Intracellular aggregated TRPV1 is associated with lower survival in breast cancer patients.
Breast cancer is a malignant disease that represents an important public health burden. The description of new molecular markers can be important to diagnosis, classification, and treatment. Transient receptor potential vanilloid 1 (TRPV1) polymodal channel is expressed in different neoplastic tissues and cell lines of breast cancer and associated with the regulation of tumor growth, tumor neurogenesis, cancer pain, and malignant progression of cancer. In primary and metastatic breast cancer tumors, TRPV1 is expressed during neoplastic transformation, invasive behavior, and resistance to cytotoxic therapy. The objective of this study was to describe the subcellular distribution of TRPV1 in invasive breast carcinomas and its association with survival. In 33 cases of invasive breast carcinomas, we identified immunohistochemical and immunofluorescent expression patterns of TRPV1 compared to healthy breast tissue. We characterized the expression of TRPV1 induced by estrogens in breast cancer cell lines MCF-7 and MDA to establish a model of the TRPV1-estrogen relationship regarding the malignant potential. We examined the association of TRPV1 patterns with patients' survival with the Kaplan-Meyer model, using the log-rank test at 5 years of follow-up. The relation of TRPV1 expression patterns to the St. Gallen breast cancer subtypes was also tested. Based on immunohistochemical expression pattern of TRPV1, we distinguished two main categories of breast cancer tissue, a "classical category" that exhibited diffuse expression of the channel and a "non-classical category" that expressed the channel in aggregates at the ER/Golgi and/or surrounding these structures. The classical pattern of TRPV1 was associated with a higher survival rate. In breast cancer cell lines, increasing doses of estrogens induced increased TRPV1 expression with nonclassical patterns at higher doses via a mechanism dependent on ER α. The expression and distribution of TRPV1 in invasive breast carcinomas may be considered as a biomarker for prognosis of the disease and a probable therapeutic target.


Prediction of the binding affinities of peptides to class II MHC using a regularized thermodynamic model.
The binding of peptide fragments of extracellular peptides to class II MHC is a crucial event in the adaptive immune response. Each MHC allotype generally binds a distinct subset of peptides and the enormous number of possible peptide epitopes prevents their complete experimental characterization. Computational methods can utilize the limited experimental data to predict the binding affinities of peptides to class II MHC. We have developed the Regularized Thermodynamic Average, or RTA, method for predicting the affinities of peptides binding to class II MHC. RTA accounts for all possible peptide binding conformations using a thermodynamic average and includes a parameter constraint for regularization to improve accuracy on novel data. RTA was shown to achieve higher accuracy, as measured by AUC, than SMM-align on the same data for all 17 MHC allotypes examined. RTA also gave the highest accuracy on all but three allotypes when compared with results from 9 different prediction methods applied to the same data. In addition, the method correctly predicted the peptide binding register of 17 out of 18 peptide-MHC complexes. Finally, we found that suboptimal peptide binding registers, which are often ignored in other prediction methods, made significant contributions of at least 50% of the total binding energy for approximately 20% of the peptides. The RTA method accurately predicts peptide binding affinities to class II MHC and accounts for multiple peptide binding registers while reducing overfitting through regularization. The method has potential applications in vaccine design and in understanding autoimmune disorders. A web server implementing the RTA prediction method is available at http://bordnerlab.org/RTA/.


Interaction of the Unc-51-like kinase and microtubule-associated protein light chain 3 related proteins in the brain: possible role of vesicular transport in axonal elongation.
We identified two mammalian ULK1 (Unc-51-like kinase involved in neurite extension) binding proteins by yeast two-hybrid screening. Both proteins showed high structural similarity to microtubule-associated protein (MAP) light chain 3 (LC3). One is identical to the Golgi-associated ATPase Enhancer of 16 kDa (GATE-16), an essential factor for intra-Golgi transport [39]. The other is identical to the gamma 2-subunit of GABA-A receptor associated protein (GABARAP) which has a possible role in receptor transport [46]. Using the yeast two-hybrid system and the in vitro GST pull-down assay, we found that the N-terminal proline/serine rich (PS) domain of ULK1 (amino acid 287-416) is required for ULK1-GATE-16 and ULK1-GABARAP protein interactions. However, the kinase activity of ULK1 affected neither ULK1-GATE-16 nor ULK1-GABARAP interaction. Immunohistochemical analysis using ULK1 and GABARAP antibodies showed that the ULK1 and the GABARAP proteins co-localized to many kind of neurons such as pyramidal cells of the hippocampus, mitral cells of the olfactory bulb, and Purkinje cells of the cerebellum. In HeLa cells, endogenous ULK1 and tagged GABARAP showed punctate structures in the cytosol, and were colocalized. These results suggest that the interaction of ULK1 and GABARAP is important to vesicle transport and axonal elongation in mammalian neurons.


Why more needs to be known about RBE effects in modern radiotherapy.
Radiation therapy remains a very effective tool in the clinical management and cure of cancer and new techniques of radiation delivery continue to be developed. Of particular note is the growing world-wide interest in particle beam therapy (PBT) using protons or light ions. Such beams (particularly light ions) are associated with an increased relative biological effectiveness (RBE) which, when viewed alongside the more favourable physical distributions of radiation dose available with all forms of particle beams, makes them especially attractive for treating tumours which are associated with disappointing outcomes following conventional X-ray therapy. Although the large body of clinical experience already gained with conventional X-ray therapy will be of paramount importance in guiding the development of treatment programmes using particle beams, understanding and quantification of the RBE effects which are unique to the latter will also be essential. This is because the magnitude of RBE effect is not fixed for any one radiation/tissue combination but is subject to a number of other radiobiological influences. Such relationships may be quantified within the linear-quadratic radiobiological model, within which the associated concept of biologically effective dose (BED) provides a way of inter-comparing the overall biological impact of existing and projected treatments. This paper summarises the main features of RBE and BED, discusses the main quantitative implications for PBT and highlights why clear understanding of RBE effects will be essential to make best use of PBT. It also summarises other clinical applications where knowledge of and allowance for RBE effects is important and suggests that more needs to be done to allow safer practical applications.


Robotics versus laparoscopic radical hysterectomy with lymphadenectomy in patients with early cervical cancer: a multicenter study.
The aim of this study was to retrospectively compare the safety, morbidity, and recurrence rate of total laparoscopic radical hysterectomy (TLRH) with lymphadenectomy and total robotic radical hysterectomy (RRH) with lymphadenectomy for early cervical carcinoma in a series of 99 consecutive women. We studied 99 consecutive patients with FIGO stage Ia1 (LVSI), Ia2, Ib1, Ib2, and IIa cervical cancer, 76 of whom underwent TLRH and 23 underwent RRH with pelvic lymph node dissection. Para-aortic lymphadenectomy, with the superior border of the dissection being the inferior mesenteric artery, was performed in all cases with positive pelvic lymph nodes discovered at frozen section evaluation. The mean blood loss was 157 ml in the RRH group (95% confidence interval [95% CI] 50-400) and 95 ml in the TLRH group (95% CI 30-500) (not significant [NS]). The median length of hospital stay was 3 days in the RRH group (95% CI 2-7) and 4 days in the TLRH group (95% CI 3-7) (NS). The mean operating time was 255 min for the TLRH group (95% CI 182-415) compared with 323 min in the RRH group (95% CI 161-433) (P < 0.05). No significant difference was found between the 2 groups when comparing the recurrence rate. Robotic radical hysterectomy can be considered a safe and effective therapeutic procedure for managing early-stage cervical cancer without significant differences, if compared with laparoscopic radical hysterectomy, in terms of the recurrence rate and intraoperative and postoperative complications, although multicenter randomized clinical trials with longer follow-up are necessary to evaluate the overall oncologic outcomes of this procedure.


Research engagement of health sciences librarians: a survey of research-related activities and attitudes.
The extent to which health sciences librarians are engaged in research is a little-studied question. This study assesses the research activities and attitudes of Medical Library Association (MLA) members, including the influence of work affiliation. An online survey was designed using a combination of multiple-choice and open-ended questions and distributed to MLA members. Responses were analyzed using descriptive statistics, content analysis, and significance testing. The authors used statistical tools and categorized open-ended question topics by the constant comparative method, also applying the broad subject categories used in a prior study. Pearson's chi-square analysis was performed on responses to determine significant differences among respondents employed in three different institutional environments. Analysis showed that 79% of respondents read research articles at least once a month; 58% applied published research studies to practice; 44% had conducted research; 62% reported acting on research had enhanced their libraries; 38% had presented findings; and 34% had authored research articles. Hospital librarians were significantly less likely than academic librarians to have participated in research activities. Highly ranked research benefits, barriers, and competencies of health sciences librarians are described. Findings indicate that health sciences librarians are actively engaged in research activities. Practice implications for practitioners, publishers, and stakeholders are discussed. Results suggest that practitioners can use published research results and results from their own research to affect practice decisions and improve services. Future studies are needed to confirm and extend these findings, including the need for intervention studies to increase research and writing productivity.


