A Systematic Review of User Expectations and Outcomes of Crisis Support Services.
Background: Crisis support services play an important role in providing free, immediate access to support people in the community experiencing a personal crisis. Recently, services have expanded from telephone to digital modalities including online chat and text message services. This raises the question of what outcomes are being achieved for increasingly diverse service users across different modalities. Aims: This systematic review aimed to determine the expectations and outcomes of users of crisis support services across three modalities (telephone, online chat, and text message/SMS). Method: Online databases (CINAHL, MEDLINE, PsycARTICLES, PsycINFO, Psychological and Behavioural Sciences Collection) and gray literature were searched for studies measuring expectations and outcomes of crisis support services. Results: A total of 31 studies were included in the review, the majority of which were telephone-based. Similar expectations were found for telephone and online chat modalities, as well as consistently positive outcomes, measured by changes in emotional state, satisfaction, and referral plans. Limitations/Conclusion: There is a paucity of consistent outcome measures across and within modalities and limited research about users of text message/SMS services.


[Year-round antibody profile of groups of horses of a herd kept in isolation after differently terminating use of an experimental viral combination vaccine].
The commercial vaccine "Resequin F Konz." devised against viral respiratory infections of horses contains the abortigenic Equine Herpesvirus-1 (EHV-1). Therefore we had used it in our protection project of the Austrian Lipizzaners+ primarily to prevent abortions. Taking into account the recent perception that for young horses the respiratory-pathogenic EHV-4 type is essential Behringwerke Marburg added this particular virus to their market product to produce a multicomponent experimental vaccine. We examined this vaccine for its antibody induction as well as their persistence against each of its viral components. On groups of foals we did this regarding its prophylactic effect against respiratory infections. Furthermore, we investigated its immunogenicity in adult horses, hoping for a potentiating effect of EHV-4 against EHV-1, mediating enhanced protection against abortion caused by the latter virus. This experimental vaccine proved excellently tolerable, its immunogenicity against either equine herpesvirus type was considerable, was very good against both equine influenza subtypes, was low, however, against retroviruses types 1 and 3. Recommendations are made for seasonal optimal spacing of vaccinations, taking into account the prevalent dissemination phases of the viruses involved, the different age groups of horses and their respective use.


Does chocolate reduce blood pressure? A meta-analysis.
Dark chocolate and flavanol-rich cocoa products have attracted interest as an alternative treatment option for hypertension, a known risk factor for cardiovascular disease. Previous meta-analyses concluded that cocoa-rich foods may reduce blood pressure. Recently, several additional trials have been conducted with conflicting results. Our study summarises current evidence on the effect of flavanol-rich cocoa products on blood pressure in hypertensive and normotensive individuals. We searched Medline, Cochrane and international trial registries between 1955 and 2009 for randomised controlled trials investigating the effect of cocoa as food or drink compared with placebo on systolic and diastolic blood pressure (SBP/DBP) for a minimum duration of 2 weeks. We conducted random effects meta-analysis of all studies fitting the inclusion criteria, as well as subgroup analysis by baseline blood pressure (hypertensive/normotensive). Meta-regression analysis explored the association between type of treatment, dosage, duration or baseline blood pressure and blood pressure outcome. Statistical significance was set at P < 0.05. Fifteen trial arms of 13 assessed studies met the inclusion criteria. Pooled meta-analysis of all trials revealed a significant blood pressure-reducing effect of cocoa-chocolate compared with control (mean BP change +/- SE: SBP: -3.2 +/- 1.9 mmHg, P = 0.001; DBP: -2.0 +/- 1.3 mmHg, P = 0.003). However, subgroup meta-analysis was significant only for the hypertensive or prehypertensive subgroups (SBP: -5.0 +/- 3.0 mmHg; P = 0.0009; DBP: -2.7 +/- 2.2 mm Hg, P = 0.01), while BP was not significantly reduced in the normotensive subgroups (SBP: -1.6 +/- 2.3 mmHg, P = 0.17; DBP: -1.3 +/- 1.6 mmHg, P = 0.12). Nine trials used chocolate containing 50% to 70% cocoa compared with white chocolate or other cocoa-free controls, while six trials compared high- with low-flavanol cocoa products. Daily flavanol dosages ranged from 30 mg to 1000 mg in the active treatment groups, and interventions ran for 2 to 18 weeks. Meta-regression analysis found study design and type of control to be borderline significant but possibly indirect predictors for blood pressure outcome. Our meta-analysis suggests that dark chocolate is superior to placebo in reducing systolic hypertension or diastolic prehypertension. Flavanol-rich chocolate did not significantly reduce mean blood pressure below 140 mmHg systolic or 80 mmHg diastolic.


Connectivity, dynamics, and memory in reservoir computing with binary and analog neurons.
Reservoir computing (RC) systems are powerful models for online computations on input sequences. They consist of a memoryless readout neuron that is trained on top of a randomly connected recurrent neural network. RC systems are commonly used in two flavors: with analog or binary (spiking) neurons in the recurrent circuits. Previous work indicated a fundamental difference in the behavior of these two implementations of the RC idea. The performance of an RC system built from binary neurons seems to depend strongly on the network connectivity structure. In networks of analog neurons, such clear dependency has not been observed. In this letter, we address this apparent dichotomy by investigating the influence of the network connectivity (parameterized by the neuron in-degree) on a family of network models that interpolates between analog and binary networks. Our analyses are based on a novel estimation of the Lyapunov exponent of the network dynamics with the help of branching process theory, rank measures that estimate the kernel quality and generalization capabilities of recurrent networks, and a novel mean field predictor for computational performance. These analyses reveal that the phase transition between ordered and chaotic network behavior of binary circuits qualitatively differs from the one in analog circuits, leading to differences in the integration of information over short and long timescales. This explains the decreased computational performance observed in binary circuits that are densely connected. The mean field predictor is also used to bound the memory function of recurrent circuits of binary neurons.


SU-D-217BCD-04: How Do We Know How Low Can We Go in Lung Cancer Screening CT?
To demonstrate a technique for determining the acceptable radiation dose level for lung cancer screening CT. 20 patients who underwent a clinically indicated routine chest CT scan with 120 kV and 180 quality reference mAs were enrolled in this IRB approved study. Automatic exposure control was used to adjust for patient size. Scanner output, as expressed in CTDIvol, varied accordingly (mean=16.8 mGy, range=7.6 to 26.6 mGy). A previously validated noise insertion software tool developed in our lab was used to simulate scans acquired with reduced dose levels (12.5%, 25%, 50% of the original dose level). Images reconstructed from the same raw data but at the original and simulated, reduced dose levels were randomized and blindly reviewed by three thoracic radiologists. Lung and soft tissue regions were graded for two different imaging tasks: 1) routine diagnostic CT exam of the chest and 2) screening exam of the chest for lung cancer. A 5 point scale was used to rate each exam for each task (1=too noisy, significantly impacted confidence to 5=excellent quality, excellent confidence). Exams were considered acceptable when at least two of the three radiologists gave a score of 3 or higher. The percentage of patients meeting this definition of acceptable was calculated for each imaging task, dose level, and tissue type (lung or soft tissue). The percentages of exams considered acceptable for the purpose of lung cancer screening were 90%, 100%, 100%, 100% (lung tissue) and 85%, 100%, 100%, 100% (soft tissue) at 12.5%, 25%, 50% and 100% of original dose level. For the purpose of routine diagnostic chest CT, the percentage of acceptable exams were 75%, 95%, 100%, 100% (lung tissue) and 35%, 85%, 90%, 100% (soft tissue) at 12.5%, 25%, 50% and 100% of original dose level. At 25% of the dose used for routine diagnostic chest CT at our institution, acceptable image quality for the purpose of CT screening for lung cancer was achieved in 100% of the evaluated cases. This factor of 4 in dose reduction relative to routine chest exams is similar to what was used in the NLST trial.


Phospholipids coupled to a carrier induce IgG antibody that blocks tumour necrosis factor induction by toxic malaria antigens.
Phospholipid-containing antigens of malaria parasites stimulate macrophages to secrete tumour necrosis factor (TNF), induce hypoglycaemia and are toxic to mice. This TNF induction is inhibited by antisera made against the antigens, the inhibitory activity of which can be removed specifically by adsorption to phosphatidylinositol (PI) liposomes. Although the same was true of antisera made against PI, the inhibitory activity of antisera made against some other phospholipids appeared to be directed against a common determinant, probably the phosphate ester head group. We have shown previously that the activity of all the antisera was associated mainly with IgM and was not boosted by repeated injections of the antigens. To try and induce a secondary response against the parasite antigens using non-toxic molecules, mice were immunized with various phosphorylated compounds coupled to keyhole limpet haemocyanin (KLH). Three injections of PI-KLH or of phosphatidylserine (PS) coupled to KLH induced significantly higher titres of inhibitory antibody than one; furthermore, the inhibitory activity was mainly in the IgG fraction. The antisera did not inhibit TNF induction by lipopolysaccharide (LPS) or lipoteichoic acid. However, antisera against PS-KLH, though not PI-KLH, inhibited the induction of TNF by the phospholipid, platelet-activating factor (PAF). These antisera, and antisera from mice immunized with phospho-threonine or galactosamine-1-phosphate conjugated to KLH, contained inhibitory antibodies of differing specificities. Mice immunized with PI-KLH, PS-KLH or phospho-threonine-KLH did not develop hypoglycaemia when challenged with the parasite toxic antigens. These results indicate that the antigenicity of non-toxic analogues can be dramatically enhanced by coupling to a protein carrier.


