Estimated age of first exposure to American football and outcome from concussion.
To examine the association between estimated age at first exposure (eAFE) to American football and clinical measures throughout recovery following concussion. Participants were recruited across 30 colleges and universities as part of the National Collegiate Athletic Association (NCAA)-Department of Defense Concussion Assessment, Research and Education Consortium. There were 294 NCAA American football players (age 19 ± 1 years) evaluated 24-48 hours following concussion with valid baseline data and 327 (age 19 ± 1 years) evaluated at the time they were asymptomatic with valid baseline data. Participants sustained a medically diagnosed concussion between baseline testing and postconcussion assessments. Outcome measures included the number of days until asymptomatic, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) composite scores, Balance Error Scoring System (BESS) total score, and Brief Symptom Inventory 18 (BSI-18) subscores. The eAFE was defined as participant's age at the time of assessment minus self-reported number of years playing football. In unadjusted regression models, younger eAFE was associated with lower (worse) ImPACT Visual Motor Speed (R 2 = 0.031, p = 0.012) at 24-48 hours following injury and lower (better) BSI-18 Somatization subscores (R 2 = 0.014, p = 0.038) when the athletes were asymptomatic. The effect sizes were very small. The eAFE was not associated with the number of days until asymptomatic, other ImPACT composite scores, BESS total score, or other BSI-18 subscores. Earlier eAFE to American football was not associated with longer symptom recovery, worse balance, worse cognitive performance, or greater psychological distress following concussion. In these NCAA football players, longer duration of exposure to football during childhood and adolescence appears to be unrelated to clinical recovery following concussion.


Mechanism of increased amplitude and duration of the plateau with sudden shortening of diastolic intervals in rabbit ventricular cells.
Action potentials and membrane currents were recorded from isolated single ventricular cells from rabbit hearts using the suction pipette whole-cell clamp method. Action potentials elicited after short diastolic intervals of less than 2 seconds showed an increase and prolongation of the plateau compared to those elicited after a 10-second rest period. The recovery of the tetrodotoxin-insensitive secondary inward current revealed a transient increase at short diastolic intervals above the level of full recovery (after 10 seconds). The increased secondary inward current recovery, however, was voltage-dependent, and the period of its increase did not cover the entire diastolic intervals of the action potential overshoots, suggesting the contribution of another ionic current to the changes in potential. During depolarizing voltage steps, from + to -20 mV, a rapid activating and then inactivating outward current was elicited, which overlapped the calcium current. This outward current exhibited time- and voltage-dependent properties similar to those of the transient outward current in Purkinje and other cardiac preparations. The recovery of the transient outward current was slow, achieving only 75% of its full level at 2 seconds, whereas the same level of calcium current recovery was achieved at 200 milliseconds. The application of 4-aminopyridine suppressed most of the transient outward current, and the rest of the current was abolished by caffeine or Co2+. The 4-aminopyridine sensitive transient outward current exhibited slow recovery kinetics compared to those of the other or calcium current, and its inhibition caused elimination of the augmented plateau during electrical restitution. The application of verapamil or Co2+ for inhibition of secondary inward current also abolished the action potential overshoot. These results indicate that an increase and prolongation of the plateau at short diastolic intervals are produced by the slower recovery from inactivation in the 4-aminopyridine-sensitive transient outward current than that in the calcium current.


Nanoparticle-based biocompatible and long-life marker for lysosome labeling and tracking.
In this paper, a novel biocompatible and long-life lysosome labeling and tracking method based on dye entrapped silica nanoparticles (DSiNPs) has been put forward. Through colocalization studies using LysoTracker Green as the standard lysosome marker, it has been demonstrated that DSiNPs selectively accumulated in lysosomes of Hela cells and the photostability of DSiNPs associated with lysosomes was detectable, at least, 30 times as long as that of LysoTracker Green involved in lysosomes. By comparison with LysoTracker Green and Alexa 488-dextran, the fluorescence of DSiNPs could be detected over a 5-day postrecultivation period and the staining pattern in lysosomes could be well retained after cell fixation and permeabilization. In addition, results from MTT assays showed that DSiNPs did not affect the viability of Hela cells at the concentration for lysosome labeling. Primary applications of DSiNPs were then further performed in lysosome tracking in chloroquine-treated Hela cells, and lysosome labeling of differnet cell lines, including MCF-7 cells, MEAR cells, and MSC cells. These results indicated that DSiNPs, therefore, can be used as a biocompatible, long-life, and highly photostable lysosome marker for lysosome-related studies.


Motivation and Factors Affecting It among Health Professionals in the Public Hospitals, Central Ethiopia.
Motivation is an individual's degree of willingness to exert and maintain an effort towards organizational goals. This study assessed motivational status and factors affecting it among health professionals in public hospitals of West Shoa Zone, Oromia Region. Facility based cross-sectional survey was employed. All health professionals who served at least for 6 months in Ambo, Gedo and Gindeberet hospitals were included. Self-administered Likert scale type questionnaire was used. Data were analyzed using SPSS version 20. Mean motivation calculated as percentage of maximum scale score was used. Bivariate and multiple linear regression analyses were done to see the independent effects of explanatory variables. The overall motivation level of health professionals was 63.63%. Motivation level of health professionals varied among the hospitals. Gindeberet Hospital had lower motivation score as compared to Ambo Hospital (B = -0.54 and 95% CI; -0.08,-0.27). The mean motivation score of health professionals who got monthly financial benefit was significantly higher than those who did not (B = 0.71 and 95% CI; 0.32, 1.10). Environmental factors had higher impact on doctors' motivation compared to nurses' (B = 0.51 and 95% CI; 0.10, 0.92). Supervisor-related factors highly varied in motivation relative to other variables. Motivation of health professionals was affected by factors related to supervisor, financial benefits, job content and hospital location. Efforts should be made to provide financial benefits to health professionals as appropriate especially, to those who did not get any such benefits. Officially recognizing best performance is also suggested.


Manipulation of host membrane machinery by bacterial pathogens.
Subversion of host membrane machinery is important for the uptake, survival, and replication of bacterial pathogens. Understanding how pathogens manipulate host membrane transport pathways provides mechanistic insight into how infection occurs and is also revealing new information on biochemical processes involved in the functioning of eukaryotic cells. In this review we discuss several of the canonical host pathways targeted by bacterial pathogens and emerging areas of investigation in this exciting field.


Population genetic structure in Atlantic and Pacific Ocean common murres (Uria aalge): natural replicate tests of post-Pleistocene evolution.
Understanding the factors that influence population differentiation in temperate taxa can be difficult because the signatures of both historic and contemporary demographics are often reflected in population genetic patterns. Fortunately, analyses based on coalescent theory can help untangle the relative influence of these historic and contemporary factors. Common murres (Uria aalge) are vagile seabirds that breed in the boreal and low arctic waters of the Northern Hemisphere. Previous analyses revealed that Atlantic and Pacific populations are genetically distinct; however, less is known about population genetic structure within ocean basins. We employed the mitochondrial control region, four microsatellite loci and four intron loci to investigate population genetic structure throughout the range of common murres. As in previous studies, we found that Atlantic and Pacific populations diverged during the Pleistocene and do not currently exchange migrants. Therefore, Atlantic and Pacific murre populations can be used as natural replicates to test mechanisms of population differentiation. While we found little population genetic structure within the Pacific, we detected significant east-west structuring among Atlantic colonies. The degree that population genetic structure reflected contemporary population demographics also differed between ocean basins. Specifically, while the low levels of population differentiation in the Pacific are at least partially due to high levels of contemporary gene flow, the east-west structuring of populations within the Atlantic appears to be the result of historic fragmentation of populations rather than restricted contemporary gene flow. The contrasting results in the Atlantic and Pacific Oceans highlight the necessity of carefully considering multilocus nonequilibrium population genetic approaches when reconstructing the demographic history of temperate Northern Hemisphere taxa.


Parentage of overlapping offspring of an arboreal-breeding frog with no nest defense: implications for nest site selection and reproductive strategy.
Overlapping offspring occurs when eggs are laid in a nest containing offspring from earlier reproduction. Earlier studies showed that the parentage is not always obvious due to difficulties in field observation and/or alternative breeding tactics. To unveil the parentage between overlapping offspring and parents is critical in understanding oviposition site selection and the reproductive strategies of parents. Amplectant pairs of an arboreal-breeding frog, Kurixalus eiffingeri, lay eggs in tadpole-occupied nests where offspring of different life stages (embryos and tadpoles) coexist. We used five microsatellite DNA markers to assess the parentage between parents and overlapping offspring. We also tested the hypothesis that the male or female frog would breed in the same breeding site because of the scarcity of nest sites. Results showed varied parentage patterns, which may differ from the phenomenon of overlapping egg clutches reported earlier. Parentage analyses showed that only 58 and 25% of the tadpole-occupied stumps were reused by the same male and female respectively, partially confirming our prediction. Re-nesting by the same individual was more common in males than females, which is most likely related to the cost of tadpole feeding and/or feeding schemes of females. On the other hand, results of parentage analyses showed that about 42 and 75% of male and female respectively bred in tadpole-occupied stumps where tadpoles were genetically unrelated. Results of a nest-choice experiment revealed that 40% of frogs chose tadpole-occupied bamboo cups when we presented identical stumps, without or with tadpoles, suggesting that the habitat saturation hypothesis does not fully explain why frogs used the tadpole-occupied stumps. Several possible benefits of overlapping offspring with different life stages were proposed. Our study highlights the importance of integrating molecular data with field observations to better understand the reproductive biology and nest site selection of anuran amphibians.


