteolytic balance.


The predictive validity of subjective adherence measures in patients with schizophrenia.
Despite frequent use of subjective adherence measures in patients with schizophrenia as well as other chronic conditions, there are several reports that question the validity of these instruments. Three well known, representative subjective measures are the Medication Adherence Questionnaire (MAQ), the Drug Attitude Inventory (DAI), and the Compliance Rating Scale (CRS). In this study we explored the predictive validity of these instruments in a European sample of 119 stabilized outpatients with schizophrenia. Clinical outcome variables were relapse and admission to a psychiatric hospital during a follow-up period of 12 months. Results indicate that the predictive validity of all three measures was poor. The MAQ was the least problematic predictor for relapse (Nagelkerke R(2) = 0.09), and time to relapse (R(2) = 0.07) and had the best sensitivity for relapse (63.6%) as well as admission (87.5%). The MAQ and CRS were both moderate predictive for admission (Nagelkerke R(2) = 0.21, and R(2) = 0.29). We conclude that the validity of the instruments studied here is questionable and have limited clinical relevance. Given the feasibility and ease of most subjective instruments, researchers may be tempted to use them but should be aware of the serious drawbacks of these instruments.


Genetic algorithm-based method for selecting wavelengths and model size for use with partial least-squares regression: application to near-infrared spectroscopy.
Genetic algorithms (GAs) are used to implement an automated wavelength selection procedure for use in building multivariate calibration models based on partial least-squares regression. The method also allows the number of latent variables used in constructing the calibration models to be optimized along with the selection of the wavelengths. The data used to test this methodology are derived from the determination of aqueous organic species by near-infrared spectroscopy. The three data sets employed focus on the determination of (1) methyl isobutyl ketone in water over the range of 1-160 ppm, (2) physiological levels of glucose in a phosphate buffer matrix containing bovine serum albumin and triacetin, and (3) glucose in a human serum matrix. These data sets feature analyte signals near the limit of detection and the presence of significant spectral interferences. Studies are performed to characterize the signal and noise characteristics of the spectral data, and optimal configurations for the GA are found for each data set through experimental design techniques. Despite the complexity of the spectral data, the GA procedure is found to perform well, leading to calibration models that significantly outperform those based on full spectrum analyses. In addition, a significant reduction in the number of spectral points required to build the models is realized.


Increasing nursing capacity in genomics: Overview of existing global genomics resources.
Global genomic literacy of all health professions, including nurses, remains low despite an inundation of genomic information with established clinical and analytic validity and clinical utility. Genomic literacy and competency deficits contribute to lost opportunities to take advantage of the benefits that genomic information provides to improve health outcomes, reduce healthcare costs, and increase patient quality and safety. Nurses are essential to the integration of genomics into healthcare. The greatest challenges to realizing their potential in successful integration include education and awareness. Identification of resources, their focus, whether they targeted at nursing, and how to access them, form the foundation for a global genomic resource initiative led by the Global Genomics Nursing Alliance. The aim was to identify existing global genomic resources and competencies, identifying the source, type and accessibility. Cross sectional online descriptive survey to ascertain existing genomic resources. Limited to eighteen countries and seven organizations represented by delegates attending the inaugural meeting in 2017 of the Global Genomics Nursing Alliance. A purposive sample of global nursing leaders and representatives of national and international nursing organizations. The primary method was by online survey administered following an orientation webinar. Given the small numbers of nurse leaders in genomics within our sample (and indeed within the world), results were analyzed and presented descriptively. Those identifying resources provided further detailed resource information. Additional data were collected during a face-to-face meeting using an electronic audience-response system. Of the twenty-three global delegates responding, 9 identified existing genomic resources that could be used for academic or continuing genomics education. Three countries have competence frameworks to guide learning and 5 countries have national organizations for genetics nurses. The genomic resources that already exist are not readily accessible or discoverable to the international nursing community and as such are underutilized.