Limitations of constitutional protections in Jackson v. Indiana pertaining to charges with no statute of limitations.
There has been a long-standing link between the civil and criminal commitment procedures for individuals found incompetent to stand trial (IST). In the criminal system, when restoration of competency fails to be realized in a reasonable time, the civil commitment process becomes the default system for commitment. While there have been recent calls for improved mechanisms for predicting competence restorability, there has been little attention paid to individuals who can oscillate indefinitely between commitment in both the criminal and civil systems. We provide an example of one such case where an individual falls into the legal space that sits outside of the judicial guidance outlined in the landmark case Jackson v. Indiana. This review of Oregon public documents surrounding an ongoing murder case highlights the potential for indefinite detention of individuals who have been charged with serious crimes that do not have a statute of limitations, who are unlikely to be restored to competency to stand trial, and who are inconsistently found to be dangerous under civil commitment standards.


Regulating of growth hormone sensitivity by sex steroids: implications for therapy.
Growth hormone (GH) is an important regulator of body composition, reducing body fat by stimulating fat oxidation and enhancing lean body mass by stimulating protein accretion. The emergence of differences in body composition between the sexes during puberty suggests sex steroids modulate the action of GH. Work from our laboratory have investigated the influence of estrogens and androgens on the metabolic actions of GH in human adults. The liver is an important site of physiological interaction as it is a sex steroid responsive organ and a major target of GH action. Estrogen, when administered orally impairs the GH-regulated endocrine and metabolic function of the liver via a first-pass effect. It reduces circulating IGF-I, fat oxidation and protein synthesis, contributing to a loss of lean and a gain of fat mass. These effects occur in normal and in GH-deficient women and are avoided by transdermal administration of physiological doses of estrogen. In contrast, studies in hypopituitary men indicate that testosterone enhances the metabolic effects of GH. Testosterone alone stimulates fat oxidation and protein synthesis, both of which are enhanced by GH. Studies in GH deficiency adults have consistently reported women to be less sensitive to GH than men. In summary, estrogens and androgens exert divergent effects on the action of GH. The results provide an explanation for sexual dimorphism in body composition in adults and the gender-related response to GH replacement in hypopituitary subjects. In the management of hypopituitarism, estrogens should be administered by the parenteral route in women and testosterone be replaced in men to optimize the benefits of GH replacement.


Relearning after damage in connectionist networks: toward a theory of rehabilitation.
Connectionist modeling offers a useful computational framework for exploring the nature of normal and impaired cognitive processes. The current work extends the relevance of connectionist modeling in neuropsychology to address issues in cognitive rehabilitation: the degree and speed of recovery through retraining, the extent to which improvement on treated items generalizes to untreated items, and how treated items are selected to maximize this generalization. A network previously used to model impairments in mapping orthography to semantics is retrained after damage. The degree of relearning and generalization varies considerably for different lesion locations, and has interesting implications for understanding the nature and variability of recovery in patients. In a second simulation, retraining on words whose semantics are atypical of their category yields more generalization than retraining on more typical words, suggesting a counterintuitive strategy for selecting items in patient therapy to maximize recovery. In a final simulation, changes in the pattern of errors produced by the network over the course of recovery is used to constrain explanations of the nature of recovery of analogous brain-damaged patients. Taken together, the findings demonstrate that the nature of relearning in damaged connectionist networks can make important contributions to a theory of rehabilitation in patients.


Mitochondrial DNA oxidative damage and repair in aging and Alzheimer's disease.
Mitochondria are fundamental to the life and proper functioning of cells. These organelles play a key role in energy production, in maintaining homeostatic levels of second messengers (e.g., reactive oxygen species and calcium), and in the coordination of apoptotic cell death. The role of mitochondria in aging and in pathophysiological processes is constantly being unraveled, and their involvement in neurodegenerative processes, such as Alzheimer's disease (AD), is very well known. A considerable amount of evidence points to oxidative damage to mitochondrial DNA (mtDNA) as a determinant event that occurs during aging, which may cause or potentiate mitochondrial dysfunction favoring neurodegenerative events. Concomitantly to reactive oxygen species production, an inefficient mitochondrial base excision repair (BER) machinery has also been pointed to favor the accumulation of oxidized bases in mtDNA during aging and AD progression. The accumulation of oxidized mtDNA bases during aging increases the risk of sporadic AD, an event that is much less relevant in the familial forms of the disease. This aspect is critical for the interpretation of data arising from tissue of AD patients and animal models of AD, as the major part of animal models rely on mutations in genes associated with familial forms of the disease. Further investigation is important to unveil the role of mtDNA and BER in aging brain and AD in order to design more effective preventive and therapeutic strategies.


Blind estimation of channel parameters and source components for EEG signals: a sparse factorization approach.
In this paper, we use a two-stage sparse factorization approach for blindly estimating the channel parameters and then estimating source components for electroencephalogram (EEG) signals. EEG signals are assumed to be linear mixtures of source components, artifacts, etc. Therefore, a raw EEG data matrix can be factored into the product of two matrices, one of which represents the mixing matrix and the other the source component matrix. Furthermore, the components are sparse in the time-frequency domain, i.e., the factorization is a sparse factorization in the time frequency domain. It is a challenging task to estimate the mixing matrix. Our extensive analysis and computational results, which were based on many sets of EEG data, not only provide firm evidences supporting the above assumption, but also prompt us to propose a new algorithm for estimating the mixing matrix. After the mixing matrix is estimated, the source components are estimated in the time frequency domain using a linear programming method. In an example of the potential applications of our approach, we analyzed the EEG data that was obtained from a modified Sternberg memory experiment. Two almost uncorrelated components obtained by applying the sparse factorization method were selected for phase synchronization analysis. Several interesting findings were obtained, especially that memory-related synchronization and desynchronization appear in the alpha band, and that the strength of alpha band synchronization is related to memory performance.


Lifestyle Intervention With or Without Lay Volunteers to Prevent Type 2 Diabetes in People With Impaired Fasting Glucose and/or Nondiabetic Hyperglycemia: A Randomized Clinical Trial.
Nearly half of the older adult population has diabetes or a high-risk intermediate glycemic category, but we still lack trial evidence for effective type 2 diabetes prevention interventions in most of the current high-risk glycemic categories. To determine whether a group-based lifestyle intervention (with or without trained volunteers with type 2 diabetes) reduced the risk of progression to type 2 diabetes in populations with a high-risk glycemic category. The Norfolk Diabetes Prevention Study was a parallel, 3-arm, group-based, randomized clinical trial conducted with up to 46 months of follow-up from August 2011 to January 2019 at 135 primary care practices and 8 intervention sites in the East of England. We identified 141 973 people at increased risk of type 2 diabetes, screened 12 778 (9.0%), and randomized those with a high-risk glycemic category, which was either an elevated fasting plasma glucose level alone (≥110 and <126 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) or an elevated glycated hemoglobin level (≥6.0% to <6.5%; nondiabetic hyperglycemia) with an elevated fasting plasma glucose level (≥100 to <110 mg/dL). A control arm receiving usual care (CON), a theory-based lifestyle intervention arm of 6 core and up to 15 maintenance sessions (INT), or the same intervention with support from diabetes prevention mentors, trained volunteers with type 2 diabetes (INT-DPM). Type 2 diabetes incidence between arms. In this study, 1028 participants were randomized (INT, 424 [41.2%] [166 women (39.2%)]; INT-DPM, 426 [41.4%] [147 women (34.5%)]; CON, 178 [17.3%] [70 women (%39.3)]) between January 1, 2011, and February 24, 2017. The mean (SD) age was 65.3 (10.0) years, mean (SD) body mass index 31.2 (5) (calculated as weight in kilograms divided by height in meters squared), and mean (SD) follow-up 24.7 (13.4) months. A total of 156 participants progressed to type 2 diabetes, which comprised 39 of 171 receiving CON (22.8%), 55 of 403 receiving INT (13.7%), and 62 of 414 receiving INT-DPM (15.0%). There was no significant difference between the intervention arms in the primary outcome (odds ratio [OR], 1.14; 95% CI, 0.77-1.7; P = .51), but each intervention arm had significantly lower odds of type 2 diabetes (INT: OR, 0.54; 95% CI, 0.34-0.85; P = .01; INT-DPM: OR, 0.61; 95% CI, 0.39-0.96; P = .033; combined: OR, 0.57; 95% CI, 0.38-0.87; P = .01). The effect size was similar in all glycemic, age, and social deprivation groups, and intervention costs per participant were low at $153 (£122). The Norfolk Diabetes Prevention lifestyle intervention reduced the risk of type 2 diabetes in current high-risk glycemic categories. Enhancing the intervention with DPM did not further reduce diabetes risk. These translatable results are relevant for current diabetes prevention efforts. ISRCTN Registry Identifier: ISRCTN34805606.


