No Evidence for a Relationship Between Hair Testosterone Concentrations and 2D:4D Ratio or Risk Taking.
Using a recently developed alternative assay procedure to measure hormone levels from hair samples, we examined the relationships between testosterone, cortisol, 2D:4D ratio, overconfidence and risk taking. A total of 162 (53 male) participants provided a 3 cm sample of hair, a scanned image of their right and left hands from which we determined 2D:4D ratios, and completed measures of overconfidence and behavioral risk taking. While our sample size for males was less than ideal, our results revealed no evidence for a relationship between hair testosterone concentrations, 2D:4D ratios and risk taking. No relationships with overconfidence emerged. Partially consistent with the Dual Hormone Hypothesis, we did find evidence for the interacting effect of testosterone and cortisol on risk taking but only in men. Hair testosterone concentrations were positively related to risk taking when levels of hair cortisol concentrations were low, in men. Our results lend support to the suggestion that endogenous testosterone and 2D:4D ratio are unrelated and might then exert diverging activating vs. organizing effects on behavior. Comparing our results to those reported in the existing literature we speculate that behavioral correlates of testosterone such as direct effects on risk taking may be more sensitive to state-based fluctuations than baseline levels of testosterone.


Chitosan oligosaccharides promote the content of polyphenols in Greek oregano (Origanum vulgare ssp. hirtum).
Greek oregano is commonly used as a spice and in traditional medicine in Eurasia. The plant is rich in secondary metabolites, such as volatile organic compounds (VOC) and polyphenols. Chitosan oligosaccharides (COS) are used as a plant elicitor. The objectives of this study were to determine the effects of COS on the growth and content of secondary metabolites in Greek oregano. Four COS treatments (50, 200, 500, and 1000 ppm) were used in a field experiment. The 200 and 500 ppm COS treatments promoted plant height growth, whereas 50 and 200 ppm COS upregulated the content of polyphenols significantly (38 and 29%, respectively). The COS treatments induced H(2)O(2) generation in Greek oregano leaves; thus, the effect of H(2)O(2) treatment was studied to investigate the possible role of H(2)O(2) in growth and polyphenol production. A low concentration of H(2)O(2) also promoted plant height growth, but only tendencies to higher polyphenol content were seen.


Increasing abundance of soil fungi is a driver for (15)N enrichment in soil profiles along a chronosequence undergoing isostatic rebound in northern Sweden.
Soil organic material (SOM) is usually enriched in (15)N in deeper soil layers. This has been explained by discrimination against the heavier isotope during decomposition or by the accumulation of (15)N-enriched microbial biomass versus plant biomass in older SOM. In particular, ectomycorrhizal (EM) fungi have been suggested to accumulate in old SOM since this group is among the most (15)N-enriched components of the microbial community. In the present study we investigated the microbial community in soil samples along a chronosequence (7,800 years) of sites undergoing isostatic rebound in northern Sweden. The composition of the microbial community was analyzed and related to the delta(15)N and delta(13)C isotope values of the SOM in soil profiles. A significant change in the composition of the microbial community was found during the first 2,000 years, and this was positively related to an increase in the delta(15)N values of the E and B horizons in the mineral soil. The proportion of fungal phospholipid fatty acids increased with time in the chronosequence and was positively related to the (15)N enrichment of the SOM. The increase in delta(13)C in the SOM was much less than the increase in delta(15)N, and delta(13)C values in the mineral soil were only weakly related to soil age. The C:N ratio and the pH of the soil were important factors determining the composition of the microbial community. We suggest that the N being transported from the soil to aboveground tissue by EM fungi is a driver for (15)N enrichment of soil profiles.


A bargaining experiment on heterogeneity and side deals in climate negotiations.
The recent global climate change agreement in Paris leaves a wide gap between pledged and requisite emissions reductions in keeping with the commonly accepted 2 °C target. A recent strand of theoretical and experimental evidence establishes pessimistic predictions concerning the ability of comprehensive global environmental agreements to improve upon the business-as-usual trajectory. We introduce an economic experiment focusing on the dynamics of the negotiation process by observing subjects' behavior in a Nash bargaining game. Throughout repeated rounds, heterogeneous players bargain over the allocation of a fixed amount of profit-generating emissions with significant losses attached to prolonged failure to reach agreement. We find that the existence of side agreements that constrain individual demands among a subset of like countries does not ensure success; however, such side agreements reduce the demands of high-emission parties. Our results highlight the importance of strong signals among high emitters in reaching agreement to shoulder a collective emission reduction target.


Novel preparation of transdermal drug-delivery patches and functional wound healing materials.
The application of an electric field to a flowing medium can result in the formation of microscale and nanoscale structures suitable for drug delivery applications. We show that the design of the drug carrier can be varied and the release mechanism can be controlled by changing the physical state of the component containing the active agent. The structures formed include loaded micrometer-scale tubes and microcapsules and nanocapsules, which can also be utilized together to fabricate patches and wound healing materials. The aim of this study was to demonstrate novel processing of such patches and wound dressings. The processing used to generate these structures is carried out at the ambient temperature and is a versatile one-step operation suitable for a range of materials with low running costs and set-up costs without the degradation of the active drug component. The process can be multiplexed and requires no solvent extraction. It also offers pharmaceutical applications outside the remit of the potential uses presented.


Atraumatic osteonecrosis of the talus.
Thirty-seven ankles in twenty-four patients were treated at our institution between July 1, 1974, and December 31, 1996, for atraumatic osteonecrosis of the talus. This group represents 2 per cent of the 1056 patients who were managed for osteonecrosis during this period. There were twenty-one women and three men, and their mean age was forty years (range, twenty-six to sixty-two years) at the time of the diagnosis. Thirteen (54 per cent) of the twenty-four patients had bilateral involvement. Sixteen patients (67 per cent) had a disease that affects the immune system, including systemic lupus erythematosus (thirteen patients), scleroderma (one), insulin-dependent diabetes mellitus (one), and multiple sclerosis (one). Four patients had a history of regular alcohol use, and four patients had a history of moderate smoking. One patient had a protein-S deficiency, one patient had had a renal transplant, and one patient had a history of asthma. Two patients had no identifiable risk factors for osteonecrosis [corrected]. Fifteen patients (63 per cent) had involvement of other large joints. The mean duration of symptoms before the patients were seen was 5.4 months (range, two months to two years). The mean ankle score at the time of presentation was 34 points (range, 2 to 75 points), according to the system of Mazur et al. A radiographic review revealed that, according to the system of Ficat and Arlet, eight ankles had stage-III or IV disease of the talus at presentation. The remaining twenty-nine ankles had stage-II disease. The osteonecrosis was seen in the posterolateral aspect of the talar dome (zones III and IV on the sagittal images and zones II, III, and IV on the coronal images) in twenty-two of the twenty-three ankles for which magnetic resonance images were available. The osteonecrosis was seen in the anteromedial aspect of the talar dome (zones I and II on the sagittal images and zone I on the coronal images) in the remaining ankle. Bone scans, which were available for eleven ankles, revealed increased uptake in the talus. All patients were initially managed non-operatively with restricted weight-bearing, an ankle-foot orthosis, and use of analgesics; two ankles responded to this regimen. Thirty-two ankles that remained severely symptomatic were treated with core decompression, which was useful in the treatment of precollapse (stage-II) disease. Twenty-nine of these ankles had a fair-to-excellent clinical outcome a mean of seven years (range, two to fifteen years) postoperatively; the remaining three ankles had an arthrodesis after the core decompression failed. Three ankles were treated initially with an arthrodesis for postcollapse (stage-III or IV) disease. All six of the ankles that had an arthrodesis fused, at a mean of seven months (range, five to nine months) postoperatively. When patients who have a history of osteonecrosis are seen because of pain in the ankle, the diagnosis of osteonecrosis of the talus should be considered. Early detection may allow the ankle to be treated non-operatively or with core decompression and thus reduce the need for arthrodesis. We also believe that when a patient has osteonecrosis of the talus, the hips should be screened with use of standard radiography or magnetic resonance imaging, or both.


The role of gender in scholarly authorship.
Gender disparities appear to be decreasing in academia according to a number of metrics, such as grant funding, hiring, acceptance at scholarly journals, and productivity, and it might be tempting to think that gender inequity will soon be a problem of the past. However, a large-scale analysis based on over eight million papers across the natural sciences, social sciences, and humanities reveals a number of understated and persistent ways in which gender inequities remain. For instance, even where raw publication counts seem to be equal between genders, close inspection reveals that, in certain fields, men predominate in the prestigious first and last author positions. Moreover, women are significantly underrepresented as authors of single-authored papers. Academics should be aware of the subtle ways that gender disparities can occur in scholarly authorship.