Intravenous contrast material-induced nephropathy: causal or coincident phenomenon?
To determine the causal association and effect of intravenous iodinated contrast material exposure on the incidence of acute kidney injury (AKI), also known as contrast material-induced nephropathy (CIN). This retrospective study was approved by an institutional review board and was HIPAA compliant. Informed consent was waived. All contrast material-enhanced (contrast group) and unenhanced (noncontrast group) abdominal, pelvic, and thoracic CT scans from 2000 to 2010 were identified at a single facility. Scan recipients were sorted into low- (<1.5 mg/dL), medium- (1.5-2.0 mg/dL), and high-risk (>2.0 mg/dL) subgroups of presumed risk for CIN by using baseline serum creatinine (SCr) level. The incidence of AKI (SCr ≥ 0.5 mg/dL above baseline) was compared between contrast and noncontrast groups after propensity score adjustment by stratification, 1:1 matching, inverse weighting, and weighting by the odds methods to reduce intergroup selection bias. Counterfactual analysis was used to evaluate the causal relation between contrast material exposure and AKI by evaluating patients who underwent contrast-enhanced and unenhanced CT scans during the study period with the McNemar test. A total of 157,140 scans among 53,439 unique patients associated with 1,510,001 SCr values were identified. AKI risk was not significantly different between contrast and noncontrast groups in any risk subgroup after propensity score adjustment by using reported risk factors of CIN (low risk: odds ratio [OR], 0.93; 95% confidence interval [CI]: 0.76, 1.13; P = .47; medium risk: odds ratio, 0.97; 95% CI: 0.81, 1.16; P = .76; high risk: OR, 0.91; 95% CI: 0.66, 1.24; P = .58). Counterfactual analysis revealed no significant difference in AKI incidence between enhanced and unenhanced CT scans in the same patient (McNemar test: χ(2) = 0.63, P = .43) (OR = 0.92; 95% CI: 0.75, 1.13; P = .46). Following adjustment for presumed risk factors, the incidence of CIN was not significantly different from contrast material-independent AKI. These two phenomena were clinically indistinguishable with established SCr-defined criteria, suggesting that intravenous iodinated contrast media may not be the causative agent in diminished renal function after contrast material administration. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12121823/-/DC1.


Response of mature unprimed CD8+ T cells to Mlsa determinants.
Contrary to existing dogma, evidence is presented that proliferative responses of mature unprimed T cells to Mlsa antigens involve CD8+ cells as well as CD4+ cells. The response of CD8+ cells to Mlsa antigens proved to be heavily dependent on help from CD4+ cells, and responses were stronger in three I-E+ strain combinations than in an I-E- combination. In I-E+ combinations, CD8+ blast cells accounted for 20-25% of the blasts generated from unseparated T cells responding to Mlsa-bearing stimulator cells in vitro; similar findings applied to blast cells generated in vivo. The observation that the majority (greater than or equal to 50%) of Mlsa-stimulated CD8+ cells (and CD4+ cells) were V beta 6+ indicated that CD8+ cells respond to Mlsa antigens, per se, rather than to nonspecific stimuli. Whether CD4+ and CD8+ cells use the same or different H-2-restricting elements to respond to Mlsa antigens has yet to be resolved.


A West African Middle Stone Age site dated to the beginning of MIS 5: Archaeology, chronology, and paleoenvironment of the Ravin Blanc I (eastern Senegal).
The Ravin Blanc I archaeological occurrence, dated to MIS 5, provides unprecedented data on the Middle Stone Age (MSA) of West Africa since well-contextualized archaeological sites pre-dating MIS 4/3 are extremely rare for this region. The combined approach on geomorphology, phytolith analysis, and OSL date estimations offers a solid framework for the MSA industry comprised in the Ravin Blanc I sedimentary sequence. The paleoenvironmental reconstruction further emphasizes on the local effects of the global increase in moisture characterizing the beginning of the Upper Pleistocene as well as the later shift to more arid conditions. The lithic industry, comprised in the lower part of the sequence and dated to MIS 5e, shows core reduction sequences among which Levallois methods are minor, as well as an original tool-kit composition, among which pieces with single wide abrupt notches, side-scrapers made by inverse retouch, and a few large crudely shaped bifacial tools. The Ravin Blanc I assemblage has neither a chronologically equivalent site to serve comparisons nor a clear techno-typological correspondent in West Africa. However, the industry represents an early MSA technology that could either retain influences from the southern West African 'Sangoan' or show reminiscences of the preceding local Acheulean. A larger-scale assessment of behavioral dynamics at work at the transition period between the Middle to Upper Pleistocene is discussed in view of integrating this new site to the global perception of this important period in the MSA evolutionary trajectories.