Optimization of TaDREB3 gene expression in transgenic barley using cold-inducible promoters.
Constitutive over-expression of the TaDREB3 gene in barley improved frost tolerance of transgenic plants at the vegetative stage of plant development, but leads to stunted phenotypes and 3- to 6-week delays in flowering compared to control plants. In this work, two cold-inducible promoters with contrasting properties, the WRKY71 gene promoter from rice and the Cor39 gene promoter from durum wheat, were applied to optimize expression of TaDREB3. The aim of the work was to increase plant frost tolerance and to decrease or prevent negative developmental phenotypes observed during constitutive expression of TaDREB3. The OsWRKY71 and TdCor39 promoters had low-to-moderate basal activity and were activated by cold treatment in leaves, stems and developing spikes of transgenic barley and rice. Expression of the TaDREB3 gene, driven by either of the tested promoters, led to a significant improvement in frost tolerance. The presence of the functional TaDREB3 protein in transgenic plants was confirmed by the detection of strong up-regulation of cold-responsive target genes. The OsWRKY71 promoter-driven TaDREB3 provides stronger activation of the same target genes than the TdCor39 promoter. Analysis of the development of transgenic plants in the absence of stress revealed small or no differences in plant characteristics and grain yield compared with wild-type plants. The WRKY71-TaDREB3 promoter-transgene combination appears to be a promising tool for the enhancement of cold and frost tolerance in crop plants but field evaluation will be needed to confirm that negative development phenotypes have been controlled.


Perceived quality of life and coping for Swedish women with breast cancer who choose complementary medicine.
The aim of the present study, which is part of a major clinical controlled study of the life situation of women with breast cancer, was to compare two groups of women concerning perceived quality of life and coping. The women were treated in two different cancer treatment programs: complementary treatment, which included anthroposophic therapy, and conventional cancer treatment. A total of 120 women were included, 60 women treated with anthroposophic medicine, and 60 individually matched women treated with conventional medicine only. Quality of life was measured by the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Core 30, and the Life Satisfaction Questionnaire. Coping was measured by the Mental Adjustment to Cancer scale. The results showed that the women who chose anthroposophic therapy perceived their quality of life to be lower on admission to the hospital and showed more anxious preoccupation than the women in conventional medicine. It can be concluded that, due to the careful matching procedure, the women in the two groups are comparable in a medical sense but not from the perspective of quality of life and coping.


A critical reassessment of second-look laparotomy in epithelial ovarian carcinoma.
Eighty-eight women with epithelial ovarian carcinoma, treated by first-line chemotherapy, achieved a complete clinical response and underwent second-look laparotomy to assess the true pathologic status of their disease. Persistent tumor was found in 50 patients (57%). Thirty-two of these (36%) had obvious gross tumor, whereas, 16 (18%) had microscopic disease. Thirty-eight patients (43%) had no pathologic evidence of persistent ovarian carcinoma. With a follow-up of 6 to 60 months, 30 of these patients (79%) remain without evidence of recurrence. Multivariate logistic regression analysis revealed three covariates that were independently significant in predicting continued disease-free status. These included: the greatest diameter of the largest residual tumor left at the primary operation; histologic features of the tumor; and the diameter of the largest tumor aggregate found at initial operation. A mathematical model based on the most significant covariates was designed to assess the relative risk of any patient having persistent tumor at second-look laparotomy. A comparison of the predicted to actual outcome revealed a sensitivity of the model of 88%, a specificity of 71%, and an accuracy of 77%. Second-look laparotomy represents the basis on which potentially curative second-line salvage therapy can be initiated. With an increasing period of follow-up and with greater numbers of patients, it can potentially document a complete pathologic response to first-line therapy administered with curative intent, and identify patients for additional, adjunctive therapy, who are at risk of recurrence.


The effects of acclimation to the United States and other demographic factors on responses to salt levels in foods: An examination utilizing face reader technology.
The aim of this study was to assess the role of extended time in the United States (as defined as a continuous period greater than two years; referred to hereafter as "US Acclimated"), as well as other demographic factors, on the level of net positive response of consumers to different salt levels in food samples. One hundred panelists were recruited, including 50 meeting our US acclimation criterion. Panelists assessed samples of potatoes with five different levels of salt concentrations, and the levels of their net positive responses were evaluated with FaceReader technology (Noldus). The data of our study showed a significant positive association between US Acclimated participants and the level of net positive response to samples with higher salt contents. This interaction remained statistically significant even when modeling the effects with consideration of race/ethnicity and gender. Another notable outcome was the unexpected significant interaction between gender and US acclimation in regards to evaluated positive response across all salt concentrations (US Acclimated females demonstrating substantially and significant higher levels of positive response than US Acclimated males). The association between living in the United States and showing more positive response to higher salt contents is consistent with many persistent characterizations of the eating habits in the United States, but it is not in fact well explained by the most recent data regarding the observed levels of average sodium consumption across worldwide geographical regions. The results of this study may be demonstrating evidence of underlying as-yet-unknown factors contributing to the responses of consumers to salt levels in foods. Further examination of these possible factors may well be warranted.


Willingness to participate in HIV vaccine trials among men who have sex with men in Chennai and Mumbai, India: a social ecological approach.
Recruitment of low- and middle-income country volunteers from most-at-risk populations in HIV vaccine trials is essential to vaccine development. In India, men who have sex with men (MSM) are at disproportionately high risk for HIV infection and an important population for trial recruitment. Investigations of willingness to participate (WTP) in HIV vaccine trials have focused predominantly on individual-level determinants. We explored multi-level factors associated with WTP among MSM in India. We conducted 12 focus groups (n = 68) with low socioeconomic MSM in Chennai and Mumbai, and 14 key informant interviews with MSM community leaders and service providers. Focus groups/interviews were recorded, transcribed and translated into English. Two bilingual investigators conducted thematic analysis using line-by-line coding and a constant comparative method, with member-checking by community representatives. Factors associated with WTP were evidenced across the social ecology of MSM-social-structural: poverty, HIV-, sexual- and gender non-conformity stigma, institutionalized discrimination and government sponsorship of trials; community-level: endorsement by MSM community leaders and organizations, and fear of within-group discrimination; interpersonal: anticipated family discord, partner rejection, having financially-dependent family members and disclosure of same-sex sexuality; and individual-level: HIV vaccine trial knowledge and misconceptions, safety concerns, altruism and preventive misconception. Pervasive familial, community and social-structural factors characteristic of the Indian sociocultural context may complicate individual-focused approaches to WTP and thereby constrain the effectiveness of interventions to support recruitment and retention in HIV vaccine trials. Interventions to reduce stigma and discrimination against MSM and people living with HIV, capacity-building of MSM community organizations and transparent communications tailored to the knowledge and educational level of local communities may support meaningful engagement of MSM in HIV vaccine trials. Vigilance in providing fair but not excessive compensation and healthcare benefits and in mitigating preventive misconception are warranted to support ethical conduct of trials among MSM in India.


The pharmacology of impulsive behaviour in rats VI: the effects of ethanol and selective serotonergic drugs on response choice with varying delays of reinforcement.
Tolerance to delay of reinforcement has been proposed as an important facet of self-control in both animals and man. Poor self-control, leading to impulsive behaviour, can be a major problem if it reaches pathological levels. The effects of five serotonergic drugs were compared to those of ethanol on a procedure for measuring tolerance to delay of reinforcement in rats in order to elucidate further the role of the serotonin systems in the regulation of impulsive behaviour. Rats were trained to choose between a single food pellet (small reinforcer) delivered immediately or five food pellets (large reinforcer) delivered after programmed delays. At the start of each session, there was no delay between the response and delivery of the large reinforcer, but this was increased stepwise during the session to delays of 10, 20, 40 and 60 s. The rats showed consistent preference for the larger reinforcer when it was not delayed but showed a shift in preference as the session continued, so that they preferred the small reinforcer when the large was delayed by 40 or 60 s. Ethanol at a dose of 1.0 g/kg produced a significance increase in preference for the small, immediate reinforcer throughout the session, although there were marked individual differences in the size of the effect. A similar, but somewhat smaller effect was seen with the 5-HT(2) agonist, DOI, at a dose of 1.0 mg/kg. In contrast, the 5-HT(1A) agonist, 8-OH-DPAT (0.3 mg/kg) reduced preference for the large reinforcer at the start of the session, and reduced preference for the small reinforcer at the end of the session, i.e. produced a regression to indifference. Lower doses of these three drugs, and treatment with the 5-HT receptor subtype selective antagonists WAY-100635 (5-HT(1A): 0.01-0.1 mg/kg), ritanserin (5-HT(2): 0.1 and 0.3 mg/kg) and MDL-72222 (5-HT(3): 1.0 and 3.0 mg/kg) had no significant effects on reinforcer choice. These data show that ethanol and DOI increase preference for the immediate reinforcer, which can be construed as evidence of an increase in impulsive behaviour (reduction in self control), whereas selective blockade of the 5-HT(1A), 5-HT(2) or 5-HT(3) receptors using selective antagonists does not affect self-control.