Efficacy of Combination of Esmolol and Diltiazem for Attenuating Hemodynamic Response to Laryngoscopy and Intubation: A Prospective Randomized Study.
Laryngoscopy and tracheal intubation (LTI) are known to release catecholamines resulting in rise in heart rate (HR) and blood pressure. Various drugs have been studied till date to attenuate the sympathomimetic effects of laryngoscopy and intubation. The aim is to study the effect and safety of esmolol, diltiazem, and their combination on pressor response of laryngoscopy and intubation. This prospective, randomized double-blind study was designed to assess the efficacy of the combination of esmolol and diltiazem and compare it with esmolol and diltiazem when used alone, for attenuating the pressor response to laryngoscopy and intubation. One hundred twenty-four adult patients of physical status American Society of Anesthesiologists Classes I and II posted for elective surgery under general anesthesia requiring endotracheal intubation were randomly allocated (using computer-generated random numbers) into four groups of 31 each, in a double-blind fashion, to receive the test drug, i.e., saline (control), diltiazem (0.2 mg/kg), esmolol (1.5 mg/kg), or a combination (diltiazem [0.1 mg/kg] and esmolol [0.75 mg/kg]). The test drug was administered intravenously as a bolus after 1 min of injecting the muscle relaxant. LTI was performed after 2 min of the test drug. Hemodynamic data - HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) - were recorded at 1 min intervals after induction, until laryngoscopy and intubation, and at 1, 2, 3, 4, 5, and 10 min thereafter. Statistical analysis was performed using one-way analysis of variance (ANOVA) for comparison among and between the groups. The Bonferroni's correction was applied when a significant difference was found between groups after applying ANOVA. Results were considered statistically significant at P ≤ 0.05. In the control and diltiazem groups, a significant increase in HR (P ≤ 0.05) was observed after laryngoscopy. Esmolol and combination groups were associated with a significant fall in HR after administration of the test drug, and no significant rise was noted after laryngoscopy. HR was significantly less in the combination and esmolol groups as compared to the control till 5 min after LTI. As compared with the control, all the other groups were associated with a fall in SBP after the test dose, and this lasted for 5 min (P < 0.001) after laryngoscopy in the esmolol and combination groups and for 1 min (P < 0.001) in the diltiazem group. All groups were associated with a significant rise in DBP and MAP for 1-2 min after LTI (P < 0.001), except the combination group in which no change was noted. DBP and MAP were significantly less in the combination group as compared to the control, from 1 min after giving the test dose till 5 min (P < 0.001) after LTI. Although esmolol and combination groups were both effective in controlling the increase in HR and SBP, only the combination group was effective in controlling the rise in DBP and MAP after LTI. HR, SBP, DBP, and MAP were significantly less in the combination group as compared to the control till 5 min after LTI. We recommend a combination of esmolol and diltiazem in appropriate doses for effectively attenuating the rise in HR and blood pressure responses during LTI.


Lupin protein positively affects plasma LDL cholesterol and LDL:HDL cholesterol ratio in hypercholesterolemic adults after four weeks of supplementation: a randomized, controlled crossover study.
A couple of studies indicate a favorable impact of lupin protein on cardiovascular risk factors in humans. These studies, however, used relatively high doses of > 33 g/d, which can hardly be consumed under physiological conditions. Therefore, we investigated the effect of 25 g/d lupin protein isolate (LPI) on selected cardiovascular markers and on serum amino acids. A total of 33 hypercholesterolemic subjects participated in a randomized, controlled, double-blind crossover study. LPI and the active comparator milk protein isolate (MPI) were incorporated in protein drinks and consumed over 8 wk separated by a 4 wk washout period. Anthropometric data, blood pressure, and nutrient intake were assessed at baseline and after 8 wk of both protein interventions. Blood was sampled at baseline, wk 4 and wk 8. All 33 subjects were included in final statistical analyses using repeated measures ANOVA with the general linear model or using linear mixed model. Except for higher HDL cholesterol at wk 4 of LPI (P ≤ 0.036), anthropometric parameters, blood pressure, and plasma lipids did not differ among LPI and MPI intervention. Compared to baseline, the primary outcome LDL cholesterol was significantly reduced after 4 wk of both interventions (P ≤ 0.008), while LDL:HDL cholesterol ratio was decreased only by LPI (P = 0.003). These time effects were restricted to subjects with higher hypercholesterolemia and disappeared after 8 wk. Blood pressure was reduced after 8 wk of LPI (P ≤ 0.044). Almost all serum amino acids were higher at wk 4 but not at wk 8 of MPI compared to LPI. Following 4 wk and 8 wk of LPI intervention, most amino acids remained unchanged. Both interventions caused a slight, but significant rise in body weight and body fat after 8 wk (P ≤ 0.045). In conclusion, 25 g LPI can beneficially modulate plasma LDL cholesterol at least over short-term. Using appropriate dietetic conditions that improve consumer compliance and avoid changes in energy intake as well as in body composition, lupin protein could positively impact cardiovascular risk factors particularly in individuals with higher hypercholesterolemia. ClinicalTrials.gov: NCT01304992.


Prognostic impact of lymphocytes in soft tissue sarcomas.
The purpose of this study was to clarify the prognostic significance of lymphocyte infiltration in soft tissue sarcomas (STS). Prognostic markers in potentially curable STS should guide therapy after surgical resection. The immune status at the time of resection may be important, but the prognostic significance of tumor infiltrating lymphocytes is controversial as the immune system has conflicting roles during cancer development. Tissue microarrays from 249 patients with STS were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. In univariate analyses, increased numbers of CD4+ (P = 0.008) and CD20+ (P = 0.006) lymphocytes in tumor correlated significantly with an improved disease-specific survival (DSS) in patients with wide resection margins (n = 108). In patients with non-wide resection margins (n = 141) increased numbers of CD3+ (P = 0.028) lymphocytes in tumor correlated significantly with shorter DSS. In multivariate analyses, a high number of CD20+ lymphocytes (HR = 5.5, CI 95% = 1.6-18.6, P = 0.006) in the tumor was an independent positive prognostic factor for DSS in patients with wide resections margins. High density of CD20+ lymphocytes in STS with wide resection margins is an independent positive prognostic indicator for these patients. Further research is needed to define if CD20+ cells can modify tumors in a way that reduces disease progression and metastatic potential.


Sampling mobile oceanic fishes and sharks: implications for fisheries and conservation planning.
Tuna, billfish, and oceanic sharks [hereafter referred to as 'mobile oceanic fishes and sharks' (MOFS)] are characterised by conservative life-history strategies and highly migratory behaviour across large, transnational ranges. Intense exploitation over the past 65 years by a rapidly expanding high-seas fishing fleet has left many populations depleted, with consequences at the ecosystem level due to top-down control and trophic cascades. Despite increases in both CITES and IUCN Red Listings, the demographic trajectories of oceanic sharks and billfish are poorly quantified and resolved at geographic and population levels. Amongst MOFS trajectories, those of tunas are generally considered better understood, yet several populations remain either overfished or of unknown status. MOFS population trends and declines therefore remain contentious, partly due to challenges in deriving accurate abundance and biomass indices. Two major management strategies are currently recognised to address conservation issues surrounding MOFS: (i) internationally ratified legal frameworks and their associated regional fisheries management organisations (RFMOs); and (ii) spatio-temporal fishery closures, including no-take marine protected areas (MPAs). In this context, we first review fishery-dependent studies relying on data derived from catch records and from material accessible through fishing extraction, under the umbrella of RFMO-administrated management. Challenges in interpreting catch statistics notwithstanding, we find that fishery-dependent studies have enhanced the accuracy of biomass indices and the management strategies they inform, by addressing biases in reporting and non-random effort, and predicting drivers of spatial variability across meso- and oceanic scales in order to inform stock assessments. By contrast and motivated by the increase in global MPA coverage restricting extractive activities, we then detail ways in which fishery-independent methods are increasingly improving and steering management by exploring facets of MOFS ecology thus far poorly grasped. Advances in telemetry are increasingly used to explore ontogenic and seasonal movements, and provide means to consider MOFS migration corridors and residency patterns. The characterisation of trophic relationships and prey distribution through biochemical analysis and hydro-acoustics surveys has enabled the tracking of dietary shifts and mapping of high-quality foraging grounds. We conclude that while a scientific framework is available to inform initial design and subsequent implementation of MPAs, there is a shortage in the capacity to answer basic but critical questions about MOFS ecology (who, when, where?) required to track populations non-extractively, thereby presenting a barrier to assessing empirically the performance of MPA-based management for MOFS. This sampling gap is exacerbated by the increased establishment of large (>10000 km2 ) and very large MPAs (VLMPAs, >100000 km2 ) - great expanses of ocean lacking effective monitoring strategies and survey regimes appropriate to those scales. To address this shortcoming, we demonstrate the use of a non-extractive protocol to measure MOFS population recovery and MPA efficiency. We further identify technological avenues for monitoring at the VLMPA scale, through the use of spotter planes, drones, satellite technology, and horizontal acoustics, and highlight their relevance to the ecosystem-based framework of MOFS management.