Advanced sine wave modulation of continuous wave laser system for atmospheric CO(2) differential absorption measurements.
In this theoretical study, modulation techniques are developed to support the Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. A continuous wave (CW) lidar system using sine waves modulated by maximum length (ML) pseudo-noise (PN) codes is described for making simultaneous online/offline differential absorption measurements. Amplitude and phase-shift keying (PSK) modulated intensity modulation (IM) carriers, in addition to a hybrid-pulse technique are investigated, which exhibit optimal autocorrelation properties. A method is presented to bandwidth limit the ML sequence based on a filter implemented in terms of Jacobi theta functions, which does not significantly degrade the resolution or introduce sidelobes as a means of reducing aliasing and IM carrier bandwidth.


Magnon excitation with spin-polarized scanning tunneling microscopy.
Using spin-polarized scanning tunneling microscopy, the local excitation of magnons in Fe and Co has been studied. A large cross section for magnon excitation was found for bulk Fe samples while for thin Co films on Cu(111) the cross section linearly scales with film thickness. Recording inelastic tunneling spectra with Fe coated W tips in a magnetic field, the magnonic nature of the excitation was proven. Magnon excitation could be detected without the use of a separating insulating layer opening up the possibility to directly study magnons in magnetic nanostructures via spin-polarized currents.


Genome-wide regulon and crystal structure of BlaI (Rv1846c) from Mycobacterium tuberculosis.
Comparative genomics with Staphylococcus aureus suggested the existence of a regulatory system governing beta-lactamase (BlaC) production in Mycobacterium tuberculosis. The crystal structure of Rv1846c, a winged helix regulator of previously unknown function, was solved thus revealing strong similarity to the BlaI and MecI repressors of S. aureus, which both respond to beta-lactam treatment. Using chromatin immunoprecipitation and hybridization to microarrays (ChIP-on-chip), the Rv1846c regulon was shown to comprise five separate genomic loci. Two of these mediate responses and resistance to beta-lactam antibiotics (rv1845c, rv1846c-rv1847; blaC-sigC); two encode membrane proteins of unknown function (rv1456c, rv3921c) while the last codes for ATP synthase (rv1303-atpBEFHAGDC-rv1312). The ChIP-on-chip findings were confirmed independently using electrophoretic mobility shift assays, DNAse footprinting and transcript analysis leading to Rv1846c being renamed BlaI. When cells were treated with beta-lactams, BlaI was released from its operator sites causing derepression of the regulon and upregulation of ATP synthase transcription. The existence of a potential regulatory loop between cell wall integrity and ATP production was previously unknown.


An emergence of coordinated communication in populations of agents.
The purpose of this article is to demonstrate that coordinated communication spontaneously emerges in a population composed of agents that are capable of specific cognitive activities. Internal states of agents are characterized by meaning vectors. Simple neural networks composed of one layer of hidden neurons perform cognitive activities of agents. An elementary communication act consists of the following: (a) two agents are selected, where one of them is declared the speaker and the other the listener; (b) the speaker codes a selected meaning vector onto a sequence of symbols and sends it to the listener as a message; and finally, (c) the listener decodes this message into a meaning vector and adapts his or her neural network such that the differences between speaker and listener meaning vectors are decreased. A Darwinian evolution enlarged by ideas from the Baldwin effect and Dawkins' memes is simulated by a simple version of an evolutionary algorithm without crossover. The agent fitness is determined by success of the mutual pairwise communications. It is demonstrated that agents in the course of evolution gradually do a better job of decoding received messages (they are closer to meaning vectors of speakers) and all agents gradually start to use the same vocabulary for the common communication. Moreover, if agent meaning vectors contain regularities, then these regularities are manifested also in messages created by agent speakers, that is, similar parts of meaning vectors are coded by similar symbol substrings. This observation is considered a manifestation of the emergence of a grammar system in the common coordinated communication.


A review of current progress in gene and stem cell therapy for erectile dysfunction.
Current gene-based strategies for treatment of erectile dysfunction (ED) are based on the nitric oxide (NO)/cGMP system; although growth factors, calcium sensitization, and potassium channel expression have been studied. Initial investigations of stem-cell-based therapy have attracted attention. Results of the first gene transfer clinical trial for treatment of ED with maxi-K channels are positive. Moreover, there is progress in gene and stem-cell therapy for the treatment of cardiovascular (CV) diseases. To improve understanding of gene and stem-cell therapy for CV disease, with emphasis on ED. Review of current literature. Treatment and prevention of ED can be improved by the application of CVD gene/cell-based therapy. New discoveries based on gene- and cell-based therapy will lead to new advances in the treatment of ED.