Melioidosis caused by Burkholderia pseudomallei in drinking water, Thailand, 2012.
We identified 10 patients in Thailand with culture-confirmed melioidosis who had Burkholderia pseudomallei isolated from their drinking water. The multilocus sequence type of B. pseudomallei from clinical specimens and water samples were identical for 2 patients. This finding suggests that drinking water is a preventable source of B. pseudomallei infection.


The impact of HIV and AIDS research: a case study from Swaziland.
Swaziland is experiencing the world's worst HIV and AIDS epidemic. Prevalence rose from four percent of antenatal clinic attendees in 1992 to 42.6 percent in 2004. The Report 'Reviewing 'Emergencies' for Swaziland: Shifting the Paradigm in a New Era' published in 2007 bought together social and economic indicators. It built a picture of the epidemic as a humanitarian emergency, requiring urgent action from international organisations, donors, and governments. Following a targeted communications effort, the report was believed to have raised the profile of the issue and Swaziland - a success story for HIV and AIDS research. Keen to understand how, where and why the report had an impact, Health Economics and HIV/AIDS Research Division commissioned an assessment to track and evaluate the influence of the research. This tapped into literature on the significance of understanding the research-to-policy interface. This paper outlines the report and its impact. It explores key findings from the assessment and suggests lessons for future research projects. The paper demonstrates that, although complex, and not without methodological issues, impact assessment of research can be of real value to researchers in understanding the research-to-policy interface. Only by gaining insight into this process can researchers move forward in delivering effective research.


Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory.
D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [(11)C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.


Modulation of collective cell behaviour by geometrical constraints.
Intracellular and extracellular mechanical forces play a crucial role during tissue growth, modulating nuclear shape and function and resulting in complex collective cell behaviour. However, the mechanistic understanding of how the orientation, shape, symmetry and homogeneity of cells are affected by environmental geometry is still lacking. Here we investigate cooperative cell behaviour and patterns under geometric constraints created by topographically patterned substrates. We show how cells cooperatively adopt their geometry, shape, positioning of the nucleus and subsequent proliferation activity. Our findings indicate that geometric constraints induce significant squeezing of cells and nuclei, cytoskeleton reorganization, drastic condensation of chromatin resulting in a change in the cell proliferation rate and the anisotropic growth of cultures. Altogether, this work not only demonstrates complex non-trivial collective cellular responses to geometrical constraints but also provides a tentative explanation of the observed cell culture patterns grown on different topographically patterned substrates. These findings provide important fundamental knowledge, which could serve as a basis for better controlled tissue growth and cell-engineering applications.


TAT-mediated delivery of a DNA repair enzyme to skin cells rapidly initiates repair of UV-induced DNA damage.
UV light causes DNA damage in skin cells, leading to more than one million cases of non-melanoma skin cancer diagnosed annually in the United States. Although human cells possess a mechanism (nucleotide excision repair) to repair UV-induced DNA damage, mutagenesis still occurs when DNA is replicated before repair of these photoproducts. Although human cells have all the enzymes necessary to complete an alternate repair pathway, base excision repair (BER), they lack a DNA glycosylase that can initiate BER of dipyrimidine photoproducts. Certain prokaryotes and viruses produce pyrimidine dimer-specific DNA glycosylases (pdgs) that initiate BER of cyclobutane pyrimidine dimers (CPDs), the predominant UV-induced lesions. Such a pdg was identified in the Chlorella virus PBCV-1 and termed Cv-pdg. The Cv-pdg protein was engineered to contain a nuclear localization sequence (NLS) and a membrane permeabilization peptide (transcriptional transactivator, TAT). Here, we demonstrate that the Cv-pdg-NLS-TAT protein was delivered to repair-proficient keratinocytes and fibroblasts, and to a human skin model, where it rapidly initiated removal of CPDs. These data suggest a potential strategy for prevention of human skin cancer.


Multimodal Learning With Transformers: A Survey.
Transformer is a promising neural network learner, and has achieved great success in various machine learning tasks. Thanks to the recent prevalence of multimodal applications and Big Data, Transformer-based multimodal learning has become a hot topic in AI research. This paper presents a comprehensive survey of Transformer techniques oriented at multimodal data. The main contents of this survey include: (1) a background of multimodal learning, Transformer ecosystem, and the multimodal Big Data era, (2) a systematic review of Vanilla Transformer, Vision Transformer, and multimodal Transformers, from a geometrically topological perspective, (3) a review of multimodal Transformer applications, via two important paradigms, i.e., for multimodal pretraining and for specific multimodal tasks, (4) a summary of the common challenges and designs shared by the multimodal Transformer models and applications, and (5) a discussion of open problems and potential research directions for the community.


Placental Hypomethylation Is More Pronounced in Genomic Loci Devoid of Retroelements.
The human placenta is hypomethylated compared to somatic tissues. However, the degree and specificity of placental hypomethylation across the genome is unclear. We assessed genome-wide methylation of the human placenta and compared it to that of the neutrophil, a representative homogeneous somatic cell. We observed global hypomethylation in placenta (relative reduction of 22%) compared to neutrophils. Placental hypomethylation was pronounced in intergenic regions and gene bodies, while the unmethylated state of the promoter remained conserved in both tissues. For every class of repeat elements, the placenta showed lower methylation but the degree of hypomethylation differed substantially between these classes. However, some retroelements, especially the evolutionarily younger Alu elements, retained high levels of placental methylation. Surprisingly, nonretrotransposon-containing sequences showed a greater degree of placental hypomethylation than retrotransposons in every genomic element (intergenic, introns, and exons) except promoters. The differentially methylated fragments (DMFs) in placenta and neutrophils were enriched in gene-poor and CpG-poor regions. The placentally hypomethylated DMFs were enriched in genomic regions that are usually inactive, whereas hypermethylated DMFs were enriched in active regions. Hypomethylation of the human placenta is not specific to retroelements, indicating that the evolutionary advantages of placental hypomethylation go beyond those provided by expression of retrotransposons and retrogenes.


Proficiency of nerve conduction using standard methods and reference values (Cl. NPhys Trial 4).
The Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver differences. Trial 4 tested whether use of written instructions and pretrial agreement on techniques and use of standard reference values, diagnostic percentile values, or broader categorization of abnormality could reduce significant interobserver disagreement and improve agreement among clinical neurophysiologists. The Trial 4 modifications markedly decreased, but did not eliminate, significant interobserver differences of measured attributes of NC. Use of standard reference values and defined percentile values of abnormality decreased interobserver disagreement and improved agreement of judgment of abnormality among evaluators. Therefore, the same clinical neurophysiologist should perform repeat NCs of therapeutic trial patients. Differences in interobserver judgment of abnormality decrease with use of common standard reference values and a defined percentile level of abnormality, providing a rationale for their use in therapeutic trials and medical practice.


An observation of a severely disabled infant chimpanzee in the wild and her interactions with her mother.
We report the physical and behavioral development of one severely disabled female infant chimpanzee (Pan troglodytes schweinfurthii) of the well-habituated M group in the Mahale Mountains National Park. We documented interactions between the infant and its mother and with other group members. Congenital disabilities occur in many primate species, including chimpanzees. However, there have been only a few case studies of congenitally disabled chimpanzee infants and no reports examining how a chimpanzee mother copes with such a disabled infant in the wild. The observed infant exhibited symptoms resembling Down syndrome, similar to those reported previously for a captive chimpanzee. The mother did not allow nonrelatives to take care of the infant even though she had been previously relatively tolerant of allomothering by nonrelatives. The mother's compensatory care for her infant's disabilities and allomothering of the infant by its sister might have helped it to survive for 23 months in the wild. Other group members did not show any aversive or fearful reactions to the disabled infant.


Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis.
The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.


Effect of oral snus and medicinal nicotine in smokers on toxicant exposure and withdrawal symptoms: a feasibility study.
Smokeless, spitless tobacco products are being introduced and marketed as cigarette substitutes. Data are needed regarding how smokers interested in cessation would use these products, the levels of resultant toxicant exposure, and the feasibility of using these products as aids for tobacco cessation. Smokers were randomized to receive Camel Snus (n = 51), Taboka (n = 52), or medicinal nicotine (n = 27) and required to quit smoking for 4 weeks. Measures of toxicant exposure and symptoms of craving and withdrawal were assessed prior to and during product use. Concentrations of exhaled carbon monoxide, urinary cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and urinary N'-nitrosonornicotine and its glucuronide (total NNN) were significantly (P values <0.05) lower at the end of treatment in each group except for total NNN in those receiving Camel Snus (P = 0.066). A significant group × time effect was observed for total NNAL concentrations (P = 0.002) with the decrease greatest in the medicinal nicotine group and smallest decrease in the Camel Snus group. No significant differences between groups were found in craving and withdrawal symptoms. Enrolling smokers into a cessation study utilizing newer smokeless tobacco products is feasible. Camel Snus and Taboka use was not found to be superior to medicinal nicotine in reducing withdrawal symptoms but decreases in NNAL were smaller in users of Camel Snus. This study demonstrates the feasibility of conducting a smoking cessation study utilizing these newer tobacco products. An appropriately powered study is needed to assess smoking cessation rates using these newer products compared with established, safer products such as medicinal nicotine.