Image tracking for the high similarity drug tablets based on light intensity reflective energy and artificial neural network.
It is obvious that tablet image tracking exerts a notable influence on the efficiency and reliability of high-speed drug mass production, and, simultaneously, it also emerges as a big difficult problem and targeted focus during production monitoring in recent years, due to the high similarity shape and random position distribution of those objectives to be searched for. For the purpose of tracking tablets accurately in random distribution, through using surface fitting approach and transitional vector determination, the calibrated surface of light intensity reflective energy can be established, describing the shape topology and topography details of objective tablet. On this basis, the mathematical properties of these established surfaces have been proposed, and thereafter artificial neural network (ANN) has been employed for classifying those moving targeted tablets by recognizing their different surface properties; therefore, the instantaneous coordinate positions of those drug tablets on one image frame can then be determined. By repeating identical pattern recognition on the next image frame, the real-time movements of objective tablet templates were successfully tracked in sequence. This paper provides reliable references and new research ideas for the real-time objective tracking in the case of drug production practices.


Effect of stretching on ankle and knee angles and gastrocnemius activity during the stance phase of gait.
Stretching exercises are commonly prescribed for patients and healthy individuals with limited extensibility of the gastrocnemius muscle. To determine effects of gastrocnemius stretching on ankle dorsiflexion, knee extension, and gastrocnemius muscle activity during gait. Randomized-control trial. Biomechanical laboratory. Sixteen volunteers (9 men and 7 women, mean age = 27 y) with less than 5 degrees of passive ankle-dorsiflexion range of motion randomly assigned to an experimental or control group. The experimental group performed gastrocnemius stretching for 3 wk. Maximum ankle dorsiflexion, maximum knee extension, and EMG amplitude of the gastrocnemius muscles were measured between heel strike and heel-off before and after intervention. No significant effect of group or time was found on maximum ankle dorsiflexion, maximum knee extension, or EMG activity of the medial or lateral gastrocnemius muscles between heel strike and heel-off. The experimental group had significantly greater passive ankle-dorsiflexion range of motion bilaterally at posttest than the control group. Stretching did not alter joint angles or gastrocnemius muscle activity in the early to midstance phase of gait.


What's Old is New Again - A Review of the Current Evidence of Colchicine in Cardiovascular Medicine.
Colchicine is a well-established drug approved by the Food and Drug Administration (FDA) for the prevention and treatment of gout. It possesses unique anti-inflammatory properties. Interests in the usage of colchicine in cardiovascular medicine have been rekindled recently with several large trials been carried out to investigate its efficacy in treatment of various cardiac conditions including pericarditis, postpericardiotomy syndrome, atrial fibrillation and coronary artery disease. In this review, the basic pharmacological properties of colchicine will be discussed, and the evidences of its benefits for different applications in cardiovascular medicine will be reviewed.


In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects.
We studied osteoclastic differentiation from normal and osteopetrotic human CD14 cells in vitro. Defects in acid transport, organic matrix removal, and cell fusion with deficient attachment were found. Analysis of genotypes showed that TCIRG1 anomalies correlated with acid transport defects, but surprisingly, organic matrix removal failure correlated with CLCN7 defects; an attachment defect had normal TCIRG1 and CLCN7. Osteopetrotic subjects usually have normal macrophage activity, and despite identification of genetic defects associated with osteopetrosis, the specific developmental and biochemical defects in most cases are unclear. Indeed, patients with identical genotypes often have different clinical courses. We classified defects in osteoclast differentiation in vitro using four osteopetrotic subjects without immune or platelet defects, three of them severe infantile cases, compared with normals. Osteoclast differentiation used isolated CD14 cells; results were correlated with independent analysis of two key genes, CLCN7 and TCIRG1. CD14 cell attachment and cell surface markers and extent of differentiation in RANKL and colony-stimulating factor (CSF)-1 were studied using acid secretion, bone pitting, enzyme, and attachment proteins assays. CD14 cells from all subjects had similar lysosomal and nonspecific esterase activity. With the exception of cells from one osteopetrotic subject, CD14 cells from osteopetrotic and control monocytes attached similarly to bone or tissue culture substrate. Cells from one osteopetrotic subject, with normal CLCN7 and TCIRG1, did not attach to bone, did not multinucleate, and formed no podosomes or actin rings in RANKL and CSF-1. Attachment defects are described in osteopetrosis, most commonly mild osteopetrosis with Glantzman's thrombasthenia. However, this case, with abnormal integrin alphavbeta3 aggregates and no osteoclasts, seems to be unique. Two subjects were compound heterozygotes for TCIRG1 defects; both had CD14 cells that attached to bone but did not acidify attachments; cell fusion and attachment occurred, however, in RANKL and CSF-1. This is consistent with TCIRG1, essential for H+-ATPase assembly at the ruffled border. A compound heterozygote for CLCN7 defects had CD14 cells that fused in vitro, attached to bone, and secreted acid, TRACP, and cathepsin K. However, lacunae were shallow and retained demineralized matrix. This suggests that CLCN7 may not limit H+-ATPase activity as hypothesized, but may be involved in control of organic matrix degradation or removal.


The use of resistance testing in the management of HIV-1-infected patients.
Resistance testing has become an important component of the recommended care for treatment-naive and treatment-experienced HIV-infected patients in the developed world, and their use has been shown to improve clinical outcomes. Despite the widespread use of resistance testing, the clinician faces a number of challenges in optimally applying these technologies to antiretroviral management. Even with the aid of a genotypic interpretation system, the interpretation of a genotype is complex and benefits from expert input. Phenotypic resistance testing is limited by cost and availability for many patients. Standard resistance testing (both genotypes and phenotypes) is unable to detect minority species. The presence of resistant minority populations has been associated with virologic failure. However, the current techniques available to detect their presence are cumbersome and not soon likely to become part of routine clinical care. The development of the chemokine (C-C motif) receptor 5 antagonists has provided new challenges in quantifying antiretroviral resistance. Resistance testing plays a central role in the management of treatment-experienced patients. Further progress in the interpretation of resistance testing, especially as new agents are developed, will continue to add value to the care of HIV-infected patients.


A dose-response study of total sleep time and the ability to maintain wakefulness.
The apparent connection between sleep debt, performance decrements and workplace accidents has generated a need for feasible vigilance tests that focus on the quantification of daytime sleepiness in occupational settings. The objective of this study was to evaluate the sensitivity of the Maintenance of Wakefulness Test (MWT) to acute sleep deprivation of various doses. Eight healthy female volunteers, mean age 28.9 years (range 23-36), participated in this laboratory study. After an adaptation night, the subjects were assigned to four counterbalanced, randomly ordered night sleep conditions. These four conditions allowed for a time in bed (TIB) of 0, 2, 4 or 8 h, producing a total sleep time of 0, 113, 218 and 427 min, respectively. The ability to sustain wakefulness was measured after the TIB period at 11.00 and 17.00 hours by the MWT. Analysis of variance with repeated measures was used to study the dependence of MWT sleep latencies on the immediately prior TIB period. Both the latency of stage 1 sleep onset and the appearance of slow eye movements reduced significantly with increased sleep loss. The quantitative relationship between the previous total sleep time and the subsequent MWT sleep latencies followed an exponentially decaying function showing a high sensitivity to acute, severe night sleep loss but low sensitivity to less severe sleep restrictions. It is concluded that the MWT seems to be a sensitive method for the estimation of acute sleep deprivation. The test results appear, however, non-linearly related to the earlier sleep debt.


MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acute myeloid leukemias (AMLs) identified germ line loss of MBD4 as an initiator of 5mC-dependent hypermutation. MBD4-deficient AMLs display a 33-fold higher mutation burden than AML generally, with >95% being C>T in the context of a CG dinucleotide. This distinctive signature was also observed in sporadic cancers that acquired biallelic mutations in MBD4 and in Mbd4 knockout mice. Sequential sampling of germ line cases demonstrated repeated expansion of blood cell progenitors with pathogenic mutations in DNMT3A, a key driver gene for both clonal hematopoiesis and AML. Our findings reveal genetic and epigenetic factors that shape the mutagenic influence of 5mC. Within blood cells, this links methylation damage to the driver landscape of clonal hematopoiesis and reveals a conserved path to leukemia. Germ line MBD4 deficiency enhances cancer susceptibility and predisposes to AML.


Examination of faecal Bifidobacterium populations in breast- and formula-fed infants during the first 18 months of life.
Bifidobacteria in the infant faecal microbiota have been the focus of much interest, especially during the exclusive milk-feeding period and in relation to the fortification of infant formulae to better mimic breast milk. However, longitudinal studies examining the diversity and dynamics of the Bifidobacterium population of infants are lacking, particularly in relation to the effects of weaning. Using a polyphasic strategy, the Bifidobacterium populations of breast- and formula-fed infants were examined during the first 18 months of life. Bifidobacterium-specific denaturing gradient gel electrophoresis demonstrated that breast-fed infants harboured greater diversity than formula-fed infants and the diversity of the infants' Bifidobacterium populations increased with weaning. Twenty-seven distinctive banding profiles were observed from ∼1100 infant isolates using ribosomal intergenic spacer analysis, 14 biotypes of which were confirmed to be members of the genus Bifidobacterium. Two profiles (H, Bifidobacterium longum subsp. infantis; and I, Bifidobacterium bifidum) were common culturable biotypes, seen in 9/10 infants, while profile E (Bifidobacterium breve) was common among breast-fed infants. Overall, inter- and intra-individual differences were observed in the Bifidobacterium populations of infants between 1 and 18 months of age, although weaning was associated with increased diversity of the infant Bifidobacterium populations. Breast-fed infants generally harboured a more complex Bifidobacterium microbiota than formula-fed infants.