Genomic Analysis of Phylotype I Strain EP1 Reveals Substantial Divergence from Other Strains in the Ralstonia solanacearum Species Complex.
Ralstonia solanacearum species complex is a devastating group of phytopathogens with an unusually wide host range and broad geographical distribution. R. solanacearum isolates may differ considerably in various properties including host range and pathogenicity, but the underlying genetic bases remain vague. Here, we conducted the genome sequencing of strain EP1 isolated from Guangdong Province of China, which belongs to phylotype I and is highly virulent to a range of solanaceous crops. Its complete genome contains a 3.95-Mb chromosome and a 2.05-Mb mega-plasmid, which is considerably bigger than reported genomes of other R. solanacearum strains. Both the chromosome and the mega-plasmid have essential house-keeping genes and many virulence genes. Comparative analysis of strain EP1 with other 3 phylotype I and 3 phylotype II, III, IV strains unveiled substantial genome rearrangements, insertions and deletions. Genome sequences are relatively conserved among the 4 phylotype I strains, but more divergent among strains of different phylotypes. Moreover, the strains exhibited considerable variations in their key virulence genes, including those encoding secretion systems and type III effectors. Our results provide valuable information for further elucidation of the genetic basis of diversified virulences and host range of R. solanacearum species.


Effects of smoked marijuana in experimentally induced asthma.
After experimental induction of acute bronchospasm in 8 subjects with clinically stable bronchial asthma, effects of 500 mg of smoked marijuana (2.0 per cent delta9-tetrahydrocannabinol) on specific airway conductance and thoracic gas volume were compared with those of 500 mg of smoked placebo marijuana (0.0 per cent delta9-tetrahydrocannabinol), 0.25 ml of aerosolized saline, and 0.25 ml of aerosolized isoproterenol (1,250 mug). Bronchospasm was induced on 4 separate occasions, by inhalation of methacholine and, on four other occasions, by exercise on a bicycle ergometer or treadmill. Methacholine and exercise caused average decreases in specific airway conductance of 40 to 55 per cent and 30 to 39 per cent, respectively, and average increases in thoracic gas volume of 35 to 43 per cent and 25 to 35 per cent, respectively. After methacholine-induced bronchospasm, placebo marijuana and saline inhalation produced minimal changes in specific airway conductance and thoracic gas volume, whereas 2.0 per cent marijuana and isoproterenol each caused a prompt correction of the bronchospasm and associated hyperinflation. After exercise-induced bronchospasm, placebo marijuana and saline were followed by gradual recovery during 30 to 60 min, whereas 2.0 per cent marijuana and isoproterenol caused an immediate reversal of exercise-induced asthma and hyperinflation.


Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois.
Tbx4 is a member of the T-box family of transcription factor genes, which have been shown to play important roles in development. We have ablated Tbx4 function using targeted mutagenesis in the mouse. Embryos homozygous for the null allele fail to undergo chorioallantoic fusion and die by 10.5 days post coitus. The allantoises of Tbx4-mutant embryos are stunted, apoptotic and display abnormal differentiation. Endothelial cells within mutant allantoises do not undergo vascular remodeling. Heterozygous embryos show a mild, transient growth defect in the allantois. Induction of a hindlimb field occurs normally in Tbx4 mutants and initial patterning of the hindlimb bud appears normal. However, hindlimb buds from Tbx4 mutants fail to develop either in vivo or in vitro and do not maintain Fgf10 expression in the mesenchyme. The expression of another, closely-linked, T-box gene, Tbx2, is reduced in both the hindlimb and the allantois of Tbx4-mutant embryos prior to the development of overt morphological abnormalities, which suggests that Tbx4 regulates Tbx2 in these tissues.


Widespread Myocardial Delivery of Heart-Derived Stem Cells by Nonocclusive Triple-Vessel Intracoronary Infusion in Porcine Ischemic Cardiomyopathy: Superior Attenuation of Adverse Remodeling Documented by Magnetic Resonance Imaging and Histology.
Single-vessel, intracoronary infusion of stem cells under stop-flow conditions has proven safe but achieves only limited myocardial coverage. Continuous flow intracoronary delivery to one or more coronary vessels may achieve broader coverage for treating cardiomyopathy, but has not been investigated. Using nonocclusive coronary guiding catheters, we infused allogeneic cardiosphere-derived cells (CDCs) either in a single vessel or sequentially in all three coronary arteries in porcine ischemic cardiomyopathy and used magnetic resonance imaging (MRI) to assess structural and physiological outcomes. Vehicle-infused animals served as controls. Single-vessel stop-flow and continuous-flow intracoronary infusion revealed equivalent effects on scar size and function. Sequential infusion into each of the three major coronary vessels under stop-flow or continuous-flow conditions revealed equal efficacy, but less elevation of necrotic biomarkers with continuous-flow delivery. In addition, multi-vessel delivery resulted in enhanced global and regional tissue function compared to a triple-vessel placebo-treated group. The functional benefits after global cell infusion were accompanied histologically by minimal inflammatory cellular infiltration, attenuated regional fibrosis and enhanced vessel density in the heart. Sequential multi-vessel non-occlusive delivery of CDCs is safe and provides enhanced preservation of left ventricular function and structure. The current findings provide preclinical validation of the delivery method currently undergoing clinical testing in the Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial of CDCs in heart failure patients.