Dynamic Chromatin Regulation from a Single Molecule Perspective.
Chromatin regulatory processes, like all biological reactions, are dynamic and stochastic in nature but can give rise to stable and inheritable changes in gene expression patterns. A molecular understanding of those processes is key for fundamental biological insight into gene regulation, epigenetic inheritance, lineage determination, and therapeutic intervention in the case of disease. In recent years, great progress has been made in identifying important molecular players involved in key chromatin regulatory pathways. Conversely, we are only beginning to understand the dynamic interplay between protein effectors, transcription factors, and the chromatin substrate itself. Single-molecule approaches employing both highly defined chromatin substrates in vitro, as well as direct observation of complex regulatory processes in vivo, open new avenues for a molecular view of chromatin regulation. This review highlights recent applications of single-molecule methods and related techniques to investigate fundamental chromatin regulatory processes.


DNA sequences required for yeast actin gene transcription do not include conserved CCAAT motifs.
Sequences required for Saccharomyces cerevisiae actin gene transcription were mapped and compared to the regulatory region of the actin gene from a thermophilic fungus, Thermomyces lanuginosus. Two CCAAT motifs conserved in position in these two species could be mutated without affecting promoter activity, regardless of whether the yeast were grown in fermentable or non-fermentable carbon sources. Two TATA-like sequences and an upstream activation sequence (UAS) composed of multiple elements were identified. The contribution of sequence motifs within these elements to UAS activity varied depending on the carbon source. The Thermomyces gene contains sequences highly homologous to this UAS, but in the opposite orientation.


Review and priority setting for substances that are listed without a specific migration limit in Table 1 of Annex 1 of Regulation 10/2011 on plastic materials and articles intended to come into contact with food.
The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) was requested by the European Commission to review the substances for which a Specific Migration Limit (SML) is not assigned in Regulation (EU) No 10/2011. These substances had been covered by the Generic SML of 60 mg/kg food, but with Regulation (EU) 2016/1416 it was removed, necessitating their re-examination. EFSA was requested to identify those substances requiring an SML to ensure the authorisation is sufficiently protective to health, grouping them in high, medium and low priority to serve as the basis for future re-evaluations of individual substances. The CEP Panel established a stepwise procedure. This took into account existing hazard assessments for each substance on carcinogenicity/mutagenicity/reprotoxicity (CMR), bioaccumulation and endocrine disruptor (ED) properties along with the use of in silico generated predictions on genotoxicity. Molecular weights and boiling points were considered with regard to their effect on potential consumer exposure. This prioritisation procedure was applied to a total of 451 substances, from which 78 substances were eliminated at the outset, as they had previously been evaluated by EFSA as food contact substances. For 89 substances, the Panel concluded that a migration limit should not be needed. These are in the lists 0 and 1 of the Scientific Committee for Food (SCF), defined as substances for which an Acceptable Daily Intake (ADI) does not need to be established, along with substances that are controlled by existing restrictions and/or generic limits. Of the remaining 284 substances, 179 were placed into the low priority group, 102 were placed into the medium priority group and 3 were placed into the high priority group, i.e. salicylic acid (FCM No 121), styrene (FCM No 193) and lauric acid, vinyl ester (FCM No 436).


Gross motor ability predicts response to upper extremity rehabilitation in chronic stroke.
The majority of rehabilitation research focuses on the comparative effectiveness of different interventions in groups of patients, while much less is currently known regarding individual factors that predict response to rehabilitation. In a recent article, the authors presented a prognostic model to identify the sensorimotor characteristics predictive of the extent of motor recovery after Constraint-Induced Movement (CI) therapy amongst individuals with chronic mild-to-moderate motor deficit using the enhanced probabilistic neural network (EPNN). This follow-up paper examines which participant characteristics are robust predictors of rehabilitation response irrespective of the training modality. To accomplish this, EPNN was first applied to predict treatment response amongst individuals who received a virtual-reality gaming intervention (utilizing the same enrollment criteria as the prior study). The combinations of predictors that yield high predictive validity for both therapies, using their respective datasets, were then identified. High predictive classification accuracy was achieved for both the gaming (94.7%) and combined datasets (94.5%). Though CI therapy employed primarily fine-motor training tasks and the gaming intervention emphasized gross-motor practice, larger improvements in gross motor function were observed within both datasets. Poorer gross motor ability at pre-treatment predicted better rehabilitation response in both the gaming and combined datasets. The conclusion of this research is that for individuals with chronic mild-to-moderate upper extremity hemiparesis, residual deficits in gross motor function are highly responsive to motor restorative interventions, irrespective of the modality of training.


Reproductive biology of the Alaska skate Bathyraja parmifera, with comments on an intersexual individual.
A total of 1357 specimens of Alaska skate Bathyraja parmifera were collected in the eastern Bering Sea by fisheries observers and during scientific groundfish surveys from 2003 to 2005. Male and female gonads were examined for maturity stage and seasonal reproductive timing. Based on seasonal reproductive data, including the occurrence of egg cases, ovum size, ovum number, shell-gland width and gonado-somatic index, this species appears to reproduce continually throughout the year. Potential effects of maternal size upon the size and number of mature oocytes were also investigated, with total length having a significant, although weak, influence on both. Morphology of a single intersexual individual encountered during the collection period is also described.


The Pleiotropic Effects of Statins - From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia.
Statins, 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, have been used for decades for the prevention of coronary artery disease and stroke. They act primarily by lowering serum cholesterol through the inhibition of cholesterol synthesis in the liver, which results in the upregulation of low-density lipoprotein receptors in the liver. This results in the removal of low-density lipoproteincholesterol. Studies have suggested that statins may demonstrate additional effects that are independent of their effects on low-density lipoprotein-cholesterol. These have been termed "pleiotropic" effects. Pleiotropic effects may be due to the inhibition of isoprenoid intermediates by statins. Isoprenoid inhibition has effects on the small guanosine triphosphate binding proteins Rac and Rho which in turn effects nicotinamide adenine dinucleotide phosphate oxidases. Therefore, there are changes in endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypetrophy development. Recently, statins have been compared to the ezetimibe and the recently published outcomes data on the proprotein convertase subtilisin kexin type 9 inhibitors has allowed for a reexamination of statin pleiotropy. As a result of these diverse effects, it has been suggested that statins also have anti-arrhythmic effects. This review focuses on the mechanisms of statin pleiotropy and discusses evidence from the statin clinical trials as well as examining the possible anti-arrhythmic effects atrial fibrillation and ventricular tachyarrhythmias.


Suboptimal health: a new health dimension for translational medicine.
One critical premise of disease-related biomarkers is the definition of the counterpart normality. Contrary to pre-clinical models that can be carefully tailored according to scientific need, heterogeneity and uncontrollability is the essence of humans in health studies. Fully characterization of consistent parameters that define the normal population is the basis to individual differences normalization irrelevant to a given disease process. Self claimed normal status may not represent health because asymptomatic subjects may carry chronic diseases or diseases at their early stage such as cancer, diabetes and hypertension. This paper exemplifies the characterization of the suboptimal health status (SHS) which represents a new public health problem in a population with ambiguous health complaints such as general weakness, unexplained medical syndrome and chronic fatigue. We applied clinical informatics approaches and developed a questionnaire for measuring SHS. The validity and reliability of this approach were evaluated in a small pilot study and then in a cross-sectional study of 3,405 individuals. The final questionnaire congregated into a score (SHSQ-25) which could significantly distinguish among several abnormal conditions. SHSQ-25 could be used as a translational medicine instrument for health measuring in the general population.


Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7.
The COVID-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Single and combination monoclonal antibody (mAb) therapeutics have received emergency use authorization1-3, with more in the pipeline4-7. Furthermore, multiple vaccine constructs have shown promise8, including two with ~95% protective efficacy against COVID-199,10. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. The recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a few mAbs to the receptor-binding domain (RBD). It is not more resistant to convalescent plasma or vaccinee sera. Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4 fold) and vaccinee sera (10.3-12.4 fold). B.1.351 and emergent variants13,14 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.


Differential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat.
1. Gavage administration of the natural flavonoids tangeretin, chrysin, apigenin, naringenin, genistein and quercetin for 2 consecutive weeks to the female rat resulted in differential effects on selected phase 1 and 2 enzymes in liver, colon and heart as well as antioxidant enzymes in red blood cells (RBC). 2. Glutathione transferase (GST) activity assayed by use of the substrate 1-chloro-2,4-dinitrobenzene was significantly induced by apigenin, genistein and tangeretin in the heart but not in colon or liver. 3. In RBC chrysin, quercetin and genistein significantly decreased the activity of glutathione reductase (GR), catalase (CAT) and glutathione peroxidase (GPx), whereas superoxide dismutase (SOD) was only significantly decreased by genistein. 4. The oxidative status of the animal, measured as plasma malondialdehyde, revealed that chrysin, quercetin, genistein, and beta-naphthoflavone (BNF) significantly protected against, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced oxidative stress. Hepatic PhIP-DNA adduct formation was not affected by any of the administered flavonoids, whereas PhIP-DNA adduct formation in colon was slightly, but significantly, inhibited by quercetin, genistein, tangeretin and BNF. 5. The observed effects of chrysin, quercetin and genistein on antioxidant enzymes, concurrently with a protection against oxidative stress, suggest a feedback mechanism on the antioxidant enzymes triggered by the flavonoid antioxidants. 6. Despite the use of high flavonoid doses, which by far exceed the human exposure levels, the effect on drug metabolizing and antioxidant enzymes was still very minor. The role of singly administered flavonoids in the protection against cancer and heart disease is thus expected to be limited.


Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy.
Immune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris is a common, immune-mediated disease, and outcomes of ICI treatment in patients with psoriasis are not well described. Thus we sought to define the safety profile and effectiveness of ICIs in patients with pre-existing psoriasis. In this retrospective cohort study, patients from eight academic centers with pre-existing psoriasis who received ICI treatment for cancer were evaluated. Main safety outcomes were psoriasis exacerbation and immune-related adverse events (irAEs). We also assessed progression-free survival (PFS) and overall survival. Of 76 patients studied (50 (66%) male; median age 67 years; 62 (82%) with melanoma, 5 (7%) with lung cancer, 2 (3%) with head and neck cancer, and 7 (9%) with other cancers; median follow-up 25.1 months (range=0.2-99 months)), 51 (67%) received anti-PD-1 antibodies, 8 (11%) anti-CTLA-4, and 17 (22%) combination of anti-PD-1/CTLA-4. All patients had pre-existing psoriasis, most frequently plaque psoriasis (46 patients (61%)) and 15 (20%) with psoriatic arthritis. Forty-one patients (54%) had received any prior therapy for psoriasis although only two (3%) were on systemic immunosuppression at ICI initiation. With ICI treatment, 43 patients (57%) experienced a psoriasis flare of cutaneous and/or extracutaneous disease after a median of 44 days of receiving ICI. Of those who experienced a flare, 23 patients (53%) were managed with topical therapy only; 16 (21%) needed systemic therapy. Only five patients (7%) required immunotherapy discontinuation for psoriasis flare. Forty-five patients (59%) experienced other irAEs, 17 (22%) of which were grade 3/4. PFS with landmark analysis was significantly longer in patients with a psoriasis flare versus those without (39 vs 8.7 months, p=0.049). In this multicenter study, ICI therapy was associated with frequent psoriasis exacerbation, although flares were manageable with standard psoriasis treatments and few required ICI discontinuation. Patients who experienced disease exacerbation performed at least as well as those who did not. Thus, pre-existing psoriasis should not prevent patients from receiving ICIs for treatment of malignancy.


Randomised cluster trial to support informed parental decision-making for the MMR vaccine.
In the UK public concern about the safety of the combined measles, mumps and rubella [MMR] vaccine continues to impact on MMR coverage. Whilst the sharp decline in uptake has begun to level out, first and second dose uptake rates remain short of that required for population immunity. Furthermore, international research consistently shows that some parents lack confidence in making a decision about MMR vaccination for their children. Together, this work suggests that effective interventions are required to support parents to make informed decisions about MMR. This trial assessed the impact of a parent-centred, multi-component intervention (balanced information, group discussion, coaching exercise) on informed parental decision-making for MMR. This was a two arm, cluster randomised trial. One hundred and forty two UK parents of children eligible for MMR vaccination were recruited from six primary healthcare centres and six childcare organisations. The intervention arm received an MMR information leaflet and participated in the intervention (parent meeting). The control arm received the leaflet only. The primary outcome was decisional conflict. Secondary outcomes were actual and intended MMR choice, knowledge, attitude, concern and necessity beliefs about MMR and anxiety. Decisional conflict decreased for both arms to a level where an 'effective' MMR decision could be made one-week (effect estimate = -0.54, p < 0.001) and three-months (effect estimate = -0.60, p < 0.001) post-intervention. There was no significant difference between arms (effect estimate = 0.07, p = 0.215). Heightened decisional conflict was evident for parents making the MMR decision for their first child (effect estimate = -0.25, p = 0.003), who were concerned (effect estimate = 0.07, p < 0.001), had less positive attitudes (effect estimate = -0.20, p < 0.001) yet stronger intentions (effect estimate = 0.09, p = 0.006). Significantly more parents in the intervention arm reported vaccinating their child (93% versus 73%, p = 0.04). Whilst both the leaflet and the parent meeting reduced parents' decisional conflict, the parent meeting appeared to enable parents to act upon their decision leading to vaccination uptake.


Fatigue in inflammatory bowel diseases: relationship with age and disease activity.
A higher rate of patients suffering from inflammatory bowel diseases (IBD) are reported to experience the symptom of fatigue compared with general population. Fatigue can impair quality of life of IBD patients by limiting their daily functioning. However, this problem is poorly understood and addressed. Our aim was to investigate the impact of fatigue in IBD patients compared with controls, and to seek for relation between age and disease activity. IBD patients aged between 16 and 75 years observed at our Unit from June 2011 through June 2012 were evaluated for fatigue. Patients were asked to fill the fatigue impact scale (FIS) questionnaire. A cohort of age- and sex-matched patients observed for other-than-IBD diseases were prospectively enrolled to act as controls. Patients diagnosed with malignancies were excluded from evaluation. Each group included 16 patients, of whom half aged over 65 years. Fatigue was more severe in IBD patients than in controls (p = 0.02), irrespective of age and disease activity. IBD patients with moderate to severe disease activity showed worse fatigue compared with controls at any age (p < 0.0001). Young IBD patients with low disease activity showed a trend toward worse FIS score when compared with old IBD counterparts (p = 0.06). IBD significantly impacted on fatigue in our series. Considering IBD patients in remission, younger patients may experience worse fatigue. Further studies are needed to explore the effects of fatigue on quality of life and the potential of appropriate intervention strategies.


Extra Luminal Entrapment of Guide Wire; A Rare Complication of Central Venous Catheter Placement in Right Internal Jugular Vein.
Central venous Catheterization (CVC) is a commonly performed procedure for venous access. It is associated with several complications. We report a rare case of extra luminal entrapment of guide wire during CVC placement in right jugular vein. We report a case of 28 years old female patient presented in our emergency with history of entrapped guide wire in right side of neck during CVC. X-ray showed coiling of guide wire in neck. CT Angiography showed guide wire coursing in between common carotid artery and internal jugular vein (IJV), closely abutting the wall of both vessels. The guide wire was coiled with end coursing behind the esophageal wall. Guide wire was removed under fluoroscopic guide manipulation under local anesthesia. We want to emphasize that even though CVC placement is common and simple procedure, serious complication can occur in hands of untrained operator. The procedure should be performed under supervision, if done by trainee. Force should never be applied to advance the guide wire if resistance is encountered.


The crystal structure of PknI from Mycobacterium tuberculosis shows an inactive, pseudokinase-like conformation.
Eukaryotic-like Ser/Thr protein kinases (ePKs) have been identified in many bacterial species, where they are known to mediate signalling mechanisms that share several features with their eukaryotic counterparts. In Mycobacterium tuberculosis, PknI is one of the 11 predicted ePKs and it has been related to bacterial virulence. In order to better understand the molecular basis of its role in mycobacterial signalling, we solved the crystal structure of the PknI cytoplasmic domain. We found that even though PknI possesses most conserved elements characteristic of Hanks-type kinases, it is degraded in several motifs that are essential for the ePKs catalytic activity. Most notably, PknI presents a remarkably short activation segment lacking a peptide-substrate binding site. Consistent with this observation and similar to earlier findings for eukaryotic pseudokinases, no kinase activity was detected for the catalytic domain of PknI, against different substrates and in various experimental conditions. Based on these results, we conclude that PknI may rely on unconventional mechanism(s) for kinase activity and/or it could play alternative role(s) in mycobacterial signalling. Atomic coordinates and structure factors for the catalytic domain of M. tuberculosis PknI are in the Protein Data Bank under the accession codes 5M06 (wild-type PknI + ADP), 5M07 (PknI_C20A), 5M08 (PknI_C20A_R136A) and 5M09 (PknI_C20A_R136N).


Experimental approaches for elucidation of stress-sensing mechanisms of the IRE1 family proteins.
Endoplasmic reticulum (ER) stress, which is often regarded as the accumulation of unfolded proteins in the ER, triggers cellular protective events including the unfolded protein response (UPR). In the yeast S. cerevisiae, the UPR signaling pathway starts from the ER-located transmembrane protein Ire1, the activation of which eventually leads to transcriptional induction of various genes including those encoding ER-located molecular chaperones. Mammals have two Ire1 paralogues, of which IRE1α exhibits ubiquitous tissue expression. Here, we show how we have approached study of the molecular mechanisms by which ER stress activates the Ire1 family proteins. Immunoprecipitation analyses indicated that the ER-located chaperone BiP associates with IRE1α and yeast Ire1, while ER stress dissociates these complexes. We also devised experimental systems for exogenous expression of wild-type or mutant versions of IRE1α and yeast Ire1 at appropriate levels, in order to monitor correctly their activity in evoking downstream events. An IRE1α partial deletion mutant with which BiP poorly associates showed considerable activity even under nonstress conditions, whereas a BiP-nonbinding mutant of yeast Ire1 was almost normally regulated in an ER-stress dependent manner. This finding suggests that the dissociation of BiP is the principal determinant of IRE1α's activation upon ER stress, while yeast Ire1 is largely controlled by another factor(s). Based on in vitro ability to inhibit aggregation of denatured proteins, we deduce that the luminal domain of yeast Ire1, but not that of IRE1α, is capable of direct interaction with unfolded proteins. Since this ability of yeast Ire1 was abolished by a mutation impairing its cellular activity, we propose that yeast Ire1 is fully activated by its direct interaction with unfolded proteins.