Surgical treatment of early stage breast cancer in elderly: an international comparison.
Over 40% of breast cancer patients are diagnosed above the age of 65. Treatment of these elderly patients will probably vary over countries. The aim of this study was to make an international comparison (several European countries and the US) of surgical and radiation treatment for elderly women with early stage breast cancer. Survival comparisons were also made. Data were obtained from national or regional population-based registries in the Netherlands, Switzerland, Ireland, Belgium, Germany, and Portugal. For the US patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Early stage breast cancer patients aged ≥ 65 diagnosed between 1995 and 2005 were included. An international comparison was made for breast and axillary surgery, radiotherapy after breast conserving surgery (BCS), and relative or cause-specific survival. Overall, 204.885 patients were included. The proportion of patients not receiving any surgery increased with age in many countries; however, differences between countries were large. In most countries more than half of all elderly patients received breast conserving surgery (BCS), with the highest percentage in Switzerland. The proportion of elderly patients that received radiotherapy after BCS decreased with age in all countries. Moreover, in all countries the proportion of patients who do not receive axillary surgery increased with age. No large differences in survival between countries were recorded. International comparisons of surgical treatment for elderly women with early stage breast cancer are scarce. This study showed large international differences in treatment of elderly early stage breast cancer patients, with the most striking result the large proportion of elderly who did not undergo surgery at all. Despite large treatment differences, survival does not seem to be affected in a major way.


Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events.
Electrical stimulation of axons in the hippocampus with short high-frequency bursts that resemble in vivo activity patterns produces stable potentiation of postsynaptic responses when the bursts occur at intervals of 200 milliseconds but not 2 seconds. When a burst was applied to one input and a second burst applied to a different input to the same target neuron 200 milliseconds later, only the synapses activated by the second burst showed stable potentiation. This effect was observed even when the two inputs innervated completely different regions of the postsynaptic cells; but did not occur when the inputs were stimulated simultaneously or when the second burst was delayed by 2 seconds. Intracellular recordings indicated that the first burst extended the decay phase of excitatory postsynaptic potentials evoked 200 milliseconds later. These results suggest that a single burst of axonal stimulation produces a transient, spatially diffuse "priming" effect that prolongs responses to subsequent bursts, and that these altered responses trigger spatially restricted synaptic modifications. The similarity of the temporal parameters of the priming effect and the theta rhythm that dominates the hippocampal electroencephalogram (EEG) during learning episodes suggests that this priming may be involved in behaviorally induced synaptic plasticity.


Total synthesis and structural revision of an isopanepoxydone analog isolated from Lentinus strigellus.
Asymmetric total synthesis of compound 1, as a proposed molecular structure of a natural product, in 11 steps is described. The inconsistency of the characterization data between our synthesized sample and the natural product prompted us to propose a different molecular structure as compound 2 and accordingly accomplish total synthesis in 9 steps and confirm the structural revision of this natural product. Both total syntheses feature highly regio- and diastereoselective epoxidation, Stille cross-coupling and cross-metathesis.


Effect of elastic bandage on postural control in subjects with chronic ankle instability: a randomised clinical trial.
To report the immediate and prolonged (one week) effects of elastic bandage (EB) on balance control in subjects with chronic ankle instability. Twenty-eight individuals successfully completed the study protocol, of whom 14 were randomly assigned to the EB group (7 men, 7 women) and 14 were assigned to the non-standardised tape (NST) group (9 men, 5 women). To objectively measure postural sway we used computerised dynamic posturography (CDP) with sensory organisation test (SOT) and unilateral stance (US) test. We analysed the following SOT parameters: the composite SOT score, the composite SOT strategy and the SOT condition 2 and its strategy. In addition, we studied the centre of gravity (COG) sway velocity with open eyes and close eyes during the US test. Repeated measures ANOVA showed a significant effect for time in composite SOT score (F= 34.98; p= <0.01), composite SOT strategy (F= 12.082; p= 0.02), and COG sway with open eyes (F= 3.382; p= 0.039) in EB group and NST group. Therefore, there were improvements in balance control after bandage applications (defined as better scores in SOT parameters and decreased COG sway in US test). However, no differences between groups were observed in the most relevant parameters. This study did not observe differences between EB and NST during the follow-up in the majority of measurements. Several outcome measures for SOT and US tests improved in both groups immediately after bandage applications and after one week of use. EB of the ankle joint has no advantage as compared to the non-standardised tape. Implications for rehabilitation Elastic bandage (EB) of the ankle joint has no advantage as compared to the non-standardised tape. The effects of the bandages could be due to a greater subjective sense of security. It is important to be prudent with the use of bandage, since a greater sense of safety could also bring with it a greater risk of injury. The application of the bandage on subjects with chronic ankle instability (CAI) should be prolonged and used alongside other physiotherapy treatments.


Don't be fooled-A no-observed-effect concentration is no substitute for a poor concentration-response experiment.
Renowned mathematician and science historian Jacob Bronowski once defined science as "the acceptance of what works and the rejection of what does not" and noted "that needs more courage than we might think." Such would also seem to be the case with no-observed-effect concentrations (NOECs) and no-observed-effect levels in ecotoxicology. Compelling arguments were advanced more than a quarter of a century ago as to why the use of a model to describe the concentration-response relationship was preferable to an isolated metric, with the NOEC singled out as a particularly poor toxicity measure. In the ensuing years numerous articles critical of the NOEC have been written, with some calling for an outright ban on its use. More recently, arguments have been made for the retention of NOECs, with supporters suggesting that this metric is particularly useful in situations where the concentration-response relationship is weak or nonexistent. In addition, it has been claimed that there are situations in ecotoxicology where suitable models are simply not available. These arguments are not correct, and they also have impeded the decades-overdue incorporation of numerous recommendations based on research that NOECs should no longer be used. In the present study the authors counter some of the most recent claims in support of NOECs and provide new insights for 1 class of problem claimed not to be amenable to such modeling. They are confident that similar insights will be developed as further original research in this area is undertaken. Environ Toxicol Chem 2016;35:2141-2148. © 2016 SETAC.


Screening of Chinese herbal medicines for antityrosinase activity in a cell free system and B16 cells.
Tyrosinase inhibitors are becoming increasingly important in controlling skin hyperpigmentation. We aimed to screen 50 extracts from traditional Chinese medicines (TCM) for tyrosinase activity-inhibiting agents. The 50 herbal extracts were prepared from 32 herbs and 18 TCM formulas, which are used as folk skin whiteners in China and have not been investigated for their skin-whitening mechanisms. Each herb and formula was extracted with 30% ethanol and water, respectively, and followed by column chromatography for isolating bioactive substances such as saponins, flavonoids and alkaloids for the antityrosinase activity study. Every extract was tested using the cell free mushroom tyrosinase inhibitory assay at 2 mg/ml for the single herb extracts and 1mg/ml for formula extracts. Extracts showing greater than 50% inhibition against mushroom tyrosinase activity were further examined by cellular tyrosinase assay in mouse B16 cells. The cytotoxicity in B16 cells was measured by methyl thiazolyl tetrazolium bromide (MTT) assay. In the cell-free assay, 10 out of the 50 extracts demonstrated more than 50% inhibition against mushroom tyrosinase activity. These 10 extracts were further assessed by cellular tyrosinase assay, and 6 showed>50% inhibition with IC(50) values <1 mg/ml. The 6 extracts are from 3 herbs namely Ampelopsis japonica, Lindera aggregata, and Polygonatum odoratum, and 3 formulas namely Qian-wang-hong-bai-san, Qiong-yu-gao, and San-bai-tang. As compared with vitamin C, these 6 extracts showed similar or greater ratio of cell growth IC(50) to cellular tyrosinase IC(50). As compared with arbutin, extract from Ampelopsis japonica, Lindera aggregata, Qian-wang-hong-bai-san, or San-bai-tang had a similar, although extract from Polygonatum odoratum or Qiong-yu-gao had a greater, IC(50) value against murine tyrosinase activity. From the screening assays we identified three Chinese medicinal herbs and three TCM formulas that have appreciable antityrosinase activity. Further studies are warranted to develop them as skin-whitening agents with convenient dosage forms or to identify active constituents from the extracts as useful leads for the development of skin whiteners.


Effects of online continuum and categorical belief manipulations on schizophrenia stigma, help-seeking, and help-provision.
Most research investigating the effect of continuum beliefs on stigma has used weak manipulations which may contribute to mixed findings within the experimental literature. There is also a lack of research into how continuum belief manipulations may impact help-seeking and help-provision. This study used an online manipulation of continuum and categorical beliefs about schizophrenia to examine the subsequent impacts on stigma, help-seeking, and help-provision. A total of 271 participants were randomised into either a continuum, categorical, or control condition. Participants received an informational video, a magazine article, and research highlights relevant to their condition. Prosocial support behaviour was assessed through a novel volunteering measure. The magnitude of change between pre-intervention and post-intervention measures of continuum and categorical beliefs was large. Continuum presentations reduced prognostic pessimism and negative stereotyping. Meanwhile, categorical presentations increased prognostic pessimism. Participants across conditions showed increased help-providing intentions after removing the highest scores to avoid ceiling effects. Fear and blame also decreased significantly across all conditions. There was no difference between conditions on our novel volunteer help-provision measure. Our findings have implications for anti-stigma programs and may help inform the design of future continuum belief manipulations.