The fossil record of ecdysis, and trends in the moulting behaviour of trilobites.
Ecdysis, the process of moulting an exoskeleton, is one of the key characters uniting arthropods, nematodes and a number of smaller phyla into Ecdysozoa. The arthropod fossil record, particularly trilobites, eurypterids and decapod crustaceans, yields information on moulting, although the current focus is predominantly descriptive and lacks a broader evolutionary perspective. We here review literature on the fossil record of ecdysis, synthesising research on the behaviour, evolutionary trends, and phylogenetic significance of moulting throughout the Phanerozoic. Approaches vary widely between taxonomic groups, but an overall theme uniting these works suggests that identifying moults in the palaeontological record must take into account the morphology, taphonomy and depositional environment of fossils. We also quantitatively analyse trends in trilobite ecdysis based on a newly generated database of published incidences of moulting behaviour. This preliminary work reveals significant taxonomic and temporal signal in the trilobite moulting fossil record, with free cheek moulting being prevalent across all Orders and throughout the Phanerozoic, and peaks of cephalic moulting in Phacopida during the Ordovician and rostral plate moulting in Redlichiida during the Cambrian. This study and a review of the literature suggest that it is feasible to extract large-scale evolutionary information from the fossil record of moulting.


Simultaneous optical recording in multiple cells by digital holographic microscopy of chloride current associated to activation of the ligand-gated chloride channel GABA(A) receptor.
Chloride channels represent a group of targets for major clinical indications. However, molecular screening for chloride channel modulators has proven to be difficult and time-consuming as approaches essentially rely on the use of fluorescent dyes or invasive patch-clamp techniques which do not lend themselves to the screening of large sets of compounds. To address this problem, we have developed a non-invasive optical method, based on digital holographic microcopy (DHM), allowing monitoring of ion channel activity without using any electrode or fluorescent dye. To illustrate this approach, GABA(A) mediated chloride currents have been monitored with DHM. Practically, we show that DHM can non-invasively provide the quantitative determination of transmembrane chloride fluxes mediated by the activation of chloride channels associated with GABA(A) receptors. Indeed through an original algorithm, chloride currents elicited by application of appropriate agonists of the GABA(A) receptor can be derived from the quantitative phase signal recorded with DHM. Finally, chloride currents can be determined and pharmacologically characterized non-invasively simultaneously on a large cellular sampling by DHM.


Economic downturns and infant health.
We study the gender-specific impact of macroeconomic conditions around birth on infant health. We use a sample of over 50,000 respondents born between 1950 and 1994 from Lifelines-a cohort and biobank from the northern Netherlands. Our results show that high provincial unemployment rates decrease fertility and lead to a lower birthweight in boys. The negative impact of high unemployment on birthweight is particularly strong for boys born to older mothers and for babies born to smoking mothers.


Predicting Surgical Complications in Patients Undergoing Elective Adult Spinal Deformity Procedures Using Machine Learning.
Cross-sectional database study. To train and validate machine learning models to identify risk factors for complications following surgery for adult spinal deformity (ASD). Machine learning models such as logistic regression (LR) and artificial neural networks (ANNs) are valuable tools for analyzing and interpreting large and complex data sets. ANNs have yet to be used for risk factor analysis in orthopedic surgery. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for patients who underwent surgery for ASD. This query returned 4,073 patients, which data were used to train and evaluate our models. The predictive variables used included sex, age, ethnicity, diabetes, smoking, steroid use, coagulopathy, functional status, American Society of Anesthesiologists (ASA) class >3, body mass index (BMI), pulmonary comorbidities, and cardiac comorbidities. The models were used to predict cardiac complications, wound complications, venous thromboembolism (VTE), and mortality. Using ASA class as a benchmark for prediction, area under receiver operating characteristic curves (AUC) was used to determine the accuracy of our machine learning models. The mean age of patients was 59.5 years. Forty-one percent of patients were male whereas 59.0% of patients were female. ANN and LR outperformed ASA scoring in predicting every complication (p<.05). The ANN outperformed LR in predicting cardiac complication, wound complication, and mortality (p<.05). Machine learning algorithms outperform ASA scoring for predicting individual risk prognosis. These algorithms also outperform LR in predicting individual risk for all complications except VTE. With the growing size of medical data, the training of machine learning on these large data sets promises to improve risk prognostication, with the ability of continuously learning making them excellent tools in complex clinical scenarios. Level III.