A standardized ultrasound approach in neuralgic amyotrophy.
Neuralgic amyotrophy (NA), also referred to as idiopathic brachial plexitis and Parsonage-Turner syndrome, is a peripheral nerve disorder characterized by acute severe shoulder pain followed by progressive upper limb weakness and muscle atrophy. While NA is incompletely understood and often difficult to diagnose, early recognition may prevent unnecessary tests and interventions and, in some situations, allow for prompt treatment, which can potentially minimize adverse long-term sequalae. High-resolution ultrasound (HRUS) has become a valuable tool in the diagnosis and evaluation of NA. Pathologic HRUS findings can be grouped into four categories: nerve swelling, swelling with incomplete constriction, swelling with complete constriction, and fascicular entwinement, which may represent a continuum of pathologic processes. Certain ultrasound findings may help predict the likelihood of spontaneous recovery with conservative management versus the need for surgical intervention. We recommend relying heavily on history and physical examination to determine which nerves are clinically affected and should therefore be assessed by HRUS. The nerves most frequently affected by NA are the suprascapular, long thoracic, median and anterior interosseous nerve (AIN) branch, radial and posterior interosseous nerve (PIN) branch, axillary, spinal accessory, and musculocutaneous. When distal upper limb nerves are affected (AIN, PIN, superficial radial nerve), the lesion is almost always located in their respective fascicles within the parent nerve, proximal to its branching point. The purpose of this review is to describe a reproducible, standardized, ultrasonographic approach for evaluating suspected NA, and to share reliable techniques and clinical considerations when imaging commonly affected nerves.


Low-molecular-weight heparin vs unfractionated heparin for perioperative thromboprophylaxis in patients with cancer: a systematic review and meta-analysis.
The relative benefits and harms of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are required for judgments regarding the appropriate perioperative thromboprophylaxis in patients with cancer. We systematically reviewed the literature to quantify these effects. The comprehensive searches included (1) an electronic search of MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL (The Cochrane Central Register of Controlled Trials); (2) a hand search of relevant conference proceedings; (3) a reference check of included trials; and (4) use of the PubMed "Related Articles" feature. Outcomes of interest included mortality, deep venous thrombosis, pulmonary embolism, bleeding complications, and thrombocytopenia. Of 3986 identified citations, we included 14 randomized clinical trials in the meta-analysis (all using preoperative prophylactic anticoagulation). The overall methodological quality was moderate. The meta-analysis showed no differences in mortality in patients receiving LMWH compared with UFH (relative risk [RR], 0.89; 95% confidence interval [CI], 0.61-1.28) or in clinically suspected deep venous thrombosis (RR, 0.73; 95% CI, 0.23-2.28). In a post hoc analysis including all studies assessing deep venous thrombosis, irrespective of the diagnostic strategy used, LMWH was superior to UFH (RR, 0.72; 95% CI, 0.55-0.94). There were no differences in rates of pulmonary embolism (RR, 0.60; 95% CI, 0.22-1.64), minor bleeding (RR, 0.88; 95% CI, 0.47-1.66), or major bleeding (RR, 0.95; 95% CI, 0.51-1.77). We found no differences in mortality in patients with cancer receiving perioperative thromboprophylaxis with LMWH vs UFH. Further trials are needed to more carefully evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population.


Venomic and antivenomic analyses of the Central American coral snake, Micrurus nigrocinctus (Elapidae).
The proteome of the venom of Micrurus nigrocinctus (Central American coral snake) was analyzed by a "venomics" approach. Nearly 50 venom peaks were resolved by RP-HPLC, revealing a complex protein composition. Comparative analyses of venoms from individual specimens revealed that such complexity is an intrinsic feature of this species, rather than the sum of variable individual patterns of simpler composition. Proteins related to eight distinct families were identified by MS/MS de novo peptide sequencing or N-terminal sequencing: phospholipase A(2) (PLA(2)), three-finger toxin (3FTx), l-amino acid oxidase, C-type lectin/lectin-like, metalloproteinase, serine proteinase, ohanin, and nucleotidase. PLA(2)s and 3FTxs are predominant, representing 48 and 38% of the venom proteins, respectively. Within 3FTxs, several isoforms of short-chain α-neurotoxins as well as muscarinic-like toxins and proteins with similarity to long-chain κ-2 bungarotoxin were identified. PLA(2)s are also highly diverse, and a toxicity screening showed that they mainly exert myotoxicity, although some are lethal and may contribute to the known presynaptic neurotoxicity of this venom. An antivenomic characterization of a therapeutic monospecific M. nigrocinctus equine antivenom revealed differences in immunorecognition of venom proteins that correlate with their molecular mass, with the weakest recognition observed toward 3FTxs.


Cost-effectiveness of alternative NTRK testing strategies in cancer patients followed by histology-independent therapy with entrectinib: an analysis of three European countries.
Aim: To explore variations in the cost-effectiveness of entrectinib across different testing strategies and settings. Methods: Four testing strategies where adult cancer patients received entrectinib if they tested positive for NTRK gene fusions compared with 'no testing' and standard of care (SoC) for all patients were evaluated. Results: Immunohistochemistry for all patients followed by RNA-based next-generation sequencing after a positive result was the optimal strategy in all included countries. However, the incremental net monetary benefit compared with SoC was negative in all countries, ranging between international euros (int€) -206 and -404. In a subgroup analysis with only NTRK-positive patients, the incremental net monetary benefit was int€ 8405 in England, int€ -53,088 in Hungary and int€ 54,372 in The Netherlands. Conclusion: Using the cost-effectiveness thresholds recommended by national guidelines, none of the testing strategies were cost-effective compared with no testing. The implementation of entrectinib is unlikely to become cost-effective in Hungary, due to the large cost difference between the entrectinib and SoC arms, while there might be more potential in England and The Netherlands.


Plasma levels of intact and cleaved urokinase plasminogen activator receptor (uPAR) in men with clinically localised prostate cancer.
Lymph node metastasis (N1) is an adverse prognostic factor for men with clinically localised prostate cancer (PCa), but the prediction of N1 disease remains difficult. Urokinase plasminogen activator receptor (uPAR) plays an important role in angiogenesis and tumorigenesis. We analysed whether plasma levels of the soluble uPAR forms uPAR(I-III), uPAR(II-III) and uPAR(I) were associated with the risk of N1 disease in men with clinically localised PCa. The present study includes all men (n=518) who underwent radical prostatectomy (RP) for clinically localised PCa, 29 of whom had N1 disease. Soluble uPAR forms were measured using three time-resolved fluorescence immunoassays. The prognostic value of the different uPAR forms together with clinicopathological parameters for N1 disease were analysed using logistic regression, receiver operating characteristic (ROC) regression analysis and quantified using the areas under the ROC curve (AUC). All soluble uPAR levels were significantly (p=0.03) higher in patients with N1 disease compared with patients with N0/x disease. ROC curves including clinical tumour stage, biopsy Gleason score, prostate-specific antigen and percent positive biopsies had an AUC of 87.7% for prediction of N1 disease. With the addition of uPAR(I) to the model, the AUC increased to 88.4%. Addition of uPAR(I) level to known diagnostic parameters did not increase the prediction of N1 disease following RP in men with clinically localised PCa. Our results indicate that the plasma levels at diagnosis of the different uPAR forms do not hold important predictive or prognostic information in men with clinically localised PCa.


Mind navigators of chemicals' experimenters? A web-based description of e-psychonauts.
Within online drug fora communities, there are some "educated and informed" users who can somehow provide reliable information on psychoactive compounds and combinations. These users, also called "e-psychonauts," may possess levels of technical knowledge relating to a range of novel psychoactive substances (NPS). The present project aimed at identifying and describing the e-psychonauts' socio-demographic characteristics and their motivations and patterns of drug intake. A netnographic research methodology, carried out through an unobtrusive observational approach of a list of cyber drug communities (blogs, fora, Facebook, and Twitter pages) was carried out. The fora posts and threads were accurately reviewed, analyzed, and compared using the empirical phenomenological psychological (EPP) method. Data were collected between January and February 2014. Psychonauts typically considered themselves as "psychedelic researchers," "new Shamans," "philosophers," or "alchemists." They appeared to be mainly young, males, unmarried, and Caucasians. They presented with good or excellent employment conditions and with a set of key skills, including attention to their inner "soul"; high standards of knowledge about drugs' chemical and pharmacological issues; and high levels of both IT skills and verbal fluency in reporting their own "on drug" experiences. The e-psychonauts seemed to "test" and at times synthesize a range of drugs to achieve the state of consciousness they find most pleasurable. There is the need to improve both the existing levels of professionals' knowledge on this novel generation of drug misusers and to design and develop novel prevention approaches that are able to attract the attention of the e-psychonauts.