Van der Waals Epitaxial Growth of agr-Alumina Nanocrystals on Mica.
Lattice mismatch stresses, which severely restrict heteroepitaxial growth, are greatly minimized when thin alumina films are grown by means of van der Waals forces on inert mica substrates. A 10-nanometer-thick epitaxial film exhibits crystallographic sixfold symmetry, a lattice constant close to that of the basal plane [0001] of alpha-alumina (sapphire), and an aluminum: oxygen atomic ratio of 1:1.51 +/- 0.02 (measured by x-ray photoelectron spectroscopy), again the same as for bulk sapphire. The film is free of steps and grain boundaries over large areas and appears to be an ideal model system for studying adhesion, tribology, and other surface phenomena at atomic scales.


pH dependence of blood-brain barrier permeability to lactate and nicotine.
Brain uptake of radiolabeled D and L-lactate, D-glucose and nicotine, as measured by the intra-carotid bolus method, was examined over a range of pH of the injected solution. The uptake of L-lactate was highest at pH 6.1, and lowered significantly at pH 7.2, 7.5 and 8.4. In contrast, the uptake of the D-enantiomer was not as dramatically affected. Glucose uptake was not affected by alterations in pH. Nicotine uptake decreased with pH reduction through a range of 8.3-4.2. These data suggest that it is the uncharged molecule which penetrates the blood-brain barrier by both carrier and lipid mediation. A mechanism relating to these observations is postulated and possible relevance to lactate washout from ischemic brain discussed.


A subset of CD163+ macrophages displays mixed polarizations in discoid lupus skin.
Lesional skin of patients with discoid lupus erythematosus (DLE) contains macrophages, whose polarization has yet to be investigated. To test our hypothesis that M1 macrophages would be increased in DLE skin, we examined transcriptome alterations in immune cell gene expression and macrophage features in DLE and normal skin by using gene expression and histochemical approaches. Gene expression of RNA from DLE lesional and normal control skin was compared by microarrays and quantitative real-time polymerase chain reaction (RT-PCR). Both skin groups were analyzed for CD163 expression by immunohistochemistry. Double immunofluorescence studies were performed to characterize protein expression of CD163+ macrophages. DLE skin had twice as many upregulated genes than downregulated genes compared with normal skin. Gene set enrichment analysis comparing differentially expressed genes in DLE and normal skin with previously published gene sets associated with M1 and M2 macrophages showed strong overlap between upregulated genes in DLE skin and M1 macrophages. Quantitative RT-PCR showed that several M1 macrophage-associated genes--e.g., chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 5 (CCL5), and signal transducer and activator of transcription 1 (STAT1)-had amplified mRNA levels in DLE skin. CD163+ macrophages were increased near the epidermal-dermal junction and perivascular areas in DLE skin compared with normal skin. However, double immunofluorescence studies of CD163+ macrophages revealed minor co-expression of M1 (CXCL10, tumor necrosis factor-alpha, and CD127) and M2 (CD209 and transforming growth factor-beta) macrophage-related proteins in DLE skin. Whereas a subset of CD163+ macrophages displays mixed polarizations in DLE skin, other immune cells such as T cells can contribute to the expression of these macrophage-related genes.


Independent initiation of primary electron transfer in the two branches of the photosystem I reaction center.
Photosystem I (PSI) is a large pigment-protein complex that unites a reaction center (RC) at the core with approximately 100 core antenna chlorophylls surrounding it. The RC is composed of two cofactor branches related by a pseudo-C2 symmetry axis. The ultimate electron donor, P(700) (a pair of chlorophylls), and the tertiary acceptor, F(X) (a Fe(4)S(4) cluster), are both located on this axis, while each of the two branches is made up of a pair of chlorophylls (ec2 and ec3) and a phylloquinone (PhQ). Based on the observed biphasic reduction of F(X), it has been suggested that both branches in PSI are competent for electron transfer (ET), but the nature and rate of the initial electron transfer steps have not been established. We report an ultrafast transient absorption study of Chlamydomonas reinhardtii mutants in which specific amino acids donating H-bonds to the 13(1)-keto oxygen of either ec3(A) (PsaA-Tyr696) or ec3(B) (PsaB-Tyr676) are converted to Phe, thus breaking the H-bond to a specific ec3 cofactor. We find that the rate of primary charge separation (CS) is lowered in both mutants, providing direct evidence that the primary ET event can be initiated independently in each branch. Furthermore, the data provide further support for the previously published model in which the initial CS event occurs within an ec2/ec3 pair, generating a primary ec2(+)ec3(-) radical pair, followed by rapid reduction by P(700) in the second ET step. A unique kinetic modeling approach allows estimation of the individual ET rates within the two cofactor branches.


The architecture of the golfer's brain.
Several recent studies have shown practice-dependent structural alterations in humans. Cross-sectional studies of intensive practice of specific tasks suggest associated long-term structural adaptations. Playing golf at a high level of performance is one of the most demanding sporting activities. In this study, we report the relationship between a particular level of proficiency in playing golf (indicated by golf handicap level) and specific neuroanatomical features. Using voxel-based morphometry (VBM) of grey (GM) and white matter (WM) volumes and fractional anisotropy (FA) measures of the fibre tracts, we identified differences between skilled (professional golfers and golfers with an handicap from 1-14) and less-skilled golfers (golfers with an handicap from 15-36 and non-golfer). Larger GM volumes were found in skilled golfers in a fronto-parietal network including premotor and parietal areas. Skilled golfers revealed smaller WM volume and FA values in the vicinity of the corticospinal tract at the level of the internal and external capsule and in the parietal operculum. However, there was no structural difference within the skilled and less-skilled golfer group. There is no linear relationship between the anatomical findings and handicap level, amount of practice, and practice hours per year. There was however a strong difference between highly-practiced golfers (at least 800-3,000 hours) and those who have practised less or non-golfers without any golfing practise, thus indicating a step-wise structural and not a linear change.


Pitch vs. spectral encoding of harmonic complex tones in primary auditory cortex of the awake monkey.
Neuromagnetic studies in humans and single-unit studies in monkeys have provided conflicting views regarding the role of primary auditory cortex (A1) in pitch encoding. While the former support a topographic organization based on the pitch of complex tones, single-unit studies support the classical tonotopic organization of A1 defined by the spectral composition of the stimulus. It is unclear whether the incongruity of these findings is due to limitations of noninvasive recordings or whether the discrepancy genuinely reflects pitch representation based on population encoding. To bridge these experimental approaches, we examined neuronal ensemble responses in A1 of the awake monkey using auditory evoked potential (AEP), multiple-unit activity (MUA) and current source density (CSD) techniques. Macaque monkeys can perceive the missing fundamental of harmonic complex tones and therefore serve as suitable animal models for studying neural encoding of pitch. Pure tones and harmonic complex tones missing the fundamental frequency (f0) were presented at 60 dB SPL to the ear contralateral to the hemisphere from which recordings were obtained. Laminar response profiles in A1 reflected the spectral content rather than the pitch (missing f0) of the compound stimuli. These findings are consistent with single-unit data and indicate that the cochleotopic organization is preserved at the level of A1. Thus, it appears that pitch encoding of multi-component sounds is more complex than suggested by noninvasive studies, which are based on the assumption of a single dipole generator within the superior temporal gyrus. These results support a pattern recognition mechanism of pitch encoding based on a topographic representation of stimulus spectral composition at the level of A1.


Cost-effectiveness of home-based stroke rehabilitation across Europe: A modelling study.
The aim of this study was to explore the cost-effectiveness of home-based versus centre-based rehabilitation in stroke patients across Europe. A state-transition cohort model was developed to simulate the impact of the intervention in 32 European countries. A cost-utility analysis was conducted from a societal perspective including healthcare, social care and informal care costs, and productivity losses. Health outcomes were expressed as QALYs. Sensitivity analyses were conducted concerning model input values and structural assumptions. Data were obtained from a population-based cohort and previously published studies. Across Europe, over 855,000 patients with stroke would be eligible for rehabilitation in 2017. Europe-wide implementation of home-based rehabilitation was estimated to produce 61,888 additional QALYs (95% CI: 3,609 to 118,679) and cost savings of €237 million (95% CI: -237 to 1,764) and of €352 million (95% CI: -340 to 2,237) in health- and social-care and societal costs, respectively. Under base case assumptions, home-based rehabilitation was found highly likely to be cost-effective (>90%), compared to centre-based rehabilitation, in most European countries (29 out of 32). Evidence from this study suggests that a shift from a centre-based to a home-based approach to stroke rehabilitation is likely to be good value for money in most European countries. Further research should be conducted to assess the generalisability of these findings to local settings.