Isolation and characterization of plasma membranes from transplantable human astrocytoma, oat cell carcinoma, and melanomas.
Purified plasma membranes were obtained from five transplantable human tumors, a grade IV astrocytoma, an oat cell carcinoma, and three melanomas. Plasma membrane fractions were isolated from tumor homogenates by differential and discontinuous sucrose gradient centrifugation. Determination of enzyme activities indicated that the plasma membranes were enriched 10- to 20-fold with respect to 5'-nucleotidase, nicotinamide adenine dinucleotide glycohydrolase, Mg2+-activated nucleoside triphosphatase, and sialic acid. Specific activities of nearly all the enzymes varied with the individual tumors, even among tumors of the same type, i.e., the melanomas. Electron micrographs of the plasma membrane fractions showed smooth single-membrane vesicles with slight contamination by lysosomes. Therefore, these membranes are suitable for comparative biochemical studies and for the preparation of tumor-specific monoclonal antibodies. Plasma membranes from all five tumors contained very high Mg2+-adenosine triphosphatase (ATPase) activities. The Na+-K+-ATPase was a minor component of the total ATPase of these membranes (less than 30%). The major component was an ATPase exhibiting similar activity toward several nucleoside triphosphates. The activity of such a nucleoside triphosphatase has been correlated with tumorigenicity in cultured liver epithelial cells. The nucleoside triphosphatase of the plasma membranes of astrocytoma and oat cell carcinoma was stimulated from 50 to 1005 by concanavalin A, whereas ATPase of the melanoma plasma membranes was not or only slightly stimulated. The different response to concanavalin A could be due to differences in the ATPase molecules of the individual tumors or to the different environment of the ATPase.


Effect of Health Insurance on Hepatitis C Sustained Virologic Response Rates to Sofosbuvir-Based Treatment Regimens in a South Florida Community Hospital.
The high cost of direct-acting antiviral-based regimens raises concerns about the outcome of treatment in uninsured patients with chronic hepatitis C virus (HCV) infection. This study assessed the relationship between health insurance status and sustained virologic response (SVR) rates in a community hospital in South Florida. Sofosbuvir-based therapy was initiated in 82 patients, of which 73% were uninsured and 28 (34%) were HIV coinfection. The overall SVR rate for those tested was 98%. The SVR rates were similar between HCV mono- and HCV/HIV coinfected patients (96% versus 100%, P = .204). Uninsured patients, with access to patient assistance programs, had comparable SVR rates to insured patients (100% versus 95%, P = .131). However, there was a trend toward a higher rate of loss to follow-up in uninsured compared to insured patients (25% versus 9%, P = .116). Strategies specific to adherence to treatment for uninsured patients are needed to reduce rates of loss to follow-up.


GHS-R1a signaling in the DMH and VMH contributes to food anticipatory activity.
Rats that have restricted access to food at a fixed time point of the circadian phase display high levels of food anticipatory activity (FAA). The orexigenic hormone ghrelin has been implicated in the regulation of FAA. However, it is not known via which brain area ghrelin exerts this effect. Growth hormone secretagogue receptor 1a (GHS-R1a) is highly expressed in the hypothalamus, including the dorsomedial hypothalamus (DMH) and the ventromedial hypothalamus (VMH). These two hypothalamic areas have been reported to play a role in FAA. To examine the role of GHS-R1a signaling in the DMH and VMH in FAA. Adeno-associated virus expressing a shRNA directed against GHS-R1a was used to establish local knockdown of GHS-R1a in the DMH and VMH in rats. Rats were subsequently subjected to a restricted feeding schedule (RFS). Under ad libitum conditions, knockdown of GHS-R1a in the VMH increased food intake and body weight gain. In addition, GHS-R1a knockdown in VMH and DMH reduced body temperature and running wheel activity (RWA). When rats were subjected to a RFS, the main effect of GHS-R1a knockdown in both DMH and VMH was a decrease in RWA and an attenuation of body weight loss. Rats with knockdown of GHS-R1a in DMH and VMH showed a delay in onset of FAA. In addition, GHS-R1a knockdown in DMH resulted in a reduction of FAA amplitude. This is the first study to investigate the effect of local hypothalamic knockdown of GHS-R1a on FAA. Our results implicate hypothalamic GHS-R1a signaling in the regulation of FAA. Nevertheless, some FAA remained, suggesting that a distributed network of brain areas and signaling pathways is involved in the development of FAA.


A model-based objective evaluation of eye movement correction in EEG recordings.
We present a method to quantitatively and objectively compare algorithms for correction of eye movement artifacts in a simulated ongoing electroencephalographic signal (EEG). A realistic model of the human head is used, together with eye tracker data, to generate a data set in which potentials of ocular and cerebral origin are simulated. This approach bypasses the common problem of brain-potential contaminated electro-oculographic signals (EOGs), when monitoring or simulating eye movements. The data are simulated for five different EEG electrode configurations combined with four different EOG electrode configurations. In order to objectively compare correction performance for six algorithms, listed in Table III, we determine the signal to noise ratio of the EEG before and after artifact correction. A score indicating correction performance is derived, and for each EEG configuration the optimal correction algorithm and the optimal number of EOG electrodes are determined. In general, the second-order blind identification correction algorithm in combination with 6 EOG electrodes performs best for all EEG configurations evaluated on the simulated data.


[Nectin and nectin-like molecules as markers, actors and targets in cancer].
Nectin and nectin-like (necl) proteins form a family of 9 adhesion molecules that belong to the immunoglobulin superfamily. They play a key role in different biological processes such as cell polarity, proliferation, differentiation and migration in epithelial, endothelial, immune and nervous systems. Besides their role in physiology, they have been involved in different pathological processes in humans. They serve as virus receptors (poliovirus and herpes simplex virus), they are involved in orofacial malformation (CLPED1) and recently they have been described as markers, actors and potential therapeutics targets in cancer. Among them, necl-5, nectin-2 and nectin-4 are overexpressed in tumors, and are associated with a poor prognosis. On the opposite, necl-1, necl-2 and necl-4 act as tumor suppressors and are repressed in cancer. The involvement of nectins and necls molecules in cancer and their potential used in therapy is discussed in this review.


A Comprehensive In Vitro Comparison of Preparation Techniques for Fat Grafting.
Lipomodeling is a technique that uses the patient's own fat for tissue regeneration and augmentation. The extent of regenerative effect is reported to be determined by the numbers of adipose-derived stem cells and the viability of cells in processed adipose tissue which, together with other factors, influence the degree of graft retention. This study addresses whether differences exist in properties of fat graft obtained by three commonly used techniques. Adipose tissue harvested from the hypogastric regions of 14 patients was processed by decantation, centrifugation, and membrane-based tissue filtration. The morphology of each preparation was assessed by electron microscopy and overall cell viability was assessed by live/dead assay. The number of adipose-derived stem cells was determined and their stem cell character was assessed by the presence of cell surface molecules (i.e., CD105, CD90, CD31, and CD45) and by their capacity to differentiate into adipogenic and osteogenic lineages. First, morphologies of processed fat samples obtained by individual procedures differed, but no preparation caused obvious damage to cellular or acellular components. Second, although the highest numbers of adipose-derived stem cells were contained in the upper fraction of centrifuged lipoaspirates, the difference between preparations was marginal. Third, the maximal concentration of adipose fraction (removal of watery component) of lipoaspirate was achieved by membrane-based tissue filtration. Finally, no significant differences in overall viability were detected. Properties of processed lipoaspirate were influenced by the preparation procedure. However, the differences were not dramatic; both centrifugation and membrane-based filtration are methods of choice whose selection depends on other criteria (e.g., practicality) for individual surgical settings.


Demonstration of heat-shock protein 70 in the sporozoite stage of malaria parasites.
Three monoclonal antibodies generated by immunization of mice with Plasmodium berghei-infected red blood cells were found to react with the 75-kDa heat-shock protein (HSP70) present in liver stages and erythrocytic forms of the parasites. These antibodies were shown to react with a recombinant protein encoding the carboxyl terminal half of PfHSP70 (aa 365-681). Differently from earlier results, we clearly demonstrated that HSP70 was also expressed in the sporozoite stage, using these monoclonal antibodies in an immunofluorescence and Western immunoblot assay. These monoclonal antibodies react not only with sporozoites of P. berghei, the parasites originally used for the immunization, but also with sporozoites of several other rodent and human plasmodial species. Passive transfer of these monoclonal antibodies into naive mice, simultaneously injected with sporozoites, failed to neutralize the infectivity of P. berghei sporozoites and to inhibit the development of liver stages of P. yoelii.


Demonstration of Parent Training to Address Early Self-Injury in Young Children with Intellectual and Developmental Delays.
Individuals with intellectual and developmental disabilities (IDD) are at a high risk for engaging in self-injurious behavior (SIB). Prognosis is poor when SIB emerges early. Limited research exists on interventions teaching parents how to manage their young child's SIB. This investigation assessed the feasibility of adapting an applied behavior analytic parent training program with 11 parents of children 1-5 years of age with IDD and SIB. Quantitative and observational measures were used to assess outcomes; semi-structured interviews assessed caregiver satisfaction. Outcomes yielded preliminary data suggesting the adapted curriculum was feasible and acceptable to parents. Initial efficacy outcomes yielded decreases in SIB and observed negative parent-child interactions on pre- and post-measures. Qualitative data provided areas for further curriculum refinement.


Non-proteolytic activity of 19S proteasome subunit RPT-6 regulates GATA transcription during response to infection.
GATA transcription factors play a crucial role in the regulation of immune functions across metazoans. In Caenorhabditis elegans, the GATA transcription factor ELT-2 is involved in the control of not only infections but also recovery after an infection. We identified RPT-6, part of the 19S proteasome subunit, as an ELT-2 binding partner that is required for the proper expression of genes required for both immunity against bacterial infections and recovery after infection. We found that the intact ATPase domain of RPT-6 is required for the interaction and that inhibition of rpt-6 affected the expression of ELT-2-controlled genes, preventing the appropriate immune response against Pseudomonas aeruginosa and recovery from infection by the pathogen. Further studies indicated that SKN-1, which is an Nrf transcription factor involved in the response to oxidative stress and infection, is activated by inhibition of rpt-6. Our results indicate that RPT-6 interacts with ELT-2 in vivo to control the expression of immune genes in a manner that is likely independent of the proteolytic activity of the proteasome.