[Selected endothelial hemostatic markers in patients with peripheral arterial disease after endovascular revascularization and restenosis formation].
Surgical and endovascular revascularization of ischemic legs in patients with peripheral arterial disease (PAD) can damage the arterial wall (endothelial and smooth muscle cells). Hemostatic factors released during endothelial dysfunction can lead to restenosis. 1. Determination of selected endothelial hemostatic factors in PAD patients and a reference group. 2. Prospective observation of new restenosis appearance in PAD patients after endovascular revascularization. 3. Comparison of selected endothelial hemostatic factors between non-restenotic and restenotic PAD patients. 150 PAD patients after endovascular revascularization - 90 men and 60 women, aged 44-88 (mean 65.5) years - were examined. During one-year observation after the revascularization procedures in 38 PAD patients restenosis occurred, when blood samples were also collected. The reference group consisted of 53 healthy persons - 44 men and 9 women, aged 20-56 years. Blood was drawn in the morning into 3.2% sodium citrate at a ratio of 9:1. Tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) were measured in plasma with commercial tests using the enzyme immunoassay. In the plasma of PAD patients after revascularization, the concentrations of TF and vWF were significantly higher, TM lower, TFPI and t-PA similar compared to the reference group. Six months after revascularization the level of TF had increased and vWF had significantly decreased. The endothelial hemostatic factors before and after restenosis did not significantly differ except TF, which after restenosis was higher. Increased TF and vWF levels in PAD patients indicate arterial endothelial cell damage, by atherosclerotic and revascularization processes. In PAD patients with restenosis compared to these patients before restenosis the determined endothelial hemostatic factors, except TF level, did not significantly differ. Perhaps TF participates in restenosis formation.


Hippocampal volume in patients with alcohol dependence.
Smaller hippocampal volumes have been reported in the brains of alcoholic patients than in those of healthy subjects, although it is unclear if the hippocampus is disproportionally smaller than the brain as a whole. There is evidence that alcoholic women are more susceptible than alcoholic men to liver and cardiac damage from alcohol. It is not known whether the hippocampi of the female brain are more vulnerable to alcohol. We compared the hippocampal volumes in 52 hospitalized alcoholic men and women with those of 36 healthy nonalcoholic men and women. All subjects were between 27 and 53 years of age. The hippocampal volumes were measured from sagittal T-weighted high-resolution magnetic resonance images. The alcoholic women had less lifetime drinking and a later age at onset of heavy drinking than alcoholic men. Both alcoholic men and women had significantly smaller right hippocampi and larger cerebrospinal fluid volumes than healthy subjects of the same sex. Only among women were the left hippocampus and the nonhippocampal brain volume also significantly smaller. The proportion of hippocampal volume relative to the rest of the brain volume was the same in alcoholic patients and healthy subjects, in both men and women. The right hippocampus was larger than the left among all subjects. Women demonstrated larger hippocampal volumes relative to total brain volume than men. Psychiatric comorbidity, including posttraumatic stress disorder, did not affect hippocampal volume. In chronic alcoholism, the reduction of hippocampal volume is proportional to the reduction of the brain volume. Alcohol consumption should be accounted for in studies of hippocampal damage.


Best friends and alcohol use in adolescence: the role of the dopamine D4 receptor gene.
The influence of friends and peers is theoretically one of the most consistent and important factors explaining adolescent alcohol use. However, not all adolescents are equally likely to be influenced by their friends' drinking behaviors. Genetic factors may underlie these inter-individual differences in susceptibility to the drinking behavior of friends. Because the long allele (≥ 7 repeats) of the dopamine D4 receptor (DRD4) gene has been associated with susceptibility to alcohol and alcohol-related cues, we tested whether associations between best friend's and adolescent's alcohol use differed for DRD4 genotypes. A Dutch nationwide sample of 308 adolescents (age 13 at baseline) participated in a prospective, community-based study with five annual waves. A cross-lagged path analysis was carried out in Mplus to examine bi-directional relations between friends' and adolescents' weekly alcohol use (number of drinks). A multi-group approach was applied to test for moderation effects of a 48-base pair variable number of tandem repeats polymorphism in exon 3 of the DRD4 gene. Additionally, with latent growth curve models, it was examined whether the interaction between friends' drinking and DRD4 genotype predicted the development of adolescents' alcohol use. Results showed that both cross-sectionally and longitudinally higher levels of friends' alcohol use resulted in higher levels of adolescents' alcohol consumption over time (and vice versa). No significant moderation of DRD4 genotype was found: Associations between adolescents' and friends' drinking did not differ for adolescent carriers of the DRD4 long allele, when compared with adolescents without the DRD4 long allele. Because this is the first study to examine DRD4 × friends' drinking effects prospectively, replication is essential. Future longitudinal studies, possibly with observational or diary designs, are needed to increase our understanding of the interplay between genetic and environmental risk factors for adolescent alcohol use.


Pullout performance comparison of novel expandable pedicle screw with expandable poly-ether-ether-ketone shells and cement-augmented pedicle screws.
Aim of this study is to assess the pullout performance of various pedicle screws in different test materials. Polyurethane foams (Grade 10 and Grade 40) produced in laboratory and bovine vertebrae were instrumented with normal, cannulated (cemented), novel expandable and normal (cemented) pedicle screws. Test samples were prepared according to the ASTM F543 standard testing protocols and surgical guidelines. To examine the screw placement and cement distribution, anteriosuperior and oblique radiographs were taken from each sample after insertion process was completed. Pullout tests were performed in an Instron 3369 testing device. Load versus displacement graphs were recorded and the ultimate pullout force was defined as the maximum load (pullout strength) sustained before failure of screw. Student's t-test was performed on each group whether the differences between pullout strength of pedicle screws were significant or not. While normal pedicle screws have the lowest pullout strength in all test materials, normal pedicle screws cemented with polymethylmethacrylate exhibit significantly higher pullout performance than others. For all test materials, there is a significant improvement in pullout strength of normal screws by augmentation. While novel expandable pedicle screws with expandable poly-ether-ether-ketone shells exhibited lower pullout performance than normal screws cemented with polymethylmethacrylate, their pullout performances in all groups were higher than the ones of normal and cannulated pedicle screws. For all test materials, although cannulated pedicle screws exhibit higher pullout strength than normal pedicle screws, there are no significant differences between the two groups. The novel expandable pedicle screws with expandable poly-ether-ether-ketone shells may be used instead of normal and cannulated pedicle screws cemented with polymethylmethacrylate due to their good performances.


Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement.
The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.


Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits.
Chronic sleep disturbances, associated with cardiometabolic diseases, psychiatric disorders and all-cause mortality, affect 25-30% of adults worldwide. Although environmental factors contribute substantially to self-reported habitual sleep duration and disruption, these traits are heritable and identification of the genes involved should improve understanding of sleep, mechanisms linking sleep to disease and development of new therapies. We report single- and multiple-trait genome-wide association analyses of self-reported sleep duration, insomnia symptoms and excessive daytime sleepiness in the UK Biobank (n = 112,586). We discover loci associated with insomnia symptoms (near MEIS1, TMEM132E, CYCL1 and TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR-OPHN1) and a composite sleep trait (near PATJ (INADL) and HCRTR2) and replicate a locus associated with sleep duration (at PAX8). We also observe genetic correlation between longer sleep duration and schizophrenia risk (rg = 0.29, P = 1.90 × 10-13) and between increased levels of excessive daytime sleepiness and increased measures for adiposity traits (body mass index (BMI): rg = 0.20, P = 3.12 × 10-9; waist circumference: rg = 0.20, P = 2.12 × 10-7).


Augmentation of centrally induced alpha-adrenergic vasodepression in spontaneously hypertensive rats.
Central alpha-adrenergic mechanisms for cardiovascular regulation were studied by injecting phenylephrine into a recipient rat whose head was isolated from its body by cross perfusion with a donor rat. Blood pressure increases produced in the donor were accompanied by concurrent reduction of blood pressure and sympathetic nerve activity in the recipient rat's body. These effects were abolished when alpha-adrenergic receptors in the perfused head were blocked with phentolamine. By contrast, intracarotid injections of angiotensin increased blood pressure not only in donor but also in recipient rats. The magnitude of phenylephrine-induced vasodepression was significantly greater in spontaneously hypertensive rats (SHR) than in normotensive or DOCA-salt hypertensive ones. Distribution of radioactive microspheres indicated that carotid arterial blood went mainly to the cerebrum, midbrain, and hypothalamus, with almost negligible amounts going to the lower brainstem. Collectively, our results suggest that centrally administered phenylephrine reduces sympathetic vasomotor tone and blood pressure by acting on alpha-adrenergic receptors located in supramedullary brain areas (possibly in the hypothalamus). In SHR, augmented, vasodepressor responsiveness may be due to reduced brain levels of endogenous norepinephrine that could increase the alpha-adrenergic receptors available.


Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.
Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.


Large Scale Anthropogenic Reduction of Forest Cover in Last Glacial Maximum Europe.
Reconstructions of the vegetation of Europe during the Last Glacial Maximum (LGM) are an enigma. Pollen-based analyses have suggested that Europe was largely covered by steppe and tundra, and forests persisted only in small refugia. Climate-vegetation model simulations on the other hand have consistently suggested that broad areas of Europe would have been suitable for forest, even in the depths of the last glaciation. Here we reconcile models with data by demonstrating that the highly mobile groups of hunter-gatherers that inhabited Europe at the LGM could have substantially reduced forest cover through the ignition of wildfires. Similar to hunter-gatherers of the more recent past, Upper Paleolithic humans were masters of the use of fire, and preferred inhabiting semi-open landscapes to facilitate foraging, hunting and travel. Incorporating human agency into a dynamic vegetation-fire model and simulating forest cover shows that even small increases in wildfire frequency over natural background levels resulted in large changes in the forested area of Europe, in part because trees were already stressed by low atmospheric CO2 concentrations and the cold, dry, and highly variable climate. Our results suggest that the impact of humans on the glacial landscape of Europe may be one of the earliest large-scale anthropogenic modifications of the earth system.


Association of Genetic Variation With Keratoconus.
Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. To identify genetic susceptibility regions for keratoconus in the human genome. This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.


Hereditary breast cancer: part I. Diagnosing hereditary breast cancer syndromes.
Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15-20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20-25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis.


'It felt like there was always someone there for us': Supporting children affected by domestic violence and abuse who are identified by general practice.
One in five children in the UK are affected by domestic violence and abuse. However, primary care clinicians (GPs and nurses) struggle to effectively identify and support children and young people living in homes where it is present. The IRIS+ (Enhanced Identification and Referral to Improve Safety) training and advocacy support intervention aimed to improve how clinicians respond to children and young people affected by domestic violence and abuse. IRIS+ training was delivered as part of a feasibility study to four general practices in an urban area in England (UK). Our mixed method design included interviews and questionnaires about the IRIS+ intervention with general practice patients, including children and young people as well as with clinicians and advocacy service providers. We collected the number of identifications and referrals by clinicians of children experiencing domestic violence and abuse through a retrospective search of medical and agency records 10 months after the intervention. Forty-nine children exposed to domestic violence and abuse were recorded in medical records. Thirty-five children were referred to a specialist domestic violence and abuse support service over a period of 10 months. Of these, 22 received direct or indirect support. The qualitative findings indicated that children benefitted from being referred by clinicians to the service. However, several barriers at the patient and professional level prevented children and young people from being identified and supported. Some of these barriers can be addressed through modifications to professional training and guidance, but others require systematic and structural changes to the way health and social care services work with children affected by domestic violence and abuse.


Inward rectification in the transverse tubular system of frog skeletal muscle studied with potentiometric dyes.
The non-penetrating potentiometric dyes NK2367 and WW375 were used to investigate the effect of inward rectification on the weighted-average tubular membrane potential in single frog muscle fibres voltage clamped using a three-Vaseline-gap method. In 100 mM-K solution, when inward rectification was activated by hyperpolarization the steady-state amplitude of the transverse tubular system (T-system) optical signal was reduced, and its rise time was faster than that recorded for an equivalent depolarization. The voltage dependence of the optical attenuation followed that of inward rectification, increasing with increasing hyperpolarization. For a voltage-clamp step of -140 mV the optical attenuation was 0.72 which corresponds to a weighted-average T-system potential change of 100 mV. When inward rectification was blocked in a Cs, TEA solution the optical attenuation was also abolished. The voltage dependence of the block of the inward currents in solutions containing low concentrations of Cs was also reflected in the T-system optical signals. Our results were satisfactorily predicted by a radial cable model of the T-system, assuming the same specific inward rectifier conductance in surface and tubular membranes. This analysis predicts that the measured optical attenuation corresponds to a decrease in the tubular space constant, lambda T, from 120 micron under passive conditions to about 40 micron when inward rectification is fully, activated. The voltage dependence of inward rectification measured at the surface membrane was reasonably well predicted by assuming that the specific conductance obeyed a Boltzmann type of voltage dependence; the major effect of tubular decrements was to reduce the steepness of the total (surface + T-system) conductance-voltage relation.


Comparison of three midsagittal planes for three-dimensional cone beam computed tomography head reorientation.
This study compared three prominent midsagittal planes (MSPs) to identify the MSP that best approximates the true symmetrical MSP. Forty-three patients (mean age, 23.0 ± 8.20 years) were grouped as follows: group 1 consisted of 10 patients with skeletal Class I and a menton (Me) deviation of < 2 mm; group 2, 11 patients with skeletal Class III and a Me deviation < 2 mm; group 3, nine patients with skeletal Class III and a Me deviation of 2 to less than 4 mm; and group 4, 13 patients with skeletal Class III and an Me deviation ≥ 4 mm. The candidate MSPs were established by three-dimensional (3D) cone beam computed tomography (CBCT) reorientation methods (RMs): (1) the MSP perpendicular to the Frankfort horizontal (FH) plane while passing through the crista galli and basion; (2) the MSP including the nasion, incisive foramen, and basion; (3) the MSP including the nasion, anterior nasal spine, and posterior nasal spine. The mean absolute distances (MADs) to the MSPs were calculated from the coordinates of 1,548 points on 129 CBCT images. The differences in the values of the 3D coordinates among RMs were compared. The MADs of the three RMs showed significant differences (p < 0.05). Most of the differences in values of the coordinates were not significant among RMs. Although the differences in distance among the three MSPs were minor, the MSP perpendicular to the FH plane while passing through the crista galli and basion best approximated the true symmetrical MSP.


Using informatics principles and tools to harness research evidence for patient care: evidence-based informatics.
With the huge worldwide investment in biomedical research during the past 50 years, there are many important advances in health care knowledge each year. Unfortunately, it commonly takes over 20 years for even the most important of these advances to be widely integrated into clinical practice. Many potentially remediable factors are responsible for this dilemma in research transfer, including defective continuing education for health professionals and patients; increasingly complex medical regimens; diminishing resources for health care; and inadequate evidence management. The principles and procedures of health informatics can help overcome some of these barriers to research transfer, particularly such evidence management tasks as retrieving, processing, summarizing, disseminating and applying evidence for clinical care. Evidence retrieval has been improved by better indexing and electronic search engines, by improved access from clinical and other settings, and by integration of evidence into clinical decision support systems. Evidence processing has been greatly accelerated by streamlined methods of critical appraisal of research and by centralization of these procedures for the development of current awareness publications and cumulative "best evidence" databases. The Cochrane Collaboration has revolutionized the summarization (systematic review) of evidence. The internet has provided access to patients, practitioners, and policy makers, alike. Direct-from-patient automated data collection promises to move the connection between evidence and practice to a higher level. In all of these innovations, health care practice is most likely to be enhanced by intertwining best evidence with best informatics techniques.


Evaluation of the decision support system for antimicrobial treatment, TREAT, in an acute medical ward of a university hospital.
TREAT, a decision support system for antimicrobial therapy, was implemented in an acute medical ward. Patients admitted on suspicion of infection were included in the study. The evaluation of TREAT was done both retrospectively and prospectively. Coverage of empirical antimicrobial treatments was compared to recommendations from TREAT and the optimal use of local guidelines. Five hundred and eleven patients were included, of whom 162 had a microbiologically documented infection. In the retrospective part of the study, TREAT, physician, and guideline antimicrobial coverage rates were 65%, 51%, and 79%, respectively, and in the prospective part, 68%, 62%, and 77%, respectively. TREAT provided lower coverage than local guidelines (p<0.001), but was similar to the performance of physicians in a university hospital (p=0.069). No differences were found in length of hospital stay, or hospital or 30-day mortality. Direct costs were significantly higher for TREAT advice than for local guidelines or the physician prescriptions (p<0.001), but the ecological costs were lower for TREAT advice than for both local guidelines (p<0.001) and physician prescriptions (p=0.247). The coverage of TREAT advice for the bacteraemia patients was non-inferior to the physicians (p=1.00). TREAT can potentially improve the ecological costs of empirical antimicrobial therapy for patients in acute medical wards, but provided lower coverage than local guidelines.


Hybrid Approach to Fabricate Uniform and Active Molecular Junctions.
Molecules can serve as ultimate building blocks for extreme nanoscale devices. This requires their precise integration into functional heterojunctions, most commonly in the form of metal-molecule-metal architectures. Structural damage and nonuniformities caused by current fabrication techniques, however, limit their effective incorporation. Here, we present a hybrid fabrication approach enabling uniform and active molecular junctions. A template-stripping technique is developed to form electrodes with sub-nanometer smooth surfaces. Combined with dielectrophoretic trapping of colloidal nanorods, uniform sub-5 nm junctions are achieved. Uniquely, in our design, the top contact is mechanically free to move under an applied stimulus. Using this, we investigate the electromechanical tuning of the junction and its tunneling conduction. Here, the molecules help control sub-nanometer mechanical modulation, which is conventionally challenging due to instabilities caused by surface adhesive forces. Our versatile approach provides a platform to develop and study active molecular junctions for emerging applications in electronics, plasmonics, and electromechanical devices.