Divergent evolution of ligand binding in the o-succinylbenzoate synthase family.
Thermobifida fusca o-succinylbenzoate synthase (OSBS), a member of the enolase superfamily that catalyzes a step in menaquinone biosynthesis, has an amino acid sequence that is 22 and 28% identical with those of two previously characterized OSBS enzymes from Escherichia coli and Amycolatopsis sp. T-1-60, respectively. These values are considerably lower than typical levels of sequence identity among homologous proteins that have the same function. To determine how such divergent enzymes catalyze the same reaction, we determined the structure of T. fusca OSBS and identified amino acids that are important for ligand binding. We discovered significant differences in structure and conformational flexibility between T. fusca OSBS and other members of the enolase superfamily. In particular, the 20s loop, a flexible loop in the active site that permits ligand binding and release in most enolase superfamily proteins, has a four-amino acid deletion and is well-ordered in T. fusca OSBS. Instead, the flexibility of a different region allows the substrate to enter from the other side of the active site. T. fusca OSBS was more tolerant of mutations at residues that were critical for activity in E. coli OSBS. Also, replacing active site amino acids found in one protein with the amino acids that occur at the same place in the other protein reduces the catalytic efficiency. Thus, the extraordinary divergence between these proteins does not appear to reflect a higher tolerance of mutations. Instead, large deletions outside the active site were accompanied by alteration of active site size and electrostatic interactions, resulting in small but significant differences in ligand binding.


CD28 family of receptors on T cells in chronic HBV infection: Expression characteristics, clinical significance and correlations with PD-1 blockade.
The aim of the present study was to investigate the overall clinical expression characteristics of the cluster of differentiation (CD)28 family receptors [CD28, inducible T-cell co-stimulator, programmed cell death protein 1 (PD‑1), cytotoxic T-lymphocyte-associated protein 4 and B‑ and T-lymphocyte attenuator] on T cells in patients with chronic hepatitis B (CHB), analyze the correlations among these receptors and the clinical parameters, and to investigate the effects of PD‑1 blockade on the receptor expression profiles, T‑cell function and other biological effects. The expression characteristics of the CD28 family of receptors, the effects of PD‑1 blockade on the receptor expression profiles and the levels of interferon (IFN)‑γ were investigated in the T cells of patients with CHB. In addition, the transcription factor, T‑box 21 (T‑bet) and GATA binding protein 3 (GATA‑3) mRNA expression levels were investigated in the peripheral blood mononuclear cells (PBMCs) of patients with CHB. The expression levels of the CD28 family receptors in the T cells of patients with CHB demonstrated distinct characteristics , for example levels of PD‑1 and CTLA‑4 on CD4 T cells and ICOS, PD‑1, and BTLA on CD8 T cells were increased in cells from patients with CHB compared with those from the healthy individuals. A significant positive correlation was demonstrated among the serum HBV DNA titers and the levels of PD‑1 on CD8+ T cells with the highest expression of PD‑1 corresponding to viral levels >106 IU/ml. A significant positive correlation was observed between the serum HBV DNA titers and the expression levels of BTLA on CD8+ T cells with the highest expression of BTLA corresponding to viral levels >106 IU/ml. PD‑1 blockade altered the expression profiles of CD28 family receptors in the T cells of patients with CHB, partly enhanced T cell function and increased the ratio of T‑bet/GATA‑3 mRNA in PBMCs. Thus, CD28 family receptors are potential clinical indicators for the rapid monitoring of changes in T cell function during CHB treatment. Furthermore, PD‑1 blockade has a therapeutic potential that may be enhanced by modulating the expression of co-stimulatory and -inhibitory receptors of the CD28 family.