The experiences and support needs of people with intellectual disabilities who identify as LGBT: A review of the literature.
People who identify as lesbian, gay, bisexual and transgender (LGBT) can face many challenges in society including accessing education, care and support appropriate to individual needs. However, there is a growing and evolving evidence base about the specific needs of people with intellectual disabilities (ID) in this regard. The aim of this review was to explore the experiences of people with ID who identified as LGBT through an examination of studies that addressed their views and highlighted specific issues, concerns and service responses. A comprehensive search of relevant databases from February 1995 to February 2015 was conducted. Studies were identified that met specific criteria that included: empirical peer reviewed studies, the use of recognised research methods and focused on people with ID whom identified as LGBT. The search yielded 161 papers in total. The search was narrowed and 37 papers were screened using rigorous inclusion and exclusion criteria. Finally, 14 papers were considered suitable for the review. The data were analysed and key themes identified that included accessing health services, gender and sexual identity, attitudes of people with ID regarding their LGBT status, and education, supports and therapeutic interventions. There is a need for service providers and carers to be more responsive to the concerns of people with ID who identify as LGBT to improve their health and well-being by reducing stigma and discrimination and by increasing awareness of their care and support needs. The implications are discussed in terms of policy, education, research and practice developments.


Remote Usability Testing and Satisfaction with a Mobile Health Medication Inquiry System in CKD.
Inappropriate medication use is common in the care of patients with CKD. The feasibility of a simple mobile health tool designed to advise patients on safe medication usage in CKD was examined. Participants with predialysis CKD (defined as eGFR<60 ml/min per 1.73 m(2)) in the Safe Kidney Care Cohort Study were recruited for home usability testing of a novel medication inquiry system between January and September of 2013. Testing was through two mobile platforms: (1) short messaging service text or (2) personal digital assistant (e.g., iPod Touch). Twenty participants (one half assigned to one device and one half assigned to the other device) were enrolled and received an in-center tutorial on device usage before the end of the study visit. Participants were subsequently mailed three sample pill bottles with the name of randomly selected medications and asked to input these medications into the medication inquiry system. The medication inquiry system response options were as follows: (1) safe in CKD, (2) not safe in CKD, (3) use with caution/speak with your health care provider, or (4) error message (for an incorrectly inputted medication). Participants were asked to record the response issued by the medication inquiry system for each medication sent for usability testing. A user satisfaction survey was administered after completion of the protocol. All participants owned a mobile telephone, but few owned a smartphone. Of 60 total medication queries, there were only three recorded errors, two of which occurred in the short messaging service texting group. Overall satisfaction with the application was high, with slightly higher satisfaction noted in the personal digital assistant group compared with the short messaging service group. The mobile health medication inquiry system application had general ease of use and high acceptance across two platforms among individuals representative of the CKD population. Tailored mobile health technology may improve medication safety in CKD.


Human papillomaviruses associated with cervical intraepithelial neoplasia. Great diversity and distinct distribution in low- and high-grade lesions.
All together, 30 genital human papillomavirus (HPV) types have been characterized so far. To evaluate the importance of HPV diversity in associated cervical diseases, we analyzed 188 biopsy specimens obtained from patients with a recent diagnosis of cervical HPV infection or intraepithelial neoplasia (CIN). Of these 188 specimens, 116 were classified as low-grade CIN (48 cases), high-grade CIN (53 cases), condylomata acuminata (10 cases), flat condylomas (five cases). Seventy-two specimens were considered nondiagnostic. Using probes specific for 18 genital HPV types, HPV DNA sequences were detected by Southern blot hybridization in 100 lesions and 21 nondiagnostic specimens. When further analyzed by the polymerase chain reaction, eight HPV-negative biopsy specimens, four CIN, and four nondiagnostic specimens were positive. Of the 129 positive biopsy specimens, 92 contained at least one of 18 known HPV types and 37 HPV that have not yet been identified. Nine specimens had more than one type. Thirteen HPV types were identified in CIN. The detection rate of HPV 16 increased from 21% in low-grade CIN to 57% in high-grade CIN. HPV 18 was detected in only 3% of CIN; HPV 31, 33, and 35 were found in 8%. HPV 30, 39, 45, 51, 52, 56, 58, and 61 were detected in 44% of low-grade CIN but in only 8% of high-grade CIN. Unidentified HPV were detected in about 25% of low-grade and high-grade CIN. Fifty-seven CIN positive for at least one HPV type were further analyzed by in situ hybridization. Thirty-five (65%) biopsy specimens were positive, including 21 of 24 low-grade CIN and 14 of 33 high-grade CIN. Ten of the 13 previously identified HPV types were detected. Thus, CIN represents an heterogeneous disease from a virologic viewpoint. This fact could explain their variable clinical evolution.


Respiratory virus shedding in a cohort of on-duty healthcare workers undergoing prospective surveillance.
Healthcare-associated transmission of respiratory viruses is a concerning patient safety issue. Surveillance for influenza virus among a cohort of healthcare workers (HCWs) was conducted in a tertiary care children's hospital from November 2009 through April 2010 using biweekly nasal swab specimen collection. If a subject reported respiratory symptoms, an additional specimen was collected. Specimens from ill HCWs and a randomly selected sample from asymptomatic subjects were tested for additional respiratory viruses by multiplex polymerase chain reaction (PCR). A total of 1,404 nasal swab specimens were collected from 170 enrolled subjects. Influenza circulated at very low levels during the surveillance period, and 74.2% of subjects received influenza vaccination. Influenza virus was not detected in any specimen. Multiplex respiratory virus PCR analysis of all 119 specimens from symptomatic subjects and 200 specimens from asymptomatic subjects yielded a total of 42 positive specimens, including 7 (16.7%) in asymptomatic subjects. Viral shedding was associated with report of any symptom (odds ratio [OR], 13.06 [95% confidence interval, 5.45-31.28]; [Formula: see text]) and younger age (OR, 0.96 [95% confidence interval, 0.92-0.99]; [Formula: see text]) when controlled for sex and occupation of physician or nurse. After the surveillance period, 46% of subjects reported working while ill with an influenza-like illness during the previous influenza season. In this cohort, HCWs working while ill was common, as was viral shedding among those with symptoms. Asymptomatic viral shedding was infrequent but did occur. HCWs should refrain from patient care duties while ill, and staffing contingencies should accommodate them.


You can't teach speed: sprinters falsify the deliberate practice model of expertise.
Many scientists agree that expertise requires both innate talent and proper training. Nevertheless, the highly influential deliberate practice model (DPM) of expertise holds that talent does not exist or makes a negligible contribution to performance. It predicts that initial performance will be unrelated to achieving expertise and that 10 years of deliberate practice is necessary. We tested these predictions in the domain of sprinting. In Studies 1 and 2 we reviewed biographies of 15 Olympic champions and the 20 fastest American men in U.S. history. In all documented cases, sprinters were exceptional prior to initiating training, and most reached world class status rapidly (Study 1 median = 3 years; Study 2 = 7.5). In Study 3 we surveyed U.S. national collegiate championships qualifiers in sprinters (n = 20) and throwers (n = 44). Sprinters recalled being faster as youths than did throwers, whereas throwers recalled greater strength and throwing ability. Sprinters' best performances in their first season of high school, generally the onset of formal training, were consistently faster than 95-99% of their peers. Collectively, these results falsify the DPM for sprinting. Because speed is foundational for many sports, they challenge the DPM generally.


Use of ibuprofen and risk of Parkinson disease.
Neuroinflammation may contribute to the pathogenesis of Parkinson disease (PD). Use of nonsteroidal anti-inflammatory drugs (NSAID) in general, and possibly ibuprofen in particular, has been shown to be related to lower PD risk in previous epidemiologic studies. We prospectively examined whether use of ibuprofen or other NSAIDs is associated with lower PD risk among 136,197 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) free of PD at baseline (1998 for NHS and 2000 for HPFS). NSAIDs use was assessed via questionnaire. Results were combined in a meta-analysis with those of published prospective investigations. We identified 291 incident PD cases during 6 years of follow-up. Users of ibuprofen had a significantly lower PD risk than nonusers (relative risk [RR], adjusted for age, smoking, caffeine, and other covariates = 0.62; 95% confidence interval [CI] 0.42-0.93; p = 0.02). There was a dose-response relationship between tablets of ibuprofen taken per week and PD risk (p trend = 0.01). In contrast, PD risk was not significantly related to use of aspirin (RR = 0.99; 95% CI 0.78-1.26), other NSAIDs (RR = 1.26; 95% CI 0.86-1.84), or acetaminophen (RR = 0.86; 95% CI 0.62-1.18). Similar results were obtained in the meta-analyses: the pooled RR was 0.73 (95% CI 0.63-0.85; p < 0.0001) for ibuprofen use, whereas use of other types of analgesics was not associated with lower PD risk. The association between use of ibuprofen and lower PD risks, not shared by other NSAIDs or acetaminophen, suggests ibuprofen should be further investigated as a potential neuroprotective agent against PD.


Molecular evidence of tissue remodeling in an animal model of heart failure.
Heart failure (HF) is the final common pathway of many cardiovascular diseases. Metalloproteinases and their inhibitors, such as MMP9 and TIMP-1, assist in maintaining the extracellular matrix, leading to tissue remodeling observed after HF. Previous studies have shown that L-Arginine (LA) appears to have beneficial effects for the treatment of HF, contributing to vasodilation, the reestablishment of the endothelial function and an increase in muscle contractile force. This study analyzed heart tissue remodeling in an animal model of HF induced by aortocaval fistula (ACF) and submitted to LA treatment. After 4 weeks of ACF, animals were treated with LA for 4 weeks (SHAM-LA, HF-LA) or for 8-12 weeks with saline (SHAM, HF8, HF12). Rats were euthanized and the hearts removed for histological processing. The samples were stained with Hematoxylin-Eosin (HE), Masson's Thichome (MT), or submitted to immunohistochemistry (IHC) for MMP9 and TIMP-1. Light microscopy analysis showed cardiac striated muscle without fibrosis in all experimental groups. Immunostaining of MMP9 and TIMP-1 were positive for all experimental groups. LA administration significatively reduced MMP9 content after HF. These data indicate molecular changes in metalloproteinases expression prior to tissue remodeling and point out LA as an adjuvant therapy to pharmacological treatment of patients with HF.