Genomic risk profiling of ischemic stroke: results of an international genome-wide association meta-analysis.
Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk. This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P<1×10(-5)) were incorporated into a multivariate risk profile model. No SNP reached genome-wide significance for ischemic stroke (P<5×10(-8)). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, ß = 14.77 [10.85,18.68], P = 5.5×10(-12)), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P<5×10(-6)). Risk profile scores based only on genomic information offered little incremental prediction. There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling.


Medicaid Statistical Information System (MSIS): a data source for quality reporting for Medicaid and the Children's Health Insurance Program (CHIP).
Section 401 of the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA) requires the Department of Health and Human Services (HHS) to identify and publish healthcare quality measures for children enrolled in the Children's Health Insurance Program (CHIP) or Medicaid. CHIPRA also requires core measures to identify disparities by race and ethnicity, among other factors. State Medicaid and CHIP programs are currently facing significant budgetary pressures that are likely to increase with eligibility expansions and programmatic changes resulting from the Patient Protection and Affordable Care Act (PPACA). To limit the burden on states and increase the likelihood of states' voluntarily reporting on core pediatric quality measures, HHS may consider utilizing existing data sources. This article examines the feasibility of utilizing Medicaid Statistical Information System (MSIS) data to identify and analyze the core children's healthcare quality measures required by CHIPRA. Five key themes related to the feasibility of using MSIS as a data source for quality measures are identified: states have significant experience with data collection, performance measurement, and quality oversight for children in Medicaid and CHIP; CHIPRA provisions related to reporting of quality measures will be implemented at a time when states are facing major fiscal constraints; MSIS provides potential opportunities as it offers a rich source of data, but the difficulties in obtaining clean data should not be underestimated; MSIS has limitations; and states, the federal government, providers, and enrollees benefit from standardization in data and quality measurement.


Complex transient dynamics of stage-structured populations in response to environmental changes.
Stage structures of populations can have a profound influence on their dynamics. However, not much is known about the transient dynamics that follow a disturbance in such systems. Here we combined chemostat experiments with dynamical modeling to study the response of the phytoplankton species Chlorella vulgaris to press perturbations. From an initially stable steady state, we altered either the concentration or dilution rate of a growth-limiting resource. This disturbance induced a complex transient response-characterized by the possible onset of oscillations-before population numbers relaxed to a new steady state. Thus, cell numbers could initially change in the opposite direction of the long-term change. We present quantitative indexes to characterize the transients and to show that the dynamic response is dependent on the degree of synchronization among life stages, which itself depends on the state of the population before perturbation. That is, we show how identical future steady states can be approached via different transients depending on the initial population structure. Our experimental results are supported by a size-structured model that accounts for interplay between cell-cycle and population-level processes and that includes resource-dependent variability in cell size. Our results should be relevant to other populations with a stage structure including organisms of higher order.


Transcranial direct current stimulation of default mode network parietal nodes decreases negative mind-wandering about the past.
Mind-wandering is a cognitive process in which people spontaneously have thoughts that are unrelated to their current activities. The types of mind-wandering thoughts that people have when affected by a negative mood resemble thoughts associated with mood disorders (e.g., negative thoughts about the past). Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that can modulate cognition and affect in healthy and clinical populations. Ninety participants received either excitatory, inhibitory, or sham tDCS to bilateral inferior parietal lobe (IPL) nodes of the default mode network (DMN) to assess changes in maladaptive mind-wandering following criticism. tDCS did not change mind-wandering frequency after hearing criticism, but it did change what people mind-wandered about. Specifically, cathodal stimulation decreased the frequency of negative mind-wandering thoughts about the past. Future studies could investigate tDCS of DMN regions as an intervention for patients with mood disorders who suffer from negative, past-oriented cognitions.


Phosphorylation of CLASP2 by GSK-3beta regulates its interaction with IQGAP1, EB1 and microtubules.
Polarised cell migration is required for various cell behaviours and functions. Actin and microtubules are coupled structurally and distributed asymmetrically along the front-rear axis of migrating cells. CLIP-associating proteins (CLASPs) accumulate near the ends of microtubules at the front of migrating cells to control microtubule dynamics and cytoskeletal coupling. Regional inhibition of GSK-3beta is responsible for this asymmetric distribution of CLASPs. However, it is not known how GSK-3beta regulates the activity of CLASPs for linkage between actin and microtubules. Here we identified IQGAP1, an actin-binding protein, as a novel CLASP-binding protein. GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules. At the leading edges of migrating fibroblasts, CLASP2 near microtubule ends partially colocalises with IQGAP1. Expression of active GSK-3beta abrogates the distribution of CLASP2 on microtubules, but not that of a nonphosphorylatable CLASP2 mutant. The phosphorylated CLASP2 does not accumulate near the ends of microtubules at the leading edges. Thus, phosphorylation of CLASP2 by GSK-3beta appears to control the regional linkage of microtubules to actin filaments through IQGAP1 for cell migration.


Evidence for oxidative stress in sugar maple stands growing on acidic, nutrient imbalanced forest soils.
Soil acidification and the disruption of nutrient cycles appear to be important factors that weaken sugar maple resistance to both abiotic and biotic stresses and predispose it to decline symptoms. Although connections between edaphic stress and decline symptoms have been identified, very little is known about the physiological and biochemical mechanisms that underlie this relationship. In this study, we tested the hypothesis that foliar nutrient imbalances impair the photosynthetic apparatus of sugar maple through oxidative stress. We examined leaf nutrition, photosynthesis and antioxidant enzyme activity (a biomarker of oxidative stress) from early June to late August in three-paired overstory sugar maple stands on Pennsylvania's Allegheny Plateau that contrast in soil nutrient availability according to slope position. Beginning in early June, trees on upper slopes (nutrient-poor) had significantly lower foliar Ca and Mg concentrations and significantly higher foliar Mn concentrations than trees on lower slopes. These differences increased throughout summer peaking in late August. Photosynthesis and antioxidant enzyme activity closely reflected changes in foliar nutrient status throughout the summer. In the latter half of the summer, leaf gas exchange and chlorophyll content were significantly lower and antioxidant enzyme activity was significantly higher in stands on upper slope soils. At the end of August, leaf nutrient imbalances corresponded with lower rates of photosynthesis and higher antioxidant enzyme activity, suggesting that foliar nutrient imbalances may impair sugar maple function through mechanisms of oxidative stress.


Exposure of C. elegans eggs to a glyphosate-containing herbicide leads to abnormal neuronal morphology.
Recent data demonstrate that chronic exposure of Caenorhabditis elegans (C. elegans) to a high-use glyphosate-containing herbicide, Touchdown (TD), potentially damages the adult nervous system. It is unknown, however, whether unhatched worms exposed to TD during the egg stage show abnormal neurodevelopment post-hatching. Therefore, we investigated whether early treatment with TD leads to aberrant neuronal or neurite development in C. elegans. Studies were completed in three different worm strains with green fluorescent protein (GFP)-tagged neurons to facilitate visual neuronal assessment. Initially, eggs from C. elegans with all neurons tagged with GFP were chronically exposed to TD. Visual inspection suggested decreased neurite projections associated with ventral nerve cord neurons. Data analysis showed a statistically significant decrease in overall green pixel numbers at the fourth larval (L4) stage (*p<0.05). We further investigated whether specific neuronal populations were preferentially vulnerable to TD by treating eggs from worms that had all dopaminergic (DAergic) or γ-aminobutyric acid (GABAergic) neurons tagged with GFP. As before, green pixel number associated with these discrete neuronal populations was analyzed at multiple larval stages. Data analysis indicated statistically significant decreases in pixel number associated with DAergic, but not GABAergic, neurons (***p<0.001) at all larval stages. Finally, statistically significant decreases (at the first larval stage, L1) or increases (at the fourth larval stage, L4) in superoxide levels, a developmental signaling molecule, were detected (*p<0.05). These data suggest that early exposure to TD may impair neuronal development, perhaps through superoxide perturbation. Since toxic insults during development may late render individuals more vulnerable to neurodegenerative diseases in adulthood, these studies provide some of the first evidence in this model organism that early exposure to TD may adversely affect the developing nervous system.


A label-free aptasensor FET based on Au nanoparticle decorated Co3O4 nanorods and a SWCNT layer for detection of cardiac troponin T protein.
Acute myocardial infarction (AMI) is a serious health problem that must be identified in its early stages. Considerable progress has been made in understanding the condition of AMI through ascertaining the role of biomarkers, such as myoglobin, cardiac troponin proteins (T and I), creatine kinase-MB, and fatty acid-binding protein (FABP). A field-effect transistor (FET) is an effective platform; however, innovations are required in all layers of the FET for it to become robust and highly sensitive. For the first time, we made use of the synergistic combination of noble metal nanoparticles (AuNPs) with Co3O4 for the detection of cardiac troponin T (cTnT) in a FET platform. We determined the morphology of Au-decorated Co3O4 NRs and their electronic properties by characterizing the channel layer using electron microscopies and transient measurements. Subsequently, we performed the detection of cardiac troponin T by immobilizing its complementary biotinylated DNA aptamer on the channel surface using a drop-casting method. To understand the changes in drain current caused by this interaction, we probed our SWCNT-Co3O4 NR transistor with limited gate and drain bias (≤1 V), achieving a sensitivity of 0.5 μA μg-1 mL-1 for the Au-decorated NRs. A 250% increase in the sensitivity and a limit of detection (LOD) of 0.1 μg mL-1 were achieved by using this device. Finally, selectivity studies proved that this synergistic combination works well in the FET configuration for the successful detection of cTnT.


Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient.
Four percent of human severe combined immunodeficiency cases are caused by a deficiency of the enzyme purine nucleoside phosphorylase (PNP). In this study we investigated the molecular basis for this rare autosomal recessive disease. Sequence analyses led to the identification of two new mutations in the PNP gene: an A to G transition in exon 5, which leads to the substitution of tyrosine 192 by a cysteine residue, and a 1-bp deletion in exon 6, which causes premature translation termination of the PNP protein. Both PNP mutations affect predicted major structural motifs of the protein and result in post-translation instability of the enzyme.


Sampling strategies for tissue microarrays to evaluate biomarkers in ovarian cancer.
Tissue microarrays (TMA) enable rapid analysis of biomarkers in large-scale studies involving archival tumor specimens, however, their utility in heterogeneous tumors such as ovarian cancer is limited. In this study, immunohistochemical analysis was done on TMAs comprised of epithelial ovarian cancer (EOC) to estimate the prevalence of loss of expression of three mismatch repair proteins. TMAs were initially created using cores sampled from the center of donor tissue blocks from 59 EOC cases. Full sections were subsequently created and levels of expression were compared between tissues sampled from the central portion versus the periphery. Follow-up analyses were done by obtaining cores from the periphery of up to five additional donor blocks per case. A linear mixed model for each protein was used to investigate differences between results from the initial and follow-up blocks. In the original TMAs created using centrally sampled cores, loss of mismatch repair expression was noted in 17 (29%) of the 59 cases. By comparison, analyses from peripherally sampled cores revealed loss of expression in only 6 of these 17 cases. For each protein, significant differences (P < 0.05) were detected between results from the initial donor block and the majority of the follow-up blocks. Our investigations, based on EOC, suggest that sampling variability in protein expression may result when TMAs are used. Thus, at least for EOC, it is important to preferentially sample from the periphery of tumor blocks where exposure to tissue fixatives is optimal.


Claims-Based Diagnostic Patterns of Patients Evaluated for Lyme Disease and Given Extended Antibiotic Therapy.
A Lyme disease (LD) diagnosis can be far from straightforward, particularly if erythema migrans does not develop or is not noticed. Extended courses of antibiotics for LD are not recommended, but their use is increasing. We sought to elucidate the patient patterns toward a diagnosis of LD, hypothesizing that a subset of patients ultimately receiving extended courses antibiotics may be symptomatic for an extended period before the first LD diagnosis. Claims submitted to a nationwide U.S. health insurance plan in 14 high-prevalence states were grouped into standardized diagnostic categories. The patterns of diagnostic categories over time were compared between patients evaluated for LD and given standard antibiotic therapy (PLDSA) and patients evaluated for LD and given extended antibiotic therapy (PLDEA) in 2011-2012. The incidence of PLDSA was 40.45 (N = 3207) and that of PLDEA was 7.57 (N = 600) per 100,000 insured over 2011-2012. 50.3% of PLDEA were diagnosed in the nonsummer months. Seven diagnostic categories were associated with PLDEA. From 180 days before the first LD diagnosis, the risks of having claims associated with back problems (odds ratio [OR], 2.1; confidence interval [95% CI], 1.4-2.9; p < 0.001) and connective tissue disease (OR, 1.6; 95% CI, 1.1-2.3; p < 0.01) complaints were higher among PLDEA. From 90 days before the diagnosis, malaise and fatigue (OR, 1.7; 95% CI, 1.1-2.6; p < 0.05), other nervous system disorders (OR, 2.0; 95% CI, 1.3-3.1; p < 0.01), and nontraumatic joint disorder (OR, 1.4; 95% CI, 1.0-2.0; p < 0.05) were more likely found among PLDEA than PLDSA. From 30 days before the diagnosis, the risk for mental health (OR 1.6; 95% CI, 1.1-2.0; p < 0.01) and headache (OR 1.5; 95% CI, 1.1-2.0; p < 0.05) among PLDEA was elevated. Among patients evaluated for LD and ultimately receiving an extended course of antibiotics for LD, 15.8% of them were symptomatic and seeking care for several months before their first LD diagnosis.


Symptom Clusters in People Living with HIV Attending Five Palliative Care Facilities in Two Sub-Saharan African Countries: A Hierarchical Cluster Analysis.
Symptom research across conditions has historically focused on single symptoms, and the burden of multiple symptoms and their interactions has been relatively neglected especially in people living with HIV. Symptom cluster studies are required to set priorities in treatment planning, and to lessen the total symptom burden. This study aimed to identify and compare symptom clusters among people living with HIV attending five palliative care facilities in two sub-Saharan African countries. Data from cross-sectional self-report of seven-day symptom prevalence on the 32-item Memorial Symptom Assessment Scale-Short Form were used. A hierarchical cluster analysis was conducted using Ward's method applying squared Euclidean Distance as the similarity measure to determine the clusters. Contingency tables, X2 tests and ANOVA were used to compare the clusters by patient specific characteristics and distress scores. Among the sample (N=217) the mean age was 36.5 (SD 9.0), 73.2% were female, and 49.1% were on antiretroviral therapy (ART). The cluster analysis produced five symptom clusters identified as: 1) dermatological; 2) generalised anxiety and elimination; 3) social and image; 4) persistently present; and 5) a gastrointestinal-related symptom cluster. The patients in the first three symptom clusters reported the highest physical and psychological distress scores. Patient characteristics varied significantly across the five clusters by functional status (worst functional physical status in cluster one, p<0.001); being on ART (highest proportions for clusters two and three, p=0.012); global distress (F=26.8, p<0.001), physical distress (F=36.3, p<0.001) and psychological distress subscale (F=21.8, p<0.001) (all subscales worst for cluster one, best for cluster four). The greatest burden is associated with cluster one, and should be prioritised in clinical management. Further symptom cluster research in people living with HIV with longitudinally collected symptom data to test cluster stability and identify common symptom trajectories is recommended.


Mechanical modulation of the transverse tubular system of ventricular cardiomyocytes.
In most mammalian cardiomyocytes, the transverse tubular system (t-system) is a major site for electrical signaling and excitation-contraction coupling. The t-system consists of membrane invaginations, which are decorated with various proteins involved in excitation-contraction coupling and mechano-electric feedback. Remodeling of the t-system has been reported for cells in culture and various types of heart disease. In this paper, we provide insights into effects of mechanical strain on the t-system in rabbit left ventricular myocytes. Based on fluorescent labeling, three-dimensional scanning confocal microscopy, and digital image analysis, we studied living and fixed isolated cells in different strain conditions. We extracted geometric features of transverse tubules (t-tubules) and characterized their arrangement with respect to the Z-disk. In addition, we studied the t-system in cells from hearts fixed either at zero left ventricular pressure (slack), at 30 mmHg (volume overload), or during lithium-induced contracture, using transmission electron microscopy. Two-dimensional image analysis was used to extract features of t-tubule cross-sections. Our analyses of confocal microscopic images showed that contracture at the cellular level causes deformation of the t-system, increasing the length and volume of t-tubules, and altering their cross-sectional shape. TEM data reconfirmed the presence of mechanically induced changes in t-tubular cross sections. In summary, our studies suggest that passive longitudinal stretching and active contraction of ventricular cardiomyocytes affect the geometry of t-tubules. This confirms that mechanical changes at cellular levels could promote alterations in partial volumes that would support a convection-assisted mode of exchange between the t-system content and extracellular space.


Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness.
Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome.


Inhibition of the met receptor in mesothelioma.
Expression of the Met receptor and its ligand, hepatocyte growth factor (HGF), has been observed in 74% to 100% and 40% to 85% of malignant pleural mesothelioma (MPM) specimens, respectively. HGF stimulation has been shown to enhance MPM cell proliferation, migration, cell scattering, and invasiveness. To investigate a potential therapeutic role for the Met receptor in MPM, we examined the effects of PHA-665752, a specific small-molecule inhibitor of the Met receptor tyrosine kinase, in a panel of 10 MPM cell lines. Two of the cell lines, H2461 and JMN-1B, exhibited autocrine HGF production as measured by ELISA (3.9 and 10.5 ng/mL, respectively, versus <0.05 ng/mL in other cell lines). Evaluation of PHA-665752 across the 10 MPM cell lines indicated that despite Met expression in all cell lines, only in cell lines that exhibited a Met/HGF autocrine loop, H2461 and JMN-1B, did PHA-665752 inhibit growth with an IC(50) of 1 and 2 micromol/L, respectively. No activating mutations in Met were detected in any of the cell lines. Consistent with observed growth inhibition, PHA-665752 caused cell cycle arrest at G(1)-S boundary accompanied by a dose-dependent decrease in phosphorylation of Met, p70S6K, Akt, and extracellular signal-regulated kinase 1/2. Growth of H2461 cells was also inhibited by neutralizing antibodies to HGF and by RNA interference knockdown of the Met receptor, confirming that growth inhibition observed was through a Met-dependent mechanism. PHA-665752 also reduced MPM in vitro cell migration and invasion. Taken together, these findings suggest that inhibition of the Met receptor may be an effective therapeutic strategy for patients with MPM and provides a mechanism, the presence of a HGF/Met autocrine loop, by which to select patients for PHA-665752 treatment.