The tympanic membrane displacement analyser for monitoring intracranial pressure in children.
Raised intracranial pressure (ICP) is a potentially treatable cause of morbidity and mortality but tools for monitoring are invasive. We sought to investigate the utility of the tympanic membrane displacement (TMD) analyser for non-invasive measurement of ICP in children. We made TMD observations on normal and acutely comatose children presenting to Kilifi District Hospital (KDH) at the rural coast of Kenya and on children on follow-up for idiopathic intracranial hypertension at Evelina Children's Hospital (ECH), in London, UK. We recruited 63 patients (median age 3.3 (inter-quartile range (IQR) 2.0-4.3) years) at KDH and 14 children (median age 10 (IQR 5-11) years) at ECH. We observed significantly higher (more negative) TMD measurements in KDH children presenting with coma compared to normal children seen at the hospital's outpatient department, in both semi-recumbent [mean -61.3 (95 % confidence interval (95 % CI) -93.5 to 29.1) nl versus mean -7.1 (95 % CI -54.0 to 68.3) nl, respectively; P = 0.03] and recumbent postures [mean -61.4 (95 % CI -93.4 to -29.3) nl, n = 59) versus mean -25.9 (95 % CI -71.4 to 123.2) nl, respectively; P = 0.03]. We also observed higher TMD measurements in ECH children with raised ICP measurements, as indicated by lumbar puncture manometry, compared to those with normal ICP, in both semi-recumbent [mean -259.3 (95 % CI -363.8 to -154.8) nl versus mean 26.7 (95 % CI -52.3 to 105.7) nl, respectively; P < 0.01] and recumbent postures [mean -137.5 (95 % CI -260.6 to -14.4) nl versus mean 96.6 (95 % CI 6.5 to 186.6) nl, respectively; P < 0.01]. The TMD analyser has a potential utility in monitoring ICP in a variety of clinical circumstances.


Innovation in industry and the diffusion of technology.
The varied definitions used in the sources that have been discussed make any aggregate analysis difficult. A simple three-stage analysis of flows to, from, and within the firm was used to facilitate comparisons. Even so, each of the generalizations is drawn from relatively small and unrepresentative samples. Case studies may continue to be a source of ideas and hypotheses for further research, but do not appear to offer a means for deeper understanding of the innovation process. The retrospective nature of nearly all of the sources discussed probably means that the process has been viewed as much more rational and well-ordered than it is in fact. This failing is partially overcome in firsthand accounts such as those of Suites and Bueche (63) and Frey and Goldman (64). Each of these accounts involves a successful innovation according to technical or commercial criteria, or both. However, many of the characteristics of innovations that have failed commercially (10) appear to be similar to those of successful cases. The few longitudinal studies, and studies comparing more and less successful cases, do support the main conclusions drawn above (10, 32, 38). More serious problems are raised by the distinctly nonrepresentative nature of the samples used. There are few cases (17, 33, 65) in which the contributions of more than one organization, or details of interactions over a significant period of time, are discussed. There is a wide variation in the importance of the innovations included, ranging from those affecting the economy as a whole to cases involving production in a single firm, albeit with significant commercial results (66). In addition to questions of comparability and sampling, a central problem for further research on innovation will be to devise an operational model to account for interfirm and interindustry differences. Polar definitions used in past studies, "high technology" and "mature industry," for example, are insufficient. One possibility is to use the strategy for growth or competition evident in a firm or an industry, such as sales maximization (automotive), cost minimization (transportation, communications), performance maximization (aircraft, chemicals), or control of materials resources (mining, petroleum), as a basis for drawing distinctions (67). For example, in an industry that seeks to maximize sales, one would expect innovations that would be highly visible to consumers to be developed rapidly (68). In a cost-minimizing situation, production, as opposed to product technology, would be a major source of uncertainty, while the reverse might be the case in a performance-maximizing situation. Greater uncertainty arising from technical sources would imply greater sophistication in effective firms' product planning approaches, while a more stable technology would imply greater sophistication in market research and market-oriented strategies for innovation, and so forth. Much more work is needed along these lines if outcomes of interventions in the innovative process are to be predicted with any accuracy. Some implications for providing incentives and reducing barriers do seem clear from the work to date. Effective directions for federal action lie in strategies such as creating new markets through purchases or procurement policies; aggregating or focusing markets through regulation and other means; providing for market entry by contracts to smaller firms, venture capital, stronger patent protection, and so on; and providing for mobility and informal contacts within the technical community. Technology "push" strategies (such as tax incentives) to increase most research spending, prizes for new technology, and documentation and information retrieval systems would probably be less important in stimulating innovation. Definitive answers will require the most difficult kind of research-experiments in the field. Since the interventions required are difficult and expensive in most cases, they will not be under the researcher's control. Nor will the effect of policy changes be visible over a short period. Thus it seems imperative to take advantage of interventions that occur fortuitously to construct "quasi-experiments" (69) with as great a degree of control over other factors as possible. For example, have recent changes in policy regarding federally held patents increased the commercial use of these patents? Have changes in the capital gains laws retarded the development and growth of "spin-off" enterprises? Has the identification of technology gaps (3) and competitive opportunities stimulated innovation? The effects of such actions on technical innovation could be carefully observed with a modest but sustained research effort, which promises to yield valuable information beyond that available from largely historical sources.


Continuing acromioclavicular joint pain after excision arthroplasty: is further surgery effective?
Little published evidence exists on the incidence of continuing acromioclavicular joint pain with no published outcomes for revision surgery. This study aimed to establish the incidence and outcomes of revision acromioclavicular joint excision surgery. A consecutive retrospective cohort of patients undergoing revision arthroscopic or open acromioclavicular joint excision was identified. Patients were identified from a prospectively collected database. Inclusion criteria were revision acromioclavicular joint excisions over a 14-year period between 2001 and 2015. Exclusion criteria were previous surgery for acromioclavicular joint instability or shoulder arthroplasty. Outcome measures were Oxford Shoulder scores and a satisfaction survey. Forty-three consecutive cases of revision acromioclavicular joint excision over 14 years (37 after arthroscopic excision with subacromial decompression, 5 after arthroscopic excision with rotator cuff repair, 1 after open excision). Continuing acromioclavicular joint pain was associated with incomplete resection from arthroscopic surgery, which was the primary indication for revision surgery. Revision occurred a mean 14.2 months after primary surgery (standard deviation 7.6 months). Mean Oxford Shoulder score was preoperatively 18 (standard deviation 8.1) and 23.4 (standard deviation 11.1) after primary surgery, which did not reach significance until after revision surgery with a mean 31.7 (standard deviation 13.6; P = 0.021). Median follow up was 15 months (interquartile range 4-31 months). A survey at a mean of 6 years (standard deviation 2.3) post-revision surgery found that 65% of patients felt improved, 77% would have their surgery again and 69% of patients felt satisfied. The incidence of postoperative frozen shoulder was 14.3%. Functional outcomes after revision surgery showed improvement from scores taken before primary surgery; however, long-term satisfaction rates were relatively low.


Real-time PCR detection of mixed Plasmodium ovale curtisi and wallikeri species infections in human and mosquito hosts.
Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) represent distinct non-recombining malaria species that are increasing in prevalence in sub-Saharan Africa. Though they circulate sympatrically, co-infection within human and mosquito hosts has rarely been described. Separate 18S rRNA real-time PCR assays that detect Poc and Pow were modified to allow species determination in parallel under identical cycling conditions. The lower limit of detection was 0.6 plasmid copies/μL (95% CI 0.4-1.6) for Poc and 4.5 plasmid copies/μL (95% CI( 2.7- 18) for Pow, or 0.1 and 0.8 parasites/μL, respectively, assuming 6 copies of 18s rRNA per genome. However, the assays showed cross-reactivity at concentrations greater than 103 plasmid copies/μL (roughly 200 parasites/μL). Mock mixtures were used to establish criteria for classifying mixed Poc/Pow infections that prevented false-positive detection while maintaining sensitive detection of the minority ovale species down to 10° copies/μL (<1 parasite/μL). When the modified real-time PCR assays were applied to field-collected blood samples from Tanzania and Cameroon, species identification by real-time PCR was concordant with nested PCR, but additionally detected two mixed Poc/Pow infections where nested PCR detected a single Po species. When real-time PCR was applied to 14 oocyst-positive Anopheles midguts saved from mosquitoes fed on P. ovate-infected persons, mixed Poc/Pow infections were detected in 11 (79%). Based on these results, 8/9 P. ovate carriers transmitted both P. ovate species to mosquitoes, though both Po species could only be detected in the blood of two carriers. The described real-time PCR approach can be used to identify the natural occurrence of mixed Poc/Pow infections in human and mosquito hosts and reveals that such co-infections and co-transmission are likely more common than appreciated.