Proteomic analysis of osteogenic sarcoma: association of tumour necrosis factor with poor prognosis.
A significant proportion of patients with osteogenic sarcoma die from lung metastasis within 5 years of diagnosis. Molecular signatures that predict pulmonary metastasis from primary osteogenic sarcoma and identify those patients at risk would be clinically useful as prognostic markers. Protein expression profiles of two clonally related murine osteogenic sarcoma cell lines with low (K12) and high (K7M2) metastatic potential were compared using two different proteomic technologies, two-dimensional difference gel electrophoresis and cell profiling by matrix-assisted laser desorption/ionization mass spectrometry. Interrogation of a molecular pathways network database suggested several additional candidate molecules that potentially predict metastatic potential of primary osteogenic sarcoma. Two such proteins, macrophage migration inhibitory factor and tumour necrosis factor were selected for further validation studies. Western blots confirmed increased expression of both cytokines in K7M2 cells compared to K12 cells. Levels of migration inhibitory factor and tumour necrosis factor were semi-quantitatively measured in human osteogenic sarcoma samples by immunohistochemistry and were correlated with clinicopathologic parameters and patient outcomes. Multivariate survival analysis demonstrated that tumour necrosis factor expression in chemotherapy naïve osteogenic sarcoma is an independent prognostic factor for overall and metastasis-free survival. No significant differences in adverse outcomes were observed based on macrophage migration inhibitory factor expression.


Prediction Models of Functional Outcomes for Individuals in the Clinical High-Risk State for Psychosis or With Recent-Onset Depression: A Multimodal, Multisite Machine Learning Analysis.
Social and occupational impairments contribute to the burden of psychosis and depression. There is a need for risk stratification tools to inform personalized functional-disability preventive strategies for individuals in at-risk and early phases of these illnesses. To determine whether predictors associated with social and role functioning can be identified in patients in clinical high-risk (CHR) states for psychosis or with recent-onset depression (ROD) using clinical, imaging-based, and combined machine learning; assess the geographic, transdiagnostic, and prognostic generalizability of machine learning and compare it with human prognostication; and explore sequential prognosis encompassing clinical and combined machine learning. This multisite naturalistic study followed up patients in CHR states, with ROD, and with recent-onset psychosis, and healthy control participants for 18 months in 7 academic early-recognition services in 5 European countries. Participants were recruited between February 2014 and May 2016, and data were analyzed from April 2017 to January 2018. Performance and generalizability of prognostic models. A total of 116 individuals in CHR states (mean [SD] age, 24.0 [5.1] years; 58 [50.0%] female) and 120 patients with ROD (mean [SD] age, 26.1 [6.1] years; 65 [54.2%] female) were followed up for a mean (SD) of 329 (142) days. Machine learning predicted the 1-year social-functioning outcomes with a balanced accuracy of 76.9% of patients in CHR states and 66.2% of patients with ROD using clinical baseline data. Balanced accuracy in models using structural neuroimaging was 76.2% in patients in CHR states and 65.0% in patients with ROD, and in combined models, it was 82.7% for CHR states and 70.3% for ROD. Lower functioning before study entry was a transdiagnostic predictor. Medial prefrontal and temporo-parieto-occipital gray matter volume (GMV) reductions and cerebellar and dorsolateral prefrontal GMV increments had predictive value in the CHR group; reduced mediotemporal and increased prefrontal-perisylvian GMV had predictive value in patients with ROD. Poor prognoses were associated with increased risk of psychotic, depressive, and anxiety disorders at follow-up in patients in the CHR state but not ones with ROD. Machine learning outperformed expert prognostication. Adding neuroimaging machine learning to clinical machine learning provided a 1.9-fold increase of prognostic certainty in uncertain cases of patients in CHR states, and a 10.5-fold increase of prognostic certainty for patients with ROD. Precision medicine tools could augment effective therapeutic strategies aiming at the prevention of social functioning impairments in patients with CHR states or with ROD.


Time to coronary angiography and outcomes among patients with high-risk non ST-segment elevation acute coronary syndromes: results from the SYNERGY trial.
Optimal timing for an early invasive strategy in patients with non-ST-segment-elevation acute coronary syndrome remains unclear. We evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with non-ST-segment-elevation acute coronary syndrome who underwent angiography within 48 hours of admission. Data from 10 027 patients enrolled in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial were analyzed. Patients were grouped by 6-hour intervals of time from hospital admission to coronary angiography. Primary outcomes were 30-day death or myocardial infarction, in-hospital Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) major bleeding, and blood transfusion. Adjusted estimates of event rates were obtained by use of a multivariable methodology that included possible confounders through baseline and accounted for propensity of time to angiography. The landmark method was used to calculate odds ratios and 95% confidence intervals of outcomes for each time period adjusted for baseline and postbaseline clinical events. Overall, 9216 patients (92%) underwent angiography, 6352 (63%) within 48 hours. Unadjusted and adjusted rates of death/myocardial infarction increased with increasing time to angiography. The adjusted odds ratio for death/myocardial infarction in patients receiving angiography in <6 hours was 0.56 (95% confidence interval 0.41 to 0.74), whereas after 30 hours, there was no significant benefit compared with further delayed angiography. Major bleeding and transfusion did not vary significantly across time-to-angiography intervals. A decrease in the time to coronary angiography was associated with fewer ischemic outcomes and no increase in bleeding. Randomized clinical trials are needed to provide definitive evidence on optimal timing of coronary angiography but are difficult to design and conduct. Ongoing trials should instead clarify whether delaying angiography to administer aggressive upstream antithrombotic therapies is effective in the current setting of non-ST-segment-elevation acute coronary syndrome management.


Influenza vaccination and mortality: differentiating vaccine effects from bias.
It is widely believed that influenza (flu) vaccination of the elderly reduces all-cause mortality, yet randomized trials for assessing vaccine effectiveness are not feasible and the observational research has been controversial. Efforts to differentiate vaccine effectiveness from selection bias have been problematic. The authors examined mortality before, during, and after 9 flu seasons in relation to time-varying vaccination status in an elderly California population in which 115,823 deaths occurred from 1996 to 2005, including 20,484 deaths during laboratory-defined flu seasons. Vaccine coverage averaged 63%; excess mortality when the flu virus was circulating averaged 7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination-mortality association increased monotonically from 0.34 early in November to 0.56 in January, 0.67 in April, and 0.76 in August. This reflects the trajectory of selection effects in the absence of flu. In analyses that included weeks with flu and adjustment for selection effects, flu season multiplied the odds ratio by 0.954. The corresponding vaccine effectiveness estimate was 4.6% (95% confidence interval: 0.7, 8.3). To differentiate vaccine effects from selection bias, the authors used logistic regression with a novel case-centered specification that may be useful in other population-based studies when the exposure-outcome association varies markedly over time.


Exercise attenuates the increase in plasma monounsaturated fatty acids and high-density lipoprotein cholesterol but not high-density lipoprotein 2b cholesterol caused by high-oleic ground beef in women.
We hypothesized that dietary monounsaturated fatty acids (MUFA) and exercise increase high-density lipoprotein cholesterol (HDL-C) by independent mechanisms, so there would be additive effects between a single, intensive session of exercise and high-MUFA ground beef on HDL-C and blood risk factors for cardiovascular disease. Seventeen postmenopausal women completed a 2-way crossover design in which they consumed five 114-g ground beef patties per week for two 6-week periods separated by a 4-week washout (habitual diet) period. The ground beef patties contained 21% total fat with either 9.97 (low-MUFA) or 12.72 (high-MUFA) g total MUFA. Blood was taken at entry, at the end of each 6-week diet period, after the 4-week washout period, and 24 hours after aerobic exercise sessions (75% VO₂peak, 2.07 MJ). After the ground beef intervention, the high-MUFA ground beef increased plasma palmitoleic acid and oleic acid, low-density lipoprotein (LDL) particle density, HDL-C, and HDL2b-C (all P < .05), whereas the low-MUFA ground beef increased LDL density. After the washout (habitual diet) period, the single exercise session increased serum LDL cholesterol, HDL-C, and HDL2a and decreased TAG and oleic acid. After the low-MUFA ground beef diet, exercise increased LDL size and HDL density and decreased LDL density and very low-density lipoprotein cholesterol, but had no effect on HDL-C fractions. After the high-MUFA ground beef intervention, exercise decreased palmitioleic acid, oleic acid, HDL-C, and HDL2a-C, but not HDL2b-C. Contrary to our hypothesis, the effects of exercise and a high-MUFA diet were not additive; instead, exercise attenuated the effects of the high-MUFA ground beef on HDL-C and plasma MUFAs. The differential effects of high-MUFA ground beef and exercise on HDL2a-C and HDL2b-C indicate that diet and exercise affect HDL-C by different mechanisms.


Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment.
Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment.


Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice.
N-palmitoylethanolamine (PEA) is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs). Recently, several studies demonstrated that PEA is an important analgesic, antiinflammatory, and neuroprotective mediator. The aim of this study was to investigate the effect of co-ultramicronized PEA + luteolin formulation on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). CIA was induced by an intradermally injection of 100 μl of the emulsion (containing 100 μg of bovine type II collagen (CII)) and complete Freund adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Mice subjected to CIA were administered PEA (10 mg/kg 10% ethanol, intraperitoneally (i.p.)) or co-ultramicronized PEA + luteolin (1 mg/kg, i.p.) every 24 hours, starting from day 25 to 35. Mice developed erosive hind-paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hindpaws. The incidence of CIA was 100% by day 28 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period with a resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint. Treatment with PEA or PEA + luteolin ameliorated the clinical signs at days 26 to 35 and improved histologic status in the joint and paw. The degree of oxidative and nitrosative damage was significantly reduced in PEA + luteolin-treated mice, as indicated by nitrotyrosine and malondialdehyde (MDA) levels. Plasma levels of the proinflammatory cytokines and chemokines were significantly reduced by PEA + luteolin treatment. We demonstrated that PEA co-ultramicronized with luteolin exerts an antiinflammatory effect during chronic inflammation and ameliorates CIA.


Feedback-induced glutamate spillover enhances negative feedback from horizontal cells to cones.
In the retina, horizontal cells feed back negatively to cone photoreceptors. Glutamate released from cones can spill over to neighbouring cones. Here we show that cone glutamate release induced by negative feedback can also spill over to neighbouring cones. This glutamate activates the glutamate transporter-associated chloride current in these neighbouring cones, which leads to a change in their membrane potential and thus modulates their output. In this way, feedback-induced glutamate spillover enhances negative feedback from horizontal cells to cones, thus forming an additional feedback pathway. This effect will be particularly prominent in cones that are strongly hyperpolarized by light. Inhibition in the outer retina functions via an unusual mechanism. When horizontal cells hyperpolarize the activation potential of the Ca(2+) current of cones shifts to more negative potentials. The underlying mechanism consists of an ephaptic component and a Panx1/ATP-mediated component. Here we identified a third feedback component, which remains active outside the operating range of the Ca(2+) current. We show that the glutamate transporters of cones can be activated by glutamate released from their neighbours. This pathway can be triggered by negative feedback from horizontal cells to cones, thus providing an additional feedback pathway. This additional pathway is mediated by a Cl(-) current, can be blocked by either removing the gradient of K(+) or by adding the glutamate transporter blocker TBOA, or low concentrations of Zn(2+) . These features point to a glutamate transporter-associated Cl(-) current. The pathway has a delay of 4.7 ± 1.7 ms. The effectiveness of this pathway in modulating the cone output depends on the equilibrium potential of Cl(-) (ECl ) and the membrane potential of the cone. Because estimates of ECl show that it is around the dark resting membrane potential of cones, the activation of the glutamate transporter-associated Cl(-) current will be most effective in changing the membrane potential during strong hyperpolarization of cones. This means that negative feedback would particularly be enhanced by this pathway when cones are hyperpolarized. Spatially, this pathway does not reach further than the direct neighbouring cones. The consequence is that this feedback pathway transmits information between cones of different spectral type.


Comparative effect of metformin versus sulfonylureas with dementia and Parkinson's disease risk in US patients over 50 with type 2 diabetes mellitus.
Type 2 diabetes is a risk factor for dementia and Parkinson's disease (PD). Drug treatments for diabetes, such as metformin, could be used as novel treatments for these neurological conditions. Using electronic health records from the USA (OPTUM EHR) we aimed to assess the association of metformin with all-cause dementia, dementia subtypes and PD compared with sulfonylureas. A new user comparator study design was conducted in patients ≥50 years old with diabetes who were new users of metformin or sulfonylureas between 2006 and 2018. Primary outcomes were all-cause dementia and PD. Secondary outcomes were Alzheimer's disease (AD), vascular dementia (VD) and mild cognitive impairment (MCI). Cox proportional hazards models with inverse probability of treatment weighting (IPTW) were used to estimate the HRs. Subanalyses included stratification by age, race, renal function, and glycemic control. We identified 96 140 and 16 451 new users of metformin and sulfonylureas, respectively. Mean age was 66.4±8.2 years (48% male, 83% Caucasian). Over the 5-year follow-up, 3207 patients developed all-cause dementia (2256 (2.3%) metformin, 951 (5.8%) sulfonylurea users) and 760 patients developed PD (625 (0.7%) metformin, 135 (0.8%) sulfonylurea users). After IPTW, HRs for all-cause dementia and PD were 0.80 (95% CI 0.73 to 0.88) and 1.00 (95% CI 0.79 to 1.28). HRs for AD, VD and MCI were 0.81 (0.70-0.94), 0.79 (0.63-1.00) and 0.91 (0.79-1.04). Stronger associations were observed in patients who were younger (<75 years old), Caucasian, and with moderate renal function. Metformin users compared with sulfonylurea users were associated with a lower risk of all-cause dementia, AD and VD but not with PD or MCI. Age and renal function modified risk reduction. Our findings support the hypothesis that metformin provides more neuroprotection for dementia than sulfonylureas but not for PD, but further work is required to assess causality.


Learning to move amid uncertainty.
We studied how subjects learned to make movements against unpredictable perturbations. Twelve healthy human subjects made goal-directed reaching movements in the horizontal plane while holding the handle of a two-joint robotic manipulator. The robot generated viscous force fields that perturbed the limb perpendicular to the desired direction of movement. The amplitude (but not the direction) of the viscous field varied randomly from trial to trial. Systems identification techniques were employed to characterize how subjects adapted to these random perturbations. Subject performance was quantified primarily using the peak deviation from a straight-line hand path. Subjects adapted their arm movements to the sequence of random force-field amplitudes. This adaptive response compensated for the approximate mean from the random sequence of perturbations and did not depend on the statistical distribution of that sequence. Subjects did not adapt by directly counteracting the mean field strength itself on each trial but rather by using information about perturbations and movement errors from a limited number of previous trials to adjust motor commands on subsequent trials. This strategy permitted subjects to achieve near-optimal performance (defined as minimizing movement errors in a least-squares sense) while maintaining computational efficiency. A simple model using information about movement errors and perturbation amplitudes from a single previous trial predicted subject performance in stochastic environments with a high degree of fidelity and further predicted key performance features observed in nonstochastic environments. This suggests that the neural structures modified during motor adaptation require only short-term memory. Explicit representations regarding movements made more than a few trials in the past are not used in generating optimal motor responses on any given trial.


Effects of an employer-based intervention on employment outcomes for youth with significant support needs due to autism.
The purpose of this study was to develop and investigate an employer-based 9-month intervention for high school youth with autism spectrum disorder to learn job skills and acquire employment. The intervention modified a program titled Project SEARCH and incorporated the use of applied behavior analysis to develop Project SEARCH plus Autism Spectrum Disorder Supports. A randomized clinical trial compared the implementation of Project SEARCH plus Autism Spectrum Disorder Supports with high school special education services as usual. Participants were 49 high-school-aged individuals between the ages of 18 and 21 years diagnosed with an autism spectrum disorder and eligible for supported employment. Students also had to demonstrate independent self-care. At 3 months post-graduation, 90% of the treatment group acquired competitive, part-time employment earning US$9.53-US$10.66 per hour. Furthermore, 87% of those individuals maintained employment at 12 months post-graduation. The control group's employment outcomes were 6% acquiring employment by 3 months post-graduation and 12% acquiring employment by 12 months post-graduation. The positive employment outcomes generated by the treatment group provide evidence that youth with autism spectrum disorder can gain and maintain competitive employment. Additionally, there is evidence that they are able to advance within that time toward more weekly hours worked, while they also displayed increasing independence in the work setting.


NeuroMeasure: A Software Package for Quantification of Cortical Motor Maps Using Frameless Stereotaxic Transcranial Magnetic Stimulation.
The recent enhanced sophistication of non-invasive mapping of the human motor cortex using MRI-guided Transcranial Magnetic Stimulation (TMS) techniques, has not been matched by refinement of methods for generating maps from motor evoked potential (MEP) data, or in quantifying map features. This is despite continued interest in understanding cortical reorganization for natural adaptive processes such as skill learning, or in the case of motor recovery, such as after lesion affecting the corticospinal system. With the observation that TMS-MEP map calculation and quantification methods vary, and that no readily available commercial or free software exists, we sought to establish and make freely available a comprehensive software package that advances existing methods, and could be helpful to scientists and clinician-researchers. Therefore, we developed NeuroMeasure, an open source interactive software application for the analysis of TMS motor cortex mapping data collected from Nexstim® and BrainSight®, two commonly used neuronavigation platforms. NeuroMeasure features four key innovations designed to improve motor mapping analysis: de-dimensionalization of the mapping data, fitting a predictive model, reporting measurements to characterize the motor map, and comparing those measurements between datasets. This software provides a powerful and easy to use workflow for characterizing and comparing motor maps generated with neuronavigated TMS. The software can be downloaded on our github page: https://github.com/EdwardsLabNeuroSci/NeuroMeasure. This paper aims to describe a software platform for quantifying and comparing maps of the human primary motor cortex, using neuronavigated transcranial magnetic stimulation, for the purpose of studying brain plasticity in health and disease.