Quantitative genetics of cranial nonmetric traits in randombred mice: heritability and etiology.
Cheverud and Buikstra (1981) demonstrated a tendency for nonmetric traits representing the number of foramina to have lower heritabilities than those representing hyperstotic or hypostotic traits in a sample of rhesus macaques. Based on this observation, Cheverud and Buikstra hypothesize that differences in the heritability of the two sets of traits may be due to differences in trait etiology. This study addresses the proposed relationship between trait heritability and etiology. Heritability values are calculated for 35 cranial nonmetric traits in a sample of 320 randombred mice using analysis of variance. The results are minimally consistent with the etiological hypothesis, but only 4 of the 35 traits showed statistically significant heritability values. These results are discussed with reference to the assumption that nonmetric traits have a strong genetic component. It is concluded that the developmental pathways that genetic variation traverses before being expressed in the form of nonmetric traits must be understood before variation in nonmetric traits can be used to its fullest potential.


Heterogeneity in susceptible-infected-removed (SIR) epidemics on lattices.
The percolation paradigm is widely used in spatially explicit epidemic models where disease spreads between neighbouring hosts. It has been successful in identifying epidemic thresholds for invasion, separating non-invasive regimes, where the disease never invades the system, from invasive regimes where the probability of invasion is positive. However, its power is mainly limited to homogeneous systems. When heterogeneity (environmental stochasticity) is introduced, the value of the epidemic threshold is, in general, not predictable without numerical simulations. Here, we analyse the role of heterogeneity in a stochastic susceptible-infected-removed epidemic model on a two-dimensional lattice. In the homogeneous case, equivalent to bond percolation, the probability of invasion is controlled by a single parameter, the transmissibility of the pathogen between neighbouring hosts. In the heterogeneous model, the transmissibility becomes a random variable drawn from a probability distribution. We investigate how heterogeneity in transmissibility influences the value of the invasion threshold, and find that the resilience of the system to invasion can be suitably described by two control parameters, the mean and variance of the transmissibility. We analyse a two-dimensional phase diagram, where the threshold is represented by a phase boundary separating an invasive regime in the high-mean, low-variance region from a non-invasive regime in the low-mean, high-variance region of the parameter space. We thus show that the percolation paradigm can be extended to the heterogeneous case. Our results have practical implications for the analysis of disease control strategies in realistic heterogeneous epidemic systems.


Physiotherapy in upper abdominal surgery - what is current practice in Australia?
Upper abdominal surgery (UAS) has the potential to cause post-operative pulmonary complications (PPCs). In the absence of high-quality research regarding post-operative physiotherapy management, consensus-based best practice guidelines formulated by Hanekom et al. (2012) are available to clinicians providing recommendations for post-UAS treatment. Such best practice guidelines have recommended that physiotherapists should be using early mobilisation and respiratory intervention to minimise risk of PPCs. However, recent evidence supports the implementation of mobilisation as a standalone treatment in PPC prevention, though the diversity in literature poses questions regarding ideal current practice. This project aimed to document and report the assessment measures and interventions physiotherapists are utilising following UAS, establishing whether current management is reflective of best practice guidelines and recent evidence. An online survey was completed by 57 experienced Australian physiotherapists working with patients following UAS (35% survey response rate, 63% completion rate). On day one following UAS, when a patient's condition is not medically limited, most physiotherapists routinely mobilise. Additionally, routine chest treatment continues to be implemented, with only 23% (n = 11/47) of physiotherapists mobilising patients without accompanying specific respiratory intervention. Variability of screening tools used to identify post-operative patients at high risk of PPC development was evident. Patient-dependent factors such as 'fatigue' and 'non-compliance' were among those identified as barriers to treatment, all influencing the commencement of treatment. Physiotherapists indicated that early mobilisation away from the bedside was the preferred post-operative treatment within the UAS patient population. Many continue to perform routine respiratory interventions despite recent literature suggesting it may provide no additional benefit to preventing PPCs. Current intervention choice is reflective of guidelines [1], however, recent literature has called this into question and more research needs to be done to establish if these recommendations are the most effective at reducing PPCs. Continued research is necessary to promote translation of knowledge to ensure physiotherapists are mobilising patients day one post-UAS. Likewise, future work should focus on identification of barriers, the strategies used to overcome limitations and the creation of a reliable and validated screening tool to ensure appropriate prioritisation and allocation of physiotherapy resources within the UAS patient population.


Suicide prevention strategies revisited: 10-year systematic review.
Many countries are developing suicide prevention strategies for which up-to-date, high-quality evidence is required. We present updated evidence for the effectiveness of suicide prevention interventions since 2005. We searched PubMed and the Cochrane Library using multiple terms related to suicide prevention for studies published between Jan 1, 2005, and Dec 31, 2014. We assessed seven interventions: public and physician education, media strategies, screening, restricting access to suicide means, treatments, and internet or hotline support. Data were extracted on primary outcomes of interest, namely suicidal behaviour (suicide, attempt, or ideation), and intermediate or secondary outcomes (treatment-seeking, identification of at-risk individuals, antidepressant prescription or use rates, or referrals). 18 suicide prevention experts from 13 European countries reviewed all articles and rated the strength of evidence using the Oxford criteria. Because the heterogeneity of populations and methodology did not permit formal meta-analysis, we present a narrative analysis. We identified 1797 studies, including 23 systematic reviews, 12 meta-analyses, 40 randomised controlled trials (RCTs), 67 cohort trials, and 22 ecological or population-based investigations. Evidence for restricting access to lethal means in prevention of suicide has strengthened since 2005, especially with regard to control of analgesics (overall decrease of 43% since 2005) and hot-spots for suicide by jumping (reduction of 86% since 2005, 79% to 91%). School-based awareness programmes have been shown to reduce suicide attempts (odds ratio [OR] 0·45, 95% CI 0·24-0·85; p=0·014) and suicidal ideation (0·5, 0·27-0·92; p=0·025). The anti-suicidal effects of clozapine and lithium have been substantiated, but might be less specific than previously thought. Effective pharmacological and psychological treatments of depression are important in prevention. Insufficient evidence exists to assess the possible benefits for suicide prevention of screening in primary care, in general public education and media guidelines. Other approaches that need further investigation include gatekeeper training, education of physicians, and internet and helpline support. The paucity of RCTs is a major limitation in the evaluation of preventive interventions. In the quest for effective suicide prevention initiatives, no single strategy clearly stands above the others. Combinations of evidence-based strategies at the individual level and the population level should be assessed with robust research designs. The Expert Platform on Mental Health, Focus on Depression, and the European College of Neuropsychopharmacology.


Resolution improvement of integral imaging based on time multiplexing sub-pixel coding method on common display panel.
Considering the limited pixel number and large pixel size of common display panel, the captured elemental images (EIs) array of high density pixels cannot be reconstructed sufficiently in the display process of integral imaging, because of matched display requirement. To solve this problem, this paper presents a novel approach to improve integral imaging resolution by designing a coded sub-pixel mask on common display panel. Specifically, multi-pixels in the captured EIs are displayed in a pixel in the common display panel with time multiplexing along with the corresponding aperture switched on/off of the coded sub-pixel mask periodically, in which the resolution of the reconstructed image is determined by the coded aperture size of the sub-pixel mask rather than the pixel size of the display panel. Then, the mapping relationship between the displayed pixel and the position of the switched on aperture of the coded sub-pixel mask is established theoretically. Computational reconstruction and optical experimental results show that this method can match the pixel number of the captured EIs with that of the display panel and the resolution of integral imaging can be improved significantly.


Metabolic risk factors, genetic predisposition, and risk of severe liver disease in Chinese: a prospective study of 0.5 million people.
Metabolic risk factors have been shown to be associated with severe liver disease (SLD) in Chinese populations. However, there is limited evidence on the combined impact of these factors, or the genetic variants associated with SLD. We examined the associations of combined metabolic risk factors with risks of SLD, both overall and by genetic predisposition to SLD. The study population involved 486,828 participants of the prospective China Kadoorie Biobank aged 30-79 years from 10 diverse areas in China without a history of cancer or liver disease at baseline. Cox regression was used to estimate adjusted HRs for SLD associated with combined metabolic risk factors (central adiposity, physical inactivity, and diabetes) by stratum of genetic risk [assessed separately by a PNPLA3 variant (rs738409) and a BMI genetic risk score]. During ∼10 years of follow-up, 3279 incident cases of SLD were recorded. The overall mean BMI was 23.8 kg/m2 (SD, 3.4 kg/m2), and 5.9% participants had diabetes. Compared with those with 3 metabolic factors, participants with 2, 1, and 0 metabolic factors had 31% (HR, 0.69; 95% CI: 0.65-0.73), 43% (HR, 0.57; 95% CI: 0.53-0.60), and 52% (HR, 0.48; 95% CI: 0.42-0.56) lower risks of SLD, respectively. For both BMI and nonalcoholic fatty liver disease variants, participants with fewer metabolic factors had a lower risk of SLD, lower levels of gamma-glutamyl transferase, and lower fatty liver index scores, in participants with low and high genetic risks (P value for interaction > 0.05). In relatively lean Chinese adults, individuals with fewer metabolic risk factors had a lower relative risk of SLD and a more favorable profile of liver biomarkers across all strata of genetic risk.