Peer review of utilisation of medical beds at Flinders Medical Centre.
A clinical audit of all medical inpatients was undertaken and the appropriateness of admissions and of length of stay was assessed from a clinical viewpoint on 4 separate days within an 11 day period. In addition, the mode of entry of hospital, length of stay of patients, occupancy rate, and the vacancy interval were analysed for all medical patients during the preceding three months. The mean length of stay of medical patients in hospital during this 3 months period was 5.6 days, with an occupancy rate of 93% and a vacancy interval of 0.43 days. Seventy-four percent of all medical inpatients were admitted through the Accident and Emergency Department (A&E). The short length of stay, high occupancy rate and low vacancy interval indicated that bed usage in the medical wards was efficient. A total of 493 reviews was carried out on 294 individual patients. In 87% of cases, both admission to hospital and length of stay were appropriate on clinical grounds alone. The number of patients whose admission to hospital (11), or length of stay (27) was not justified on medical grounds alone was 38 (13% of total patients). These patients were elderly, or had complex social and psychological problems contributing to their illness. It was concluded that stricter control of admissions or length of stay was unlikely to make a significant numbers of beds available for other admissions.


Replication stress as a source of telomere recombination during replicative senescence in Saccharomyces cerevisiae.
Replicative senescence is triggered by short unprotected telomeres that arise in the absence of telomerase. In addition, telomeres are known as difficult regions to replicate due to their repetitive G-rich sequence prone to secondary structures and tightly bound non-histone proteins. Here we review accumulating evidence that telomerase inactivation in yeast immediately unmasks the problems associated with replication stress at telomeres. Early after telomerase inactivation, yeast cells undergo successive rounds of stochastic DNA damages and become dependent on recombination for viability long before the bulk of telomeres are getting critically short. The switch from telomerase to recombination to repair replication stress-induced damage at telomeres creates telomere instability, which may drive further genomic alterations and prepare the ground for telomerase-independent immortalization observed in yeast survivors and in 15% of human cancer.


Treatment outcome and readmission risk among women in women-only versus mixed-gender drug treatment programs in Chile.
Traditional treatment programs for substance use disorder (SUD) tend to be male-dominated environments, which can negatively affect women's access to treatment and related outcomes. Women's specific treatment needs have led some providers to develop women-only SUD treatment programs in several countries. In Chile, women-only programs were only fully implemented in 2010. We compared treatment outcomes and readmission risk for adult women admitted to state-funded women-only versus mixed-gender SUD treatment programs in Chile. We used a registry-based retrospective cohort design of adult women in women-only (N = 8200) and mixed-gender (N = 13,178) SUD treatment programs from 2010 to 2019. The study obtained data from the National Drug and Alcohol Service from Chile. We used a multistate model to estimate the probabilities of experiencing treatment completion, discharge without completion (i.e., patient-initiated discharge and administrative discharge), or readmission, as well as the likelihood of being readmitted, conditioned on prior treatment outcome. We adjusted models for multiple baseline characteristics (e.g., substance use, socioeconomic). Overall, 24% of women completed treatment and 54% dropped out of treatment. The proportion of patient-initiated discharges within the first three month was larger in women-only than in mixed-gender programs (19% vs. 12%). In both programs, women who completed treatment were more likely to experience readmission at three months, and one and three years. In the long term, women in the women-only programs were more likely to complete treatment than women in mixed-gender programs (34% vs. 23%, respectively). The readmission probability was higher among women who previously completed treatment than those who had a discharge without completion (40% vs 21% among women in women-only programs; 38% vs. 19% among women in mixed-gender programs, respectively); no differences occurred in the risk of readmission between women-only and mixed-gender programs. In terms of treatment outcomes and readmission risk, women-only programs had similar results to mixed-gender programs in Chile. The added value of these specialized programs should be addressed in further research.


Diagnosis and management of anxiety disorders.
Major anxiety disorders are more prevalent in women than in men. Although the tendency toward anxiety disorders appears familial, other factors such as environmental influences can play a role in the risk for anxiety. This clinical review focuses on the pathophysiologic basis for anxiety disorders. It provides brief overviews of panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. It also summarizes treatment options for patients with anxiety disorders.


Once-per-step control of ankle-foot prosthesis push-off work reduces effort associated with balance during walking.
Individuals with below-knee amputation have more difficulty balancing during walking, yet few studies have explored balance enhancement through active prosthesis control. We previously used a dynamical model to show that prosthetic ankle push-off work affects both sagittal and frontal plane dynamics, and that appropriate step-by-step control of push-off work can improve stability. We hypothesized that this approach could be applied to a robotic prosthesis to partially fulfill the active balance requirements of human walking, thereby reducing balance-related activity and associated effort for the person using the device. We conducted experiments on human participants (N = 10) with simulated amputation. Prosthetic ankle push-off work was varied on each step in ways expected to either stabilize, destabilize or have no effect on balance. Average ankle push-off work, known to affect effort, was kept constant across conditions. Stabilizing controllers commanded more push-off work on steps when the mediolateral velocity of the center of mass was lower than usual at the moment of contralateral heel strike. Destabilizing controllers enforced the opposite relationship, while a neutral controller maintained constant push-off work regardless of body state. A random disturbance to landing foot angle and a cognitive distraction task were applied, further challenging participants' balance. We measured metabolic rate, foot placement kinematics, center of pressure kinematics, distraction task performance, and user preference in each condition. We expected the stabilizing controller to reduce active control of balance and balance-related effort for the user, improving user preference. The best stabilizing controller lowered metabolic rate by 5.5% (p = 0.003) and 8.5% (p = 0.02), and step width variability by 10.0% (p = 0.009) and 10.7% (p = 0.03) compared to conditions with no control and destabilizing control, respectively. Participants tended to prefer stabilizing controllers. These effects were not due to differences in average push-off work, which was unchanged across conditions, or to average gait mechanics, which were also unchanged. Instead, benefits were derived from step-by-step adjustments to prosthesis behavior in response to variations in mediolateral velocity at heel strike. Once-per-step control of prosthetic ankle push-off work can reduce both active control of foot placement and balance-related metabolic energy use during walking.


Neuronal elements in the testis of the rhesus monkey: ontogeny, characterization and relationship to testicular cells.
Intrinsic neuron-like cells expressing the catecholamine-biosynthetic enzyme tyrosine hydroxylase (TH) were recently identified in the testis of the prepubertal rhesus monkey. In this study, we characterized the neuron-like nature of these cells and examined distribution and frequency of neuronal elements in the testes of monkeys during postnatal development, puberty and adulthood. Using immunohistochemical methods, we detected both nerve fibers and cell bodies, immunoreactive for the neuronal markers neurofilament 200 (NF-200) and synaptosomal associated protein of 25 kDa (SNAP-25), TH and neuropeptide Y (NPY) in perivascular locations, intermingled with interstitial cells and close to the wall of seminiferous tubules. Marked age-related differences in the numbers of these neuronal elements became apparent, when we quantified NF-200-immunoreactive neuronal elements. Thus, intrinsic neuron-like cell bodies were found only in the testes from immature animals (i.e. , until about 3 years of age). Conversely, nerve fibers, presumably representing mainly the extrinsic innervation, were observed at all ages although they became more prominent after the pubertal increase in LH and testosterone levels. Interestingly, another testicular cell type known to contain potent regulatory substances, mast cells, was found to be in close anatomical proximity to nerve fibers. The number of these cells, positively identified with an antibody to tryptase, increased significantly after puberty following the same pattern as nerve fibers. These results confirm that the testicular nervous system of the monkey is composed of two components, intrinsic nerve cells and extrinsic fibers, both of which are catecholaminergic and peptidergic in nature. Furthermore, both components show a marked degree of plasticity during development, especially around the time of puberty. The intratesticular locations of neuron-like cells and fibers suggest that catecholamines and neuropeptides are likely to have multiple sites of actions, and may affect Leydig cells, cells of the tubular wall and vascular cells directly and/or indirectly via intermediation of mast cells.


Cytokine modulation of muscarinic receptors in the murine intestine.
The extent to which gut motility and smooth muscle contractility are altered by intestinal inflammation depends on the nature of the underlying immune activation. The muscarinic receptor on smooth muscle plays a critical role in mediating acetylcholine-driven motor function. We examined the ability of cytokines to influence muscarinic receptor characteristics on intestinal longitudinal muscle and related the findings to studies on carbachol-induced contraction. Cells were isolated from longitudinal muscle myenteric plexus (LMMP). Cytokine receptor expression, muscle contractility, and muscarinic agonist receptor characteristics were examined by agonist displacement of [N-methyl-(3)H]scopolamine ([(3)H]NMS) binding. The TGF-beta1 receptor (543 bp) and the IFN-gamma receptor 1 (660 bp) were identified on smooth muscle cells. Scatchard analysis revealed dissociation constant and maximum binding values for [(3)H]NMS of 2.6 nM and 2.4 x 10(4) sites/cell, respectively, in control cells. Nematode infection was accompanied by a reduction in inhibitory constant of the high-affinity sites (K(H)), and this was independent of signal transduction and activator of transcription 6. Preincubation with TGF-beta1 enhanced longitudinal muscle contractility and decreased the K(H) to 2.2 pM (increased muscarinic receptor affinity), whereas preincubation with IFN-gamma increased the K(H) to 0.4 muM (decreased muscarinic receptor affinity) and decreased longitudinal muscle contractility. Preincubation of LMMP with IL-13 decreased the K(H) to 0.2 nM. Cytokines exert differential effects on the muscarinic receptor on intestinal longitudinal smooth muscle. These findings explain the basis for altered muscle contractility observed in Th1 and Th2 models of inflammation, as well as in the post-nematode-infected state.