Estimates of driving abilities and skills in different conditions.
This research was a preliminary effort to determine whether various driving situations seemed to require different driving skills and abilities and to identify the relative demands of specific physical, perceptual, cognitive, behavioral, and operational skills and abilities in different driving situations. Experienced driver evaluators and trainers estimated the magnitude of driving abilities and skills for different photographed driving situations. Pictures of driving scenarios were counterbalanced for road type, traffic condition, and weather condition. A multifactorial analysis of variance of the total score for each scenario revealed significant main effects for road type and traffic condition but not for weather condition. Highway and city driving were rated as significantly more demanding overall than residential driving, but no difference was found between city and highway driving. Estimates of the overall demands for driving in heavy traffic were significantly greater than in light traffic. However, driving in inclement weather was not regarded as significantly more demanding than driving in sunny weather. Additionally, significant interaction effects were found for road type by weather condition and traffic by weather condition but not for road type by traffic condition. Through multivariate methods to evaluate the significance of individual abilities and skills across conditions, significant main and interactive effects were found for road type, traffic condition, and weather condition. Post hoc analyses showed the impact of these effects on such abilities and skills as scanning, attention and concentration, information-processing speed, and others. Evaluators' quantified estimates of driving demands showed driving as a complex task that (a) requires high levels of abilities and skills in all situations; (b) demands greater abilities in some situations than in others; and (c) involves different kinds and various degrees of abilities and skills, depending on the demand characteristics of the situation.


Examination of Spiritual Needs in Hurricane Sandy Disaster Recovery Through Clinical Pastoral Education Verbatims.
Objectives Spiritual support is an essential component to disaster response and recovery. The goals of this study were to (a) provide a qualitative examination of spiritual needs of recipients of disaster relief after Hurricane Sandy, as observed by spiritual care interns in "verbatims"; (b) demonstrate the feasibility of conducting research with providers of disaster spiritual care. Methods The study was accomplished through analysis (including codebook development and transcript coding) of written pastoral reports-aka "verbatims" ( n = 18)-as well as audio-recorded, transcribed seminars ( n = 23). Clinical Pastoral Education verbatims offer qualitative data in the form of confidential, anonymous reports of what the students do in the field. Results Analysis of coded transcripts yielded several themes and subthemes as results. Significance of Results Major themes include: (a) the feasibility of research for CPE students as subject; (b) the discussion of magnitude of the storm and aftermath, as a spiritual need in disaster;


HbA1c method performance: The great success story of global standardization.
Diagnosing and monitoring the treatment of people with diabetes is a global issue and uses considerable resources in laboratories and clinics worldwide. Hemoglobin A1c (HbA1c) has been the mainstay of monitoring glycemic control in people with diabetes for many years and more recently it has been advocated as a diagnostic tool for type 2 diabetes mellitus (T2DM). Good analytical performance is key to the successful use of any laboratory test, but is critical when using the test to diagnose disease, especially when the potential number of diagnoses could exceed 500 million people. Very small variations in bias or increased imprecision could lead to either a missed diagnosis or overdiagnosis of the disease and given the scale of the global disease burden, this could mean erroneous categorization of potentially millions of people. Fundamental to good performance of diagnostic testing is standardization, with defined reference materials and measurement procedures. In this review, we discuss the historical steps to first harmonize HbA1c testing, followed by the global standardization efforts and provide an update on the current situation and future goals for HbA1c testing.


Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma.
Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification. Three miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis. Our study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.


New role of (-)-epicatechin in enhancing the induction of growth inhibition and apoptosis in human lung cancer cells by curcumin.
Curcumin, a phenolic compound isolated from the plant Curcuma longa (Linn), is ingested every day in the Indian subcontinent and is well reported to possess cancer-preventive activity. To achieve effective cancer prevention with curcumin, we need to find a new method to enhance the effects of curcumin in the diet. Based on our evidence that (-)-epicatechin (EC), an inert catechin, enhances the cancer-preventive activity of green tea catechins, we studied the enhancing effects of EC on inductions of growth inhibition and apoptosis in human lung cancer cell lines PC-9 and A549 with curcumin. The combination of curcumin with EC significantly increased the inhibition of cell growth compared with curcumin or EC alone. The combination similarly increased both apoptosis and expression of GADD153 and GADD45 genes, associated with their enhanced protein production. Knockdown of GADD153 or GADD45 by small interfering RNA abrogated the apoptosis induction and growth inhibition induced by the combination, indicating the crucial role of their upregulation. Treatments of PC-9 cells with c-Jun-NH(2)-kinase inhibitor SP600125, with p38 mitogen-activated protein kinase inhibitor SB202190 and with PD98059 (extracellular signal-regulated kinase 1/2 inhibitor) all increased the upregulation of GADD153 and GADD45 genes by the combination. Because EC was previously shown to enhance the incorporation of EGCG into PC-9 cells, we think that EC has similar effects on curcumin. This report is the first report on the enhancing effects of EC on curcumin, and the data suggest that EC plays a significant role in the enhancement of the cancer-preventive activity of curcumin in the diet.


A review of clinical trials of tai chi and qigong in older adults.
Initiation and maintenance of physical activity (PA) in older adults is of increasing concern as the benefits of PA have been shown to improve physical functioning, mood, weight, and cardiovascular risk factors. Meditative movement forms of PA, such as tai chi and qigong (TC & QG), are holistic in nature and have increased in popularity over the past few decades. Several randomized controlled trials have evaluated TC & QG interventions from multiple perspectives, specifically targeting older adults. The purpose of this report is to synthesize intervention studies targeting TC & QG and identify the physical and psychological health outcomes shown to be associated with TC & QG in community dwelling adults older than 55. Based on specific inclusion criteria, 36 research reports with a total of 3,799 participants were included in this review. Five categories of study outcomes were identified, including falls and balance, physical function, cardiovascular disease, and psychological and additional disease-specific responses. Significant improvement in clusters of similar outcomes indicated interventions utilizing TC & QG may help older adults improve physical function and reduce blood pressure, fall risk, and depression and anxiety. Missing from the reviewed reports is a discussion of how spiritual exploration with meditative forms of PA, an important component of these movement activities, may contribute to successful aging.


Twenty years of communication intervention research with individuals who have severe intellectual and developmental disabilities.
This literature review was conducted to evaluate the current state of evidence supporting communication interventions for individuals with severe intellectual and developmental disabilities. We reviewed 116 articles published between 1987 and 2007 in refereed journals meeting three criteria: (a) described a communication intervention, (b) involved one or more participants with severe intellectual and developmental disabilities, and (c) addressed one or more areas of communication performance. Many researchers failed to report treatment fidelity or to assess basic aspects of intervention effects, including generalization, maintenance, and social validity. The evidence reviewed indicates that 96% of the studies reported positive changes in some aspects of communication. These findings support the provision of communication intervention to persons with severe intellectual and developmental disabilities. Gaps in the research were reported as were recommendations for future research.


The prevalence and trends in overweight and obesity in Irish adults between 1990 and 2011.
Obesity is a serious public health issue, the prevalence of which is increasing globally. The present study aimed to investigate trends in overweight and obesity in Irish adults between 1990 and 2011. Anthropometric data from three Irish national food consumption surveys were used to calculate trends in BMI, waist circumference and waist:hip ratio. Three cross-sectional food consumption surveys: the Irish National Nutrition Survey (1990), the North/South Ireland Food Consumption Survey (2001) and the National Adult Nutrition Survey (2011). A collective sample of free-living Irish adults (n 3125), aged 18-64 years. There were significant increases in mean weight, height and BMI from 1990 to 2011. Significant increments were also reported in waist and hip circumferences and waist:hip ratio between 2001 and 2011, with concurrent increases in the proportion of individuals at risk of developing CVD, particularly females aged 18-35 years. In 2011, 23·4 % of the Irish population was classified as obese; with the mean BMI increasing by 1·1 kg/m2 between 1990 and 2001 and by 0·6 kg/m2 between 2001 and 2011. The present paper characterises obesity levels in Irish adults from 1990 to 2011. Absolute levels of overweight and obesity have increased between these time points. Of concern is the increase in the proportion of young women classified as at risk of CVD, using waist circumference and waist:hip ratio. Effective prevention strategies are needed to avoid further increases.


Structure of an APC3-APC16 complex: insights into assembly of the anaphase-promoting complex/cyclosome.
The anaphase-promoting complex/cyclosome (APC/C) is a massive E3 ligase that controls mitosis by catalyzing ubiquitination of key cell cycle regulatory proteins. The APC/C assembly contains two subcomplexes: the "Platform" centers around a cullin-RING-like E3 ligase catalytic core; the "Arc Lamp" is a hub that mediates transient association with regulators and ubiquitination substrates. The Arc Lamp contains the small subunits APC16, CDC26, and APC13, and tetratricopeptide repeat (TPR) proteins (APC7, APC3, APC6, and APC8) that homodimerize and stack with quasi-2-fold symmetry. Within the APC/C complex, APC3 serves as center for regulation. APC3's TPR motifs recruit substrate-binding coactivators, CDC20 and CDH1, via their C-terminal conserved Ile-Arg (IR) tail sequences. Human APC3 also binds APC16 and APC7 and contains a >200-residue loop that is heavily phosphorylated during mitosis, although the basis for APC3 interactions and whether loop phosphorylation is required for ubiquitination are unclear. Here, we map the basis for human APC3 assembly with APC16 and APC7, report crystal structures of APC3Δloop alone and in complex with the C-terminal domain of APC16, and test roles of APC3's loop and IR tail binding surfaces in APC/C-catalyzed ubiquitination. The structures show how one APC16 binds asymmetrically to the symmetric APC3 dimer and, together with biochemistry and prior data, explain how APC16 recruits APC7 to APC3, show how APC3's C-terminal domain is rearranged in the full APC/C assembly, and visualize residues in the IR tail binding cleft important for coactivator-dependent ubiquitination. Overall, the results provide insights into assembly, regulation, and interactions of TPR proteins and the APC/C.