Effect of vitamin D supplementation on cardiometabolic risks and health-related quality of life among urban premenopausal women in a tropical country--a randomized controlled trial.
Many observational studies linked vitamin D to cardiometabolic risks besides its pivotal role in musculoskeletal diseases, but evidence from trials is lacking and inconsistent. To determine whether Vitamin D supplementation in urban premenopausal women with vitamin D deficiency can improve cardiometabolic risks and health-related quality of life (HRQOL). A double-blind randomized controlled trial was conducted in Kuala Lumpur, Malaysia. A total of 192 vitamin D deficient (<50 nmol/l) premenopausal women were randomized to receive either vitamin D 50,000 IU or placebo once a week for 2 months and then monthly for 10 months. Primary outcomes were serum 25(OH)D, serum lipid profiles, blood pressure and HOMA-IR measured at baseline, 6 months and 12 months. HRQOL was assessed with SF-36 at baseline and 12 months. Ninety three and ninety-nine women were randomised into intervention and placebo groups respectively. After 12 months, there were significant differences in the serum 25(OH)D concentration (mean difference: 49.54; 95% CI: 43.94 to 55.14) nmol/l) and PTH levels (mean difference: -1.02; 95% CI: -1.67 to -0.38 pmol/l) in the intervention group compared to placebo group. There was significant difference between treatment group in both serum 25(OH)D and PTH. There was no effect of supplementation on HOMA-IR, serum lipid profiles and blood pressure (all p>0.05) between two groups. There was a small but significant improvement in HRQOL in the components of vitality (mean difference: 5.041; 95% CI: 0.709 to 9.374) and mental component score (mean difference: 2.951; 95% CI: 0.573 to 5.329) in the intervention group compared to placebo group. Large and less frequent dosage vitamin D supplementation was safe and effective in the achievement of vitamin D sufficiency. However, there was no improvement in measured cardiometabolic risk factors in premenopausal women. Conversely vitamin D supplementation improves some components of HRQOL. Australian New Zealand Clinical Trial Registry ACTRN12612000452897.


Allochthonous carbon is a major regulator to bacterial growth and community composition in subarctic freshwaters.
In the subarctic region, climate warming and permafrost thaw are leading to emergence of ponds and to an increase in mobility of catchment carbon. As carbon of terrestrial origin is increasing in subarctic freshwaters the resource pool supporting their microbial communities and metabolism is changing, with consequences to overall aquatic productivity. By sampling different subarctic water bodies for a one complete year we show how terrestrial and algal carbon compounds vary in a range of freshwaters and how differential organic carbon quality is linked to bacterial metabolism and community composition. We show that terrestrial drainage and associated nutrients supported higher bacterial growth in ponds and river mouths that were influenced by fresh terrestrial carbon than in large lakes with carbon from algal production. Bacterial diversity, however, was lower at sites influenced by terrestrial carbon inputs. Bacterial community composition was highly variable among different water bodies and especially influenced by concentrations of dissolved organic carbon (DOC), fulvic acids, proteins and nutrients. Furthermore, a distinct preference was found for terrestrial vs. algal carbon among certain bacterial tribes. The results highlight the contribution of the numerous ponds to cycling of terrestrial carbon in the changing subarctic and arctic regions.


On the possibility of constructive neutral evolution.
The neutral theory often is presented as a theory of "noise" or silent changes at an isolated "molecular level," relevant to marking the steady pace of divergence, but not to the origin of biological structure, function, or complexity. Nevertheless, precisely these issues can be addressed in neutral models, such as those elaborated here with regard to scrambled ciliate genes, gRNA-mediated RNA editing, the transition from self-splicing to spliceosomal splicing, and the retention of duplicate genes. All of these are instances of a more general scheme of "constructive neutral evolution" that invokes biased variation, epistatic interactions, and excess capacities to account for a complex series of steps giving rise to novel structures or operations. The directional and constructive outcomes of these models are due not to neutral allele fixations per se, but to these other factors. Neutral models of this type may help to clarify the poorly understood role of nonselective factors in evolutionary innovation and directionality.


Experimental food restriction reveals individual differences in corticosterone reaction norms with no oxidative costs.
Highly plastic endocrine traits are thought to play a central role in allowing organisms to respond rapidly to environmental change. Yet, not all individuals display the same degree of plasticity in these traits, and the costs of this individual variation in plasticity are unknown. We studied individual differences in corticosterone levels under varying conditions to test whether there are consistent individual differences in (1) baseline corticosterone levels; (2) plasticity in the hormonal response to an ecologically relevant stressor (food restriction); and (3) whether individual differences in plasticity are related to fitness costs, as estimated by oxidative stress levels. We took 25 wild-caught house sparrows into captivity and assigned them to repeated food restricted and control treatments (60% and 110% of their daily food intake), such that each individual experienced both food restricted and control diets twice. We found significant individual variation in baseline corticosterone levels and stress responsiveness, even after controlling for changes in body mass. However, these individual differences in hormonal responsiveness were not related to measures of oxidative stress. These results have implications for how corticosterone levels may evolve in natural populations and raise questions about what we can conclude from phenotypic correlations between hormone levels and fitness measures.


Changes in Hospital Adverse Events and Patient Outcomes Associated With Private Equity Acquisition.
The effects of private equity acquisitions of US hospitals on the clinical quality of inpatient care and patient outcomes remain largely unknown. To examine changes in hospital-acquired adverse events and hospitalization outcomes associated with private equity acquisitions of US hospitals. Data from 100% Medicare Part A claims for 662 095 hospitalizations at 51 private equity-acquired hospitals were compared with data for 4 160 720 hospitalizations at 259 matched control hospitals (not acquired by private equity) for hospital stays between 2009 and 2019. An event study, difference-in-differences design was used to assess hospitalizations from 3 years before to 3 years after private equity acquisition using a linear model that was adjusted for patient and hospital attributes. Hospital-acquired adverse events (synonymous with hospital-acquired conditions; the individual conditions were defined by the US Centers for Medicare & Medicaid Services as falls, infections, and other adverse events), patient mix, and hospitalization outcomes (including mortality, discharge disposition, length of stay, and readmissions). Hospital-acquired adverse events (or conditions) were observed within 10 091 hospitalizations. After private equity acquisition, Medicare beneficiaries admitted to private equity hospitals experienced a 25.4% increase in hospital-acquired conditions compared with those treated at control hospitals (4.6 [95% CI, 2.0-7.2] additional hospital-acquired conditions per 10 000 hospitalizations, P = .004). This increase in hospital-acquired conditions was driven by a 27.3% increase in falls (P = .02) and a 37.7% increase in central line-associated bloodstream infections (P = .04) at private equity hospitals, despite placing 16.2% fewer central lines. Surgical site infections doubled from 10.8 to 21.6 per 10 000 hospitalizations at private equity hospitals despite an 8.1% reduction in surgical volume; meanwhile, such infections decreased at control hospitals, though statistical precision of the between-group comparison was limited by the smaller sample size of surgical hospitalizations. Compared with Medicare beneficiaries treated at control hospitals, those treated at private equity hospitals were modestly younger, less likely to be dually eligible for Medicare and Medicaid, and more often transferred to other acute care hospitals after shorter lengths of stay. In-hospital mortality (n = 162 652 in the population or 3.4% on average) decreased slightly at private equity hospitals compared with the control hospitals; there was no differential change in mortality by 30 days after hospital discharge. Private equity acquisition was associated with increased hospital-acquired adverse events, including falls and central line-associated bloodstream infections, along with a larger but less statistically precise increase in surgical site infections. Shifts in patient mix toward younger and fewer dually eligible beneficiaries admitted and increased transfers to other hospitals may explain the small decrease in in-hospital mortality at private equity hospitals relative to the control hospitals, which was no longer evident 30 days after discharge. These findings heighten concerns about the implications of private equity on health care delivery.


A naturally occurring gamma globin gene mutation enhances SP1 binding activity.
Transcription of the human fetal globin genes in erythroid cells is tightly regulated during different stages of development and differentiation. Two naturally occurring mutations 202 base pairs upstream of the duplicated gamma globin genes are associated with incorrectly regulated gamma globin gene gene expression; elevated levels of fetal globin are synthesized during adult life. A C-to-G base substitution upstream of the G gamma-globin gene is highly correlated with a dramatic increase in gene expression. It increases the similarity of the region to the consensus Sp1 recognition site. We determined that the mutated DNA had a 5- to 10-fold-higher affinity for Sp1 than did normal gamma globin gene sequence. We also observed a reduction in normal factor-binding activity. A different substitution at -202, C to T, upstream of the A gamma-globin gene was associated with a more moderate increase in fetal globin expression. This mutation decreased the similarity of the sequence to an Sp1 recognition site. We determined that it did not result in enhanced Sp1 binding but did alter normal factor binding. We suggest that these changes in nuclear protein-binding properties detected in vitro are responsible for the enhanced gamma globin gene expression found in -202 G gamma beta + patients with hereditary persistence of fetal hemoglobin.


Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism.
Polycystic ovaries were defined with ultrasound imaging in a series of 173 women who presented to a gynaecological endocrine clinic with anovulation or hirsutism. Polycystic ovaries were found in 26% of women with amenorrhoea, 87% with oligomenorrhoea, and 92% with idiopathic hirsutism--that is, hirsutism but with regular menstrual cycles. Fewer than half the anovulatory patients with polycystic ovaries were hirsute, but in 93% of cases there was at least one endocrine abnormality to support the diagnosis of polycystic ovaries--that is, raised serum concentrations of luteinising hormone, raised luteinising hormone: follicle stimulating hormone ratio, or raised serum concentrations of testosterone or androstenedione. This study shows that polycystic ovaries, as defined by pelvic ultrasound, are very common in anovulatory women (57% of cases) and are not necessarily associated with hirsutism or a raised serum luteinising hormone concentration. Most women with hirsutism and regular menses have polycystic ovaries so that the term "idiopathic" hirsutism no longer seems appropriate.


Three-dimensional electron diffraction of plant light-harvesting complex.
Electron diffraction patterns of two-dimensional crystals of light-harvesting chlorophyll a/b-protein complex (LHC-II) from photosynthetic membranes of pea chloroplasts, tilted at different angles up to 60 degrees , were collected to 3.2 A resolution at -125 degrees C. The reflection intensities were merged into a three-dimensional data set. The Friedel R-factor and the merging R-factor were 21.8 and 27.6%, respectively. Specimen flatness and crystal size were critical for recording electron diffraction patterns from crystals at high tilts. The principal sources of experimental error were attributed to limitations of the number of unit cells contributing to an electron diffraction pattern, and to the critical electron dose. The distribution of strong diffraction spots indicated that the three-dimensional structure of LHC-II is less regular than that of other known membrane proteins and is not dominated by a particular feature of secondary structure.


Prevalence and restrictiveness of smoking policies in King County, Washington, manufacturing worksites.
This study examined prevalence of smoking policies and of significant smoking restrictions in a 1988 random sample of 1,528 manufacturing companies in the Seattle, Washington area, and related these characteristics to worksite size and industry type. Sixty-nine percent of companies had formal smoking policies and 85 percent regulated smoking to some degree. Workforce size was directly related to prevalence of significant smoking restrictions, but when type of industry was controlled, the linear trend in the size/prevalence relationship was sustained in only three of the 18 industry groupings.


Ageing populations in the Nordic countries: Mortality and longevity from 1990 to 2014.
Aims: Cross-country comparisons of mortality and longevity patterns of Nordic populations could contribute with novel insights into the compositional changes of these populations. We investigated three metrics of population ageing: the proportion of the population aged 75+ and 90+ years, the proportion of birth cohorts reaching 75 and 90 years, and life expectancy (LE) at age 75 and 90 years in Sweden, Norway, Iceland, Denmark and Finland, in the period 1990-2014. Methods: Demographic information was collected from national statistical databases and the Human Mortality Database. Results: All metrics on population ageing increased during the study period, but there were some cross-country variations. Finland experienced a notably steep increase in the proportion of 75+ and 90+ year olds compared to the other countries. Regarding the proportion reaching old ages, the Finnish lagged behind from the beginning, but females decreased this difference. The Danes were more similar to the other countries at the beginning, but did not experience the same increase over time. Gender-specific LE at age 75 and 90 years was similar overall in the five countries. Conclusions: Developments in cross-country variation suggest that survival until old age has become more similar for Finnish females and more different for Danish males and females compared with the other countries in recent decades. This provides perspectives on the potential to improve longevity in Denmark and Finland. Similarities in LE in old age suggest that expected mortality in old age has been more similar throughout the study period.


A comparative analysis of different approaches for integrated WWTP modelling.
In this paper a comparative analysis of the most important approaches for integrated WWTP modelling is presented. After an introductory presentation of the most important drawbacks and challenges for plant wide modelling, the fundamentals of three different approaches to construct integrated models are presented: "Interfaces" "Standard Supermodel" and "Tailored Supermodel". Afterwards, a comparative analysis of these approaches from different points of view (difficulties for the model end user, characterization of the process in the plant, flexibility or adaptability for each case of study, simulation platform requirements and computational costs) is carried out. From this comparison, some important conclusions about the suitability of each alternative depending on the simulation case study are extracted.


Invasion-mediated effects on marine trophic interactions in a changing climate: positive feedbacks favour kelp persistence.
The interactive effects of ocean warming and invasive species are complex and remain a source of uncertainty for projecting future ecological change. Climate-mediated change to trophic interactions can have pervasive ecological consequences, but the role of invasion in mediating trophic effects is largely unstudied. Using manipulative experiments in replicated outdoor mesocosms, we reveal how near-future ocean warming and macrophyte invasion scenarios interactively impact gastropod grazing intensity and preference for consumption of foundation macroalgae ( Ecklonia radiata and Sargassum vestitum). Elevated water temperature increased the consumption of both macroalgae through greater grazing intensity. Given the documented decline of kelp ( E. radiata) growth at higher water temperatures, enhanced grazing could contribute to the shift from kelp-dominated to Sargassum-dominated reefs that is occurring at the low-latitude margins of kelp distribution. However, the presence of a native invader ( Caulerpa filiformis) was related to low consumption by the herbivores on dominant kelp at warmer temperatures. Thus, antagonistic effects between climate change and a range expanding species can favour kelp persistence in a warmer future. Introduction of species should, therefore, not automatically be considered unfavourable under climate change scenarios. Climatic changes are increasing the need for effective management actions to address the interactive effects of multiple stressors and their ecological consequences, rather than single threats in isolation.


Signals in human striatum are appropriate for policy update rather than value prediction.
Influential reinforcement learning theories propose that prediction error signals in the brain's nigrostriatal system guide learning for trial-and-error decision-making. However, since different decision variables can be learned from quantitatively similar error signals, a critical question is: what is the content of decision representations trained by the error signals? We used fMRI to monitor neural activity in a two-armed bandit counterfactual decision task that provided human subjects with information about forgone and obtained monetary outcomes so as to dissociate teaching signals that update expected values for each action, versus signals that train relative preferences between actions (a policy). The reward probabilities of both choices varied independently from each other. This specific design allowed us to test whether subjects' choice behavior was guided by policy-based methods, which directly map states to advantageous actions, or value-based methods such as Q-learning, where choice policies are instead generated by learning an intermediate representation (reward expectancy). Behaviorally, we found human participants' choices were significantly influenced by obtained as well as forgone rewards from the previous trial. We also found subjects' blood oxygen level-dependent responses in striatum were modulated in opposite directions by the experienced and forgone rewards but not by reward expectancy. This neural pattern, as well as subjects' choice behavior, is consistent with a teaching signal for developing habits or relative action preferences, rather than prediction errors for updating separate action values.


Tocilizumab in adult-onset Still's disease: the Israeli experience.
To describe the Israeli experience of treating adult-onset Still's disease (AOSD) with tocilizumab (TCZ). Israeli rheumatologists who treated AOSD with TCZ filled in questionnaires on symptoms, number of tender and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and dosage of prednisone at initial TCZ administration, after 6 months, and at the end of followup. Nine male and 6 female patients, aged 33 ± 12 years, mean disease duration 9 years (range: 1-25) were identified. They had used a mean of 3.6 disease-modifying drugs, including 10 patients with tumor necrosis factor blockers. Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (3 patients). All patients completed at least 6 months of treatment. The mean followup period was 15.7 ± 9 months. At the onset of therapy, despite the use of prednisone (27.6 ± 26.3 mg/d), all patients reported joint pain. Fever was reported in 9 patients, rash in 7, pleuritis in 3, and hepatitis in 2 before TCZ use, with mean ESR and CRP levels of 60 ± 28 mm/h and 11.6 ± 15 mg/dl, respectively. After 6 months of treatment and at the end of followup, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly. Only 2 patients still complained of mild arthralgias, and none reported systemic symptoms at the end of followup. TCZ 8 mg/kg was extremely efficacious in treating adult patients with refractory Still's disease. Both TCZ and interleukin 1 blockade should be considered in the treatment algorithm of AOSD. Randomized controlled studies are needed to validate these findings.


Postcopulatory sexual selection influences baculum evolution in primates and carnivores.
The extreme morphological variability of the baculum across mammals is thought to be the result of sexual selection (particularly, high levels of postcopulatory selection). However, the evolutionary trajectory of the mammalian baculum is little studied and evidence for the adaptive function of the baculum has so far been elusive. Here, we use Markov chain Monte Carlo methods implemented in a Bayesian phylogenetic framework to reconstruct baculum evolution across the mammalian class and investigate the rate of baculum length evolution within the primate order. We then test the effects of testes mass (postcopulatory sexual selection), polygamy, seasonal breeding and intromission duration on the baculum in primates and carnivores. The ancestral mammal did not have a baculum, but both ancestral primates and carnivores did. No relationship was found between testes mass and baculum length in either primates or carnivores. Intromission duration correlated with baculum presence over the course of primate evolution, and prolonged intromission predicts significantly longer bacula in extant primates and carnivores. Both polygamous and seasonal breeding systems predict significantly longer bacula in primates. These results suggest the baculum plays an important role in facilitating reproductive strategies in populations with high levels of postcopulatory sexual selection.