Evidence for an active inflammatory process in the hibernating human myocardium.
Myocardial hibernation refers to a state of prolonged impairment of left ventricular function in the presence of coronary artery disease, which may be reversed by revascularization. In this study we present evidence for a local inflammatory reaction in hibernating myocardial segments from patients undergoing coronary revascularization. We obtained transmural myocardial biopsies guided by transesophageal echocardiography from patients with ischemic ventricular dysfunction undergoing bypass surgery. Among the 28 biopsied segments included in the study, 23 showed evidence of systolic dysfunction. The majority of dysfunctional segments (85.7%) were viable ((201)Tl uptake >/= 60%). The samples were stained with markers for mast cells, mature resident macrophages, and the monoclonal antibody Mac387 that labels newly recruited myeloid cells. Dysfunctional segments showed more extensive fibrosis and higher macrophage density than normal segments. Among the 23 dysfunctional segments, 12 recovered function as assessed with echocardiograms 3 months after revascularization. Segments with postoperative functional recovery had comparable macrophage and mast cell density with those showing persistent dysfunction. However, biopsied segments that subsequently recovered function contained significantly higher numbers of newly recruited Mac387-positive leukocytes (18.7 +/- 3.1 cells/mm(2), n = 12 versus 8.6 +/- 0.9 cells/mm(2), n = 11; P = 0.009). In addition, monocyte chemotactic protein-1, a potent mononuclear cell chemoattractant, was predominantly expressed in segments with recovery of function. Myocardial hibernation is associated with an inflammatory response leading to active leukocyte recruitment. Dysfunctional myocardial segments that show an active inflammatory reaction have a greater potential for recovery of function after revascularization. We postulate that revascularization may promote resolution of the ongoing inflammation, preventing further tissue injury and fibrosis.


An international multi-site, randomized controlled trial of a mindfulness-based psychoeducation group programme for people with schizophrenia.
We aimed to test a mindfulness-based psychoeducation group (MBPEG), v. a conventional psychoeducation group (CPEG) v. treatment as usual (TAU), in patients with schizophrenia-spectrum disorders over a 24-month follow-up. This single-blind, multi-site, pragmatic randomized controlled trial was conducted in six community treatment facilities across three countries (Hong Kong, mainland China and Taiwan). Patients were randomly allocated to one of the treatment conditions, and underwent 6 months of treatment. The primary outcomes were changes in duration of re-hospitalizations and mental state (Positive and Negative Syndrome Scale; PANSS) between baseline and 1 week, and 6, 12 and 18 months post-treatment. A total of 300 patients in each country were assessed for eligibility between October 2013 and 30 April 2014, 38 patients per country (n = 342) were assigned to each treatment group and included in the intention-to-treat analysis. There was a significant difference in the length of re-hospitalizations between the three groups over 24 months (F 2,330 = 5.23, p = 0.005), with MBPEG participants having a shorter mean duration of re-hospitalizations than those in the other groups. The MBPEG and CPEG participants had significant differential changes in proportional odds ratios of complete remission (all individual PANSS items <3) over the 24-month follow-up (37 and 26%, respectively), as opposed to only 7.2% of the TAU group (χ2 = 8.9 and 8.0, p = 0.001 and 0.003, relative risk = 3.5 and 3.1, 95% confidence interval 2.0-7.2 and 1.6-6.3). Compared with TAU and CPEG, MBPEG improves remission and hospitalization rates of people with schizophrenia spectrum disorders over 24 months.


Membrane Association Landscape of Myelin Basic Protein Portrays Formation of the Myelin Major Dense Line.
Compact myelin comprises most of the dry weight of myelin, and its insulative nature is the basis for saltatory conduction of nerve impulses. The major dense line (MDL) is a 3-nm compartment between two cytoplasmic leaflets of stacked myelin membranes, mostly occupied by a myelin basic protein (MBP) phase. MBP is an abundant myelin protein involved in demyelinating diseases, such as multiple sclerosis. The association of MBP with lipid membranes has been studied for decades, but the MBP-driven formation of the MDL remains elusive at the biomolecular level. We employed complementary biophysical methods, including atomic force microscopy, cryo-electron microscopy, and neutron scattering, to investigate the formation of membrane stacks all the way from MBP binding onto a single membrane leaflet to the organisation of a stable MDL. Our results support the formation of an amorphous protein phase of MBP between two membrane bilayers and provide a molecular model for MDL formation during myelination, which is of importance when understanding myelin assembly and demyelinating conditions.


Analysis of 100 high-coverage genomes from a pedigreed captive baboon colony.
Baboons (genus Papio) are broadly studied in the wild and in captivity. They are widely used as a nonhuman primate model for biomedical studies, and the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute has maintained a large captive baboon colony for more than 50 yr. Unlike other model organisms, however, the genomic resources for baboons are severely lacking. This has hindered the progress of studies using baboons as a model for basic biology or human disease. Here, we describe a data set of 100 high-coverage whole-genome sequences obtained from the mixed colony of olive (P. anubis) and yellow (P. cynocephalus) baboons housed at the SNPRC. These data provide a comprehensive catalog of common genetic variation in baboons, as well as a fine-scale genetic map. We show how the data can be used to learn about ancestry and admixture and to correct errors in the colony records. Finally, we investigated the consequences of inbreeding within the SNPRC colony and found clear evidence for increased rates of infant mortality and increased homozygosity of putatively deleterious alleles in inbred individuals.


Effects of skin contactants on evolution of atopic dermatitis in children: a case control study.
There is little published literature on the effects of skin contactants during early infancy on eventual development of atopic dermatitis (AD). The purpose of this study was to determine whether or not a relationship exists between the use of skin care products in early infancy and the subsequent development of AD. We studied a group of 54 Kenyan children with AD and 63 age and sex matched controls. Emollients had been used to lubricate the skin during early infancy in a similar proportion of children in both groups (odds ratio = 0.33; 95% CI = 0.14, 0.80). Similarly, no association was found between the use of toilet soaps or laundry detergents in early infancy and development of AD. These findings suggest that baby soaps and vaseline petroleum jelly can safely be used in the skin care of AD susceptible individuals.


Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society.
Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality. To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer. The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screening method for women at average risk. The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation). Women aged 45 to 54 years should be screened annually (qualified recommendation). Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation). Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation). Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation). These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening.


Activity positioning and ischial tuberosity pressure: a pilot study.
Ipsilateral ischial tuberosity pressure of 12 subjects seated in wheelchairs was measured during reach to an activity positioned on both an upright and a flat plane. Ischial tuberosity pressure during cross-body, forward, and lateral reach was measured with a static pressure measurement device. Differences between flat-plane readings and upright-plane readings were analyzed with a t test; no significant difference was obtained. A repeated-measures analysis of variance revealed significant differences in ischial tuberosity pressure between cross-body, forward, and lateral reach in the flat plane activity. However, no significant difference was found between cross-body, forward, and lateral reach in the upright-plane activity. Results of this study support the theory that forward and lateral positioning of activity can supplement standard techniques for relieving pressure.


Food allergy: when and how to perform oral food challenges.
In many situations, the diagnosis of food allergy rests simply upon a history of an acute onset of typical symptoms, such as hives and wheezing, following the isolated ingestion of a suspected food, with confirmatory laboratory studies of positive prick skin tests or Radioallergosorbent tests. However, the diagnosis is more complicated when multiple foods are implicated or when chronic diseases, such as asthma or atopic dermatitis, are evaluated. The diagnosis of food allergy and identification of the particular foods responsible is also more difficult when reactions are not mediated by IgE antibody, as is the case with a number of gastrointestinal food allergies. In these latter circumstances, well-devised elimination diets followed by physician-supervised oral food challenges are critical in the identification and proper treatment of these disorders. Because childhood food allergies to common allergenic foods such as milk, egg, wheat and soy are usually outgrown, oral food challenges are also an integral part of the long-term management of these children.


Responses of aerial insectivorous bats to local and landscape-level features of coffee agroforestry systems in Western Ghats, India.
Shade coffee has shown great promise in providing crucial habitats for biodiversity outside formal protected areas. Insectivorous bats have been understudied in coffee, although they may provide pest control services. We investigated the influence of local and landscape-level features of coffee farms on aerial insectivorous bats in Chikmagalur district in the Western Ghats biodiversity hotspot, India. Bats were monitored in 20 farm sites using ultrasound detectors, and the response of bat species richness and activity to changes in tree density, proportion of built-up area in the neighborhood, and distance of farm from forest areas quantified. We examined if models built to explain the species richness and activity could also predict them in nine additional sites. We detected nine phonic types/species in the study area. The quantified predictors had no effect on assemblage-level species richness and activity of bats. Responses of edge-space and cluttered-space forager guilds mirrored those of the overall assemblage, but some species vulnerable to forest conversion like Rhinolophus beddomei were detected rarely. Best models explained up to 20% and 15% variation in assemblage-level species richness and activity respectively, and were poor predictors of both response variables. We conclude that coffee farms in our study area offer an important commuting space for insectivorous bats across a gradient of shade management. Further research should include species-specific responses to management decisions for at-risk species and quantification of ecosystem services like natural pest control to inform biodiversity conservation initiatives in the Western Ghats coffee landscapes.