The effect of CO2 enrichment on net photosynthesis of the red alga Furcellaria lumbricalis in a brackish water environment.
Anthropogenic carbon dioxide (CO2) emissions to the atmosphere are causing reduction in the global ocean pH, also known as ocean acidification. This change alters the equilibrium of different forms of dissolved inorganic carbon in seawater that macroalgae use for their photosynthesis. In the Baltic Sea, benthic macroalgae live in a highly variable environment caused by seasonality and rapid changes in meteorological conditions. The effect of increasing water CO2 concentration on the net photosynthesis of the red macroalgae Furcellaria lumbricalis (Hudson) Lamouroux was tested in short-term mesocosm experiments conducted in Kõiguste Bay (N Gulf of Riga) in June-July 2012 and 2013. Separate mesocosms were maintained at different pCO2 levels: ca. 2,000, ca. 1,000 and ca. 200 µatm. In parallel, different environmental factors were measured such as nutrients, light and water temperature. Thus, the current study also investigated whether elevated pCO2 and different environmental factors exerted interactive effects on the photosynthetic rate of F. lumbricalis. In addition, laboratory experiments were carried out to determine the optimal temperature for photosynthesis of F. lumbricalis. The results of our field experiments demonstrated that elevated pCO2 levels may remarkably enhance the photosynthetic rate of F. lumbricalis. However, the magnitude of this effect is altered by different environmental factors, mainly by changes in water temperature.


Pitfalls of rubella serology while on the brink of elimination: evaluation of national data, Belgium, 2017.
BackgroundIn Belgium, rubella serology is frequently requested in women of childbearing age, despite high vaccination coverage and a near-absence of congenital rubella cases. Different test kits are available and should be standardised by an international standard preparation.AimTo analyse and compare rubella serology practices in Belgian laboratories.MethodsAs part of the mandatory External Quality Assessment programme for rubella serology in Belgium, the national public health institute, Sciensano, sent a voluntary questionnaire concerning anti-rubella IgM/IgG analyses in women aged 15 to 45 years in 2017 to 130 laboratories.ResultsThe questionnaire response rate was 83.8% (109/130). The majority of 169,494 IgG analyses were performed on Roche (55%), Abbott (17%) and Diasorin (13%) analysers. Not all laboratories used the proposed international cut-off of 10 IU/mL. Assumed median seroprevalence ranged from 76.3% with Liaison (Diasorin) to 96.3% with Modular (Roche). Despite very low rubella incidence in Belgium, 93 laboratories performed 85,957 IgM analyses, with 748 positive and 394 grey zone results. The National Reference Centre for Measles, Mumps and Rubella virus and the National Reference Centre for Congenital infections did not confirm any positive rubella cases in 2017.ConclusionThis retrospective analysis shows that rubella serology results may differ considerably according to the assay used. It is therefore important to use the same test when comparing results or performing follow-up testing. The number of anti-rubella IgM analyses was very high. Incorrect use of IgM for screening women of childbearing age can lead to unwarranted anxiety and overuse of confirmation tests.


Sleep in ankylosing spondylitis and non-radiographic axial spondyloarthritis: associations with disease activity, gender and mood.
The study aims were to assess the prevalence of good or poor sleep in a cohort of axial spondyloarthritis patients and to investigate its correlation with a range of objectively and subjectively measured variables in order to develop a model for distinguishing good from poor sleepers. Five hundred ninety-eight patients with ankylosing spondylitis and 61 with non-radiographic axial spondyloarthritis completed the Jenkins Sleep Evaluation Questionnaire. Measures of disease activity, mobility, function, mood, fatigue, quality of life, work productivity, night-time pain and general health were gathered. Patients with ankylosing spondylitis or non-radiographic axial spondyloarthritis were initially compared. With the exception of waking up tired less often and having lower mobility and functioning, the two groups were similar so were combined for subsequent analysis. Twenty-nine percent of all patients were classified as good sleepers and 19% as poor sleepers. Poor sleepers had higher disease activity and fatigue scores and more night-time back pain than good sleepers. They reported poorer quality of life, general health, mood and work-related measures. A model incorporating mood, gender, fatigue and objective and subjective judgements of disease activity correctly classified 87.3% of good and poor sleepers. Poor sleep was strongly associated with poor mood, female gender, greater fatigue, greater disease activity (specifically, spinal pain and stiffness) and better mobility; however, the direction of causality between poor sleep and markers of active disease was undetermined. This study also highlights the need to standardise the measurement of sleep disturbance in axSpA to facilitate comparisons between patient groups and interventions.


Evidence-based medicine training in undergraduate medical education: a review and critique of the literature published 2006-2011.
To characterize recent evidence-based medicine (EBM) educational interventions for medical students and suggest future directions for EBM education. The authors searched the MEDLINE, Scopus, Educational Resource Information Center, and Evidence-Based Medicine Reviews databases for English-language articles published between 2006 and 2011 that featured medical students and interventions addressing multiple EBM skills. They extracted data on learner and instructor characteristics, educational settings, teaching methods, and EBM skills covered. The 20 included articles described interventions delivered in 12 countries in classroom (75%), clinic (25%), and/or online (20%) environments. The majority (60%) focused on clinical students, whereas 30% targeted preclinical students and 10% included both. EBM skills addressed included recognizing a knowledge gap (20%), asking a clinical question (90%), searching for information (90%), appraising information (85%), applying information (65%), and evaluating practice change (5%). Physicians were most often identified as instructors (60%); co-teachers included librarians (20%), allied health professionals (10%), and faculty from other disciplines (10%). Many studies (60%) included interventions at multiple points during one year, but none were longitudinal across students' tenures. Teaching methods varied. Intervention efficacy could not be determined. Settings, learner levels and instructors, teaching methods, and covered skills differed across interventions. Authors writing about EBM interventions should include detailed descriptions and employ more rigorous research methods to allow others to draw conclusions about efficacy. When designing EBM interventions, educators should consider trends in medical education (e.g., online learning, interprofessional education) and in health care (e.g., patient-centered care, electronic health records).


Global dynamics of two-compartment models for cell production systems with regulatory mechanisms.
We present a global stability analysis of two-compartment models of a hierarchical cell production system with a nonlinear regulatory feedback loop. The models describe cell differentiation processes with the stem cell division rate or the self-renewal fraction regulated by the number of mature cells. The two-compartment systems constitute a basic version of the multicompartment models proposed recently by Marciniak-Czochra and collaborators [25] to investigate the dynamics of the hematopoietic system. Using global stability analysis, we compare different regulatory mechanisms. For both models, we show that there exists a unique positive equilibrium that is globally asymptotically stable if and only if the respective reproduction numbers exceed one. The proof is based on constructing Lyapunov functions, which are appropriate to handle the specific nonlinearities of the model. Additionally, we propose a new model to test biological hypothesis on the regulation of the fraction of differentiating cells. We show that such regulatory mechanism is incapable of maintaining homeostasis and leads to unbounded cell growth. Potential biological implications are discussed.


The human PMS2L proteins do not interact with hMLH1, a major DNA mismatch repair protein.
The human PMS2 gene encodes one of the bacterial mutL homologs that is associated with hereditary nonpolyposis colorectal cancer (HNPCC). One of the interesting features of the hPMS2 gene is that it is part of a multiple gene family which is localized on chromosome bands 7p22, 7p12-p13, 7q11, and 7q22. Here we report four newly identified hPMS2-like (PMS2L) genes. All four novel members of the PMS2L gene family encode relatively short polypeptides composed of the amino-terminal portion of hPMS2 and are expressed ubiquitously except in the heart. To clarify whether the PMS2L polypeptides contribute to the DNA mismatch repair (MMR) pathway through an interaction with hMLH1, we have performed a yeast two-hybrid assay and an immunoprecipitation study using an hPMS2 mutant cell line, HEC-1-A. Our results clearly indicate that hMLH1 does not interact with two representative PMS2Ls, whereas the carboxyl-terminal portion of hPMS2, not the amino-terminal portion, does interact with hMLH1. Thus, PMS2Ls are not likely to participate in the MMR pathway through association with hMLH1; they must play some other roles in the living cells.


Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study.
The prognostic value of circulating polyunsaturated fatty acid (PUFA) levels is unclear. To determine the associations between red blood cell (RBC) PUFA levels and risk for death. This prospective cohort study included 6501 women aged 65 to 80 years who participated in the Women's Health Initiative Memory Study (enrolment began 1996). RBC PUFA levels were measured at baseline and expressed as a percent of total RBC PUFAs. PUFAs of primary interest were the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum (the Omega-3 Index). PUFAs of secondary interest included the 2 major n-6 PUFAs, linoleic acid and arachidonic acid, and the PUFA factor score (a calculated variable including 6 PUFAs that accounts for their intercorrelations). The primary outcome was total mortality through August 2014. After a median of 14.9 years of follow-up, 1851 women (28.5%) had died. RBC levels of EPA and DHA were higher in the survivors (P < .002 for each). In the fully adjusted models, the hazard ratios (99% confidence intervals) for mortality associated with a 1 standard deviation PUFA increase for total mortality were 0.92 (0.85, 0.98) for the Omega-3 Index, 0.89 (0.82, 0.96) for EPA, 0.93 (0.87, 1.0) for DHA, and 0.76 (0.64, 0.90) for the PUFA factor score. There were no significant associations of alpha-linolenic acid, arachidonic acid or linoleic acid with total mortality. Higher RBC levels of marine n-3 PUFAs were associated with reduced risk for all-cause mortality. These findings support the beneficial relationship between the Omega-3 Index and health outcomes.


Article-level classification of scientific publications: A comparison of deep learning, direct citation and bibliographic coupling.
Classification schemes for scientific activity and publications underpin a large swath of research evaluation practices at the organizational, governmental, and national levels. Several research classifications are currently in use, and they require continuous work as new classification techniques becomes available and as new research topics emerge. Convolutional neural networks, a subset of "deep learning" approaches, have recently offered novel and highly performant methods for classifying voluminous corpora of text. This article benchmarks a deep learning classification technique on more than 40 million scientific articles and on tens of thousands of scholarly journals. The comparison is performed against bibliographic coupling-, direct citation-, and manual-based classifications-the established and most widely used approaches in the field of bibliometrics, and by extension, in many science and innovation policy activities such as grant competition management. The results reveal that the performance of this first iteration of a deep learning approach is equivalent to the graph-based bibliometric approaches. All methods presented are also on par with manual classification. Somewhat surprisingly, no machine learning approaches were found to clearly outperform the simple label propagation approach that is direct citation. In conclusion, deep learning is promising because it performed just as well as the other approaches but has more flexibility to be further improved. For example, a deep neural network incorporating information from the citation network is likely to hold the key to an even better classification algorithm.


Automated Registration of Freehand B-Mode Ultrasound and Magnetic Resonance Imaging of the Carotid Arteries Based on Geometric Features.
An automated method for registering B-mode ultrasound (US) and magnetic resonance imaging (MRI) of the carotid arteries is proposed. The registration uses geometric features, namely, lumen centerlines and lumen segmentations, which are extracted fully automatically from the images after manual annotation of three seed points in US and MRI. The registration procedure starts with alignment of the lumen centerlines using a point-based registration algorithm. The resulting rigid transformation is used to initialize a rigid and subsequent non-rigid registration procedure that jointly aligns centerlines and segmentations by minimizing a weighted sum of the Euclidean distance between centerlines and the dissimilarity between segmentations. The method was evaluated in 28 carotid arteries from eight patients and six healthy volunteers. First, the automated US lumen segmentation method was validated and optimized in a cross-validation experiment. Next, the effect of the weighting parameter of the proposed registration dissimilarity metric and the control point spacing in the non-rigid registration was evaluated. Finally, the proposed registration method was evaluated in comparison to an existing intensity-and-point-based method, a registration using only the centerlines and a registration using manual US lumen segmentations. Registration accuracy was measured in terms of the mean surface distance between manual US segmentations and the registered MRI segmentations. The average mean surface distance was 0.78 ± 0.34 mm for all subjects, 0.65 ± 0.09 mm for healthy volunteers and 0.87 ± 0.42 mm for patients. The results for the complete set were significantly better (Wilcoxon test, p < 0.01) than the results for the intensity-and-point-based method and the centerline-based registration method. We conclude that the proposed method can robustly and accurately register US and MR images of the carotid artery, allowing multimodal analysis of the carotid plaque to improve plaque assessment.


Risk for depression and neural responses to fearful facial expressions of emotion.
Depression is associated with neural abnormalities in emotional processing. This study explored whether these abnormalities underlie risk for depression. We compared the neural responses of volunteers who were at high and low-risk for the development of depression (by virtue of high and low neuroticism scores; high-N group and low-N group respectively) during the presentation of fearful and happy faces using functional magnetic resonance imaging (fMRI). The high-N group demonstrated linear increases in response in the right fusiform gyrus and left middle temporal gyrus to expressions of increasing fear, whereas the low-N group demonstrated the opposite effect. The high-N group also displayed greater responses in the right amygdala, cerebellum, left middle frontal and bilateral parietal gyri to medium levels of fearful v. happy expressions. Risk for depression is associated with enhanced neural responses to fearful facial expressions similar to those observed in acute depression.


Distinguishing between early and late responders to symptoms of acute myocardial infarction.
The present study identified factors that distinguish early responders (i.e., requested medical assistance < 60 minutes after the onset of acute myocardial infarction [AMI] symptoms) from late responders (i.e., request made > or = 60 minutes after symptom onset). A questionnaire developed to assess demographic characteristics, contextual factors, antecedents to symptom onset, and behavioral, affective, and cognitive responses was administered in the hospital to 501 patients with documented AMI. Patients who believed that their symptoms were cardiac in nature were more likely to be early responders, whereas patients who attributed their symptoms to indigestion, muscle pain, fatigue, or another cause responded later (p < 0.0009). Early responders believed their symptoms to be more serious (p < 0.0001), felt more comfortable seeking medical assistance (p < 0.0001), were more anxious or upset when they first noticed symptoms (p = 0.0118), and perceived that they had less control of their symptoms (p < 0.0001) than late responders. A stepwise multiple regression analysis further suggested that unmarried patients responded significantly later than married patients, and patients who first experienced their symptoms at work responded significantly later than those who first experienced their symptoms outside of the home but not at work. These results suggest that situational and psychological variables are important determinants of lengthy decision delays in responding to symptoms of AMI.


Melatonin Affects Postural Control in Community-Dwelling Older Adults While Dual Tasking: A Randomized Observation Study.
The effects of a single 3-mg dose of melatonin on the postural control and cognitive performance of community-dwelling older adults were documented. The testing involved stepping down while performing a cognitive task (a Stroop test). Thirty-four older adults were recruited. Immediately before and 1 hr after taking a dose of melatonin, they completed a single-leg standing task after stepping down with and without a simultaneous Stroop test, and a double-leg standing task. The findings indicated a statistically significant increase in sway area under the dual-tasking condition after taking melatonin (p = .04) and the double-leg standing task (p = .018). However, cognitive performance per se was not affected by the melatonin. Melatonin impairs postural control in older adults but not cognitive performance.


The Human Basal Ganglia Mediate the Interplay between Reactive and Proactive Control of Response through Both Motor Inhibition and Sensory Modulation.
The basal ganglia (BG) have long been known for contributing to the regulation of motor behaviour by means of a complex interplay between tonic and phasic inhibitory mechanisms. However, after having focused for a long time on phasic reactive mechanisms, it is only recently that psychological research in healthy humans has modelled tonic proactive mechanisms of control. Mutual calibration between anatomo-functional and psychological models is still needed to better understand the unclear role of the BG in the interplay between proactive and reactive mechanisms of control. Here, we implemented an event-related fMRI design allowing proper analysis of both the brain activity preceding the target-stimulus and the brain activity induced by the target-stimulus during a simple go/nogo task, with a particular interest in the ambiguous role of the basal ganglia. Post-stimulus activity was evoked in the left dorsal striatum, the subthalamus nucleus and internal globus pallidus by any stimulus when the situation was unpredictable, pinpointing its involvement in reactive, non-selective inhibitory mechanisms when action restraint is required. Pre-stimulus activity was detected in the ventral, not the dorsal, striatum, when the situation was unpredictable, and was associated with changes in functional connectivity with the early visual, not the motor, cortex. This suggests that the ventral striatum supports modulatory influence over sensory processing during proactive control.


EXO1 is critical for embryogenesis and the DNA damage response in mice with a hypomorphic Nbs1 allele.
The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair. The MRE11 complex has been shown to function both upstream and in concert with the 5'-3' exonuclease EXO1 in DNA resection, but it remains unclear to what extent EXO1 influences DSB responses independently of the MRE11 complex. Here we examine the genetic relationship of the MRE11 complex and EXO1 during mammalian development and in response to DNA damage. Deletion of Exo1 in mice expressing a hypomorphic allele of Nbs1 leads to severe developmental impairment, embryonic death and chromosomal instability. While EXO1 plays a minimal role in normal cells, its loss strongly influences DNA replication, DNA repair, checkpoint signaling and damage sensitivity in NBS1 hypomorphic cells. Collectively, our results establish a key role for EXO1 in modulating the severity of hypomorphic MRE11 complex mutations.


The epidemiology of sex chromosome abnormalities.
Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.


Efficacy of intermittent androgen deprivation therapy vs conventional continuous androgen deprivation therapy for advanced prostate cancer: a meta-analysis.
To compare the efficacy of intermittent androgen deprivation therapy (IADT) vs continuous androgen deprivation therapy (CADT) for the treatment of advanced prostate cancer; we performed a meta-analysis of randomized controlled trials (RCTs), assessing the risks of disease progression, all-cause, and disease-specific mortality. We conducted a systematic search of several bibliographic systems to identify all RCTs of IADT in men with newly diagnosed metastatic or biochemical only prostate cancer. We abstracted outcome data, study characteristics, and participant demographics. We performed heterogeneity tests and calculated the summarized risk differences (RD) and risk ratios at 95% confidence intervals (CI), using inverse variance methods in random-effects approaches. We identified 8 RCTs (N = 4664) comparing mortality between IADT and CADT. For all men combined, we observed small but nonsignificant differences in all-cause mortality (RD = 0.02, 95% CI = -0.02, 0.06), disease-specific mortality (RD = 0.04, 95% CI = -0.01, 0.08), and disease progression (RD = -0.03, 95% CI = -0.09, 0.04). Among the prespecified subgroup with histologically confirmed, newly diagnosed metastatic disease, we found no difference in overall survival (RD = 0.00, 95% CI = -0.09, 0.09). We found no difference in overall survival, but a small increased risk in disease-specific survival for men treated with IADT relative to CADT was observed. IADT could be considered as an alternative to CADT because of better quality of life outcome. Patients should be informed of the possible risks and benefits of both therapies. More research confirming the benefits of IADT vs CADT is needed to inform treatment decisions.


Single-mode and high power waveguide lasers fabricated by ion-exchange.
We report on a single-end diode-pumped waveguide laser providing output power in excess of 20 mW with 17% slope efficiency in robust single longitudinal and transverse mode operation at 1533.5 nm. The active medium was an Er:Yb-doped waveguide only 9-mm long fabricated by Ag-Na ion-exchange in a phosphate glass. The overall cavity length including butt-coupled fiber-Bragg-grating mirrors was <60 mm. We also report on high power waveguide lasers providing more than 160 mW output power and 46% slope efficiency in multimode operation. Feasibility of high power single mode waveguide lasers based on ion-exchange technology in phosphate glasses is also experimentally investigated by using a 50-mm long active waveguide specially designed for efficient single-end pumping.