Indian Society for Study of Pain, Cancer Pain Special Interest Group Guidelines on Pharmacological Management of Cancer Pain (Part II).
The Indian Society for Study of Pain (ISSP), Cancer Pain Special Interest Group (SIG) guidelines on pharmacological management of cancer pain in adults provide a structured, stepwise approach, which will help to improve the management of cancer pain and to provide the patients with a minimally acceptable quality of life. The guidelines have been developed based on the available literature and evidence, to suit the needs, patient population, and situations in India. A questionnaire, based on the key elements of each sub draft addressing certain inconclusive areas where evidence was lacking, was made available on the ISSP website and circulated by e-mail to all the ISSP and Indian Association of Palliative Care members. We recommend that analgesics for cancer pain management should follow the World Health Organization 3-step analgesic ladder appropriate for the severity of pain. The use of paracetamol and nonsteroidal anti-inflammatory drugs alone or in combination with opioids for mild-to-moderate pain should be used. For mild-to-moderate pain, weak opioids such as tramadol, tapentadol, and codeine can be given in combination with nonopioid analgesics. We recommend morphine as the opioid of the first choice for moderate-to-severe cancer pain. Sustained-release formulations can be started 12 hourly, once the effective 24 h dose with immediate-release morphine is established. Opioid switch or rotation should be considered if there is inadequate analgesia or intolerable side effects. For opioid-induced respiratory depression, μ receptor antagonists (e.g. naloxone) must be used promptly. Antidepressants and/or anticonvulsants should be used to treat neuropathic cancer pain, and the dose should be titrated according to the clinical response and side effects. External beam radiotherapy should be offered to all patients with painful metastatic bone pain. There is evidence on use of ketamine in cancer neuropathic pain, but with no beneficial effect, thus, it is not recommended.


Anti-proliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm.
Nine indolocarbazole alkaloids of the staurosporine type, including three new derivatives, were evaluated for their potential as inhibitors of cell proliferation and macromolecule synthesis. Four derivatives were tested as inhibitors of cell proliferation with twelve human leukemia cell lines and demonstrated powerful antiproliferative activities, with 3-hydroxystaurosporine being the most potent. IC(50) values were determined using the cell line MONO-MAC-6 and with an IC(50) of 13 ng/ml, 3-hydroxystaurosporine turned out to be one of the most active staurosporine-type inhibitors described so far. All derivatives, except 3-hydroxy-3'-demethoxy-3'-hydroxystaurosporine and 4'-N-methylstaurosporine very strongly reduced RNA and DNA synthesis with 3-hydroxystaurosporine again being the strongest inhibitor. Analysis of structure-activity relationships demonstrated that hydroxylation of staurosporine at position 3 of the indolocarbazole moiety caused an increase in anti-proliferative activity, while hydroxylation at carbon 11 resulted in a decrease in activity. Our results suggest that not only the presence or absence of hydrophilic substitutions, but also the position of the alteration within the molecule, is important in the antiproliferative properties of the various staurosporine analogues.


DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs.
MicroRNAs (miRNAs) control cell proliferation, differentiation and fate through modulation of gene expression by partially base-pairing with target mRNA sequences. Drosha is an RNase III enzyme that is the catalytic subunit of a large complex that cleaves pri-miRNAs with distinct structures into pre-miRNAs. Here, we show that both the p68 and p72 DEAD-box RNA helicase subunits in the mouse Drosha complex are indispensable for survival in mice, and both are required for primary miRNA and rRNA processing. Gene disruption of either p68 or p72 in mice resulted in early lethality, and in both p68(-/-) and p72(-/-) embryos, expression levels of a set of, but not all, miRNAs and 5.8S rRNA were significantly lowered. In p72(-/-) MEF cells, expression of p72, but not a mutant lacking ATPase activity, restored the impaired expression of miRNAs and 5.8S rRNA. Furthermore, we purified the large complex of mouse Drosha and showed it could generate pre-miRNA and 5.8S rRNA in vitro. Thus, we suggest that DEAD-box RNA helicase subunits are required for recognition of a subset of primary miRNAs in mDrosha-mediated processing.


Loss of the mu opioid receptor induces strain-specific alterations in hippocampal neurogenesis and spatial learning.
Alterations in hippocampal neurogenesis affect spatial learning, though, the relative contributions of cell proliferation and cell survival on this process are poorly understood. The current study utilized mu opioid receptor (MOR-1) knockout (KO) mice on two background strains, C57BL/6 and 129S6, to assess cell survival as well as determine the impact on spatial learning using the Morris water maze. These experiments were designed to extend prior work showing that both C57BL/6 and 129S6 MOR-1 KO mice have an increased number of proliferating cells in the dentate gyrus (DG) when compared to wild-type (WT) mice. The current study indicates that newly born neurons in the DG of C57BL/6 MOR-1 KO mice exhibit enhanced survival when compared to WT mice, while new neurons in the DG of 129S6 MOR-1 KO mice do not. In addition, C57BL/6 MOR-1 KO mice have a lower number of apoptotic cells in the DG compared to WT mice while, in contrast, 129S6 MOR-1 KO mice have a higher number of apoptotic cells in this region. These alterations collectively contribute to an increase in the granule cell number in the DG of C57BL/6 MOR-1 KO mice, while the total number of granule cells in 129S6 MOR-1 KO mice is unchanged. Thus, although C57BL/6 and 129S6 MOR-1 KO mice both exhibit increased cell proliferation in the DG, the impact of the MOR-1 mutation on cell survival differs between strains. Furthermore, the decrease in DG cell survival displayed by 129S6 MOR-1 KO mice is correlated with functional deficits in spatial learning, suggesting that MOR-1-dependent alterations in the survival of new neurons in the DG, and not MOR-1-dependent changes in proliferation of progenitor cells in the DG, is important for spatial learning.


British Escherichia coli O157 in Cattle Study (BECS): to determine the prevalence of E. coli O157 in herds with cattle destined for the food chain.
Escherichia coli O157 are zoonotic bacteria for which cattle are an important reservoir. Prevalence estimates for E. coli O157 in British cattle for human consumption are over 10 years old. A new baseline is needed to inform current human health risk. The British E. coli O157 in Cattle Study (BECS) ran between September 2014 and November 2015 on 270 farms across Scotland and England & Wales. This is the first study to be conducted contemporaneously across Great Britain, thus enabling comparison between Scotland and England & Wales. Herd-level prevalence estimates for E. coli O157 did not differ significantly for Scotland (0·236, 95% CI 0·166-0·325) and England & Wales (0·213, 95% CI 0·156-0·283) (P = 0·65). The majority of isolates were verocytotoxin positive. A higher proportion of samples from Scotland were in the super-shedder category, though there was no difference between the surveys in the likelihood of a positive farm having at least one super-shedder sample. E. coli O157 continues to be common in British beef cattle, reaffirming public health policy that contact with cattle and their environments is a potential infection source.


Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer's disease?
Elevated plasma homocysteine (tHcy) concentrations have been associated with an increased risk of developing dementia and Alzheimer's disease (AD). It is not clear, however, if an elevation in tHcy concentration is a "risk factor" with a direct pathophysiological role in the development of the disease or merely a "risk marker" reflecting an underlying process such as oxidative stress responsible for both the high tHcy concentrations and the development of AD. Epidemiological studies have confirmed that elevations in plasma tHcy temporally precede the development of dementia and that there is a continuous, inverse linear relation between plasma tHcy concentrations and cognitive performance in older persons. Several potential biological pathways that could mediate the observed association are briefly reviewed. In light of these data and the growing parallel interest in plasma tHcy as an emerging vascular risk factor there was considerable hope that vitamin therapy with folate, B12 and B6, shown to lower plasma tHcy levels, could significantly reduce the risk of stroke and dementia permitting healthy brain aging. The results from recent trials addressing the secondary prevention of stroke and myocardial infarction trials have been disappointing. However, the role of vitamins and other homocysteine lowering treatments in the primary prevention of stroke and dementia, as well as their role in preserving cognition among persons with mild cognitive impairment and early dementia deserves to be fully pursued.


The Use of Social Media in Graduate Medical Education: A Systematic Review.
Despite the growing presence of social media in graduate medical education (GME), few studies have attempted to characterize their effect on residents and their training. The authors conducted a systematic review of the peer-reviewed literature to understand the effect of social media on resident (1) education, (2) recruitment, and (3) professionalism. The authors identified English-language peer-reviewed articles published through November 2015 using Medline, Embase, Cochrane, PubMed, Scopus, and ERIC. They extracted and synthesized data from articles that met inclusion criteria. They assessed study quality for quantitative and qualitative studies through, respectively, the Medical Education Research Study Quality Instrument and the Consolidated Criteria for Reporting Qualitative Studies. Twenty-nine studies met inclusion criteria. Thirteen (44.8%) pertained to residency education. Twitter, podcasts, and blogs were frequently used to engage learners and enhance education. YouTube and wikis were more commonly used to teach technical skills and promote self-efficacy. Six studies (20.7%) pertained to the recruitment process; these suggest that GME programs are transitioning information to social media to attract applicants. Ten studies (34.5%) pertained to resident professionalism. Most were exploratory, highlighting patient and resident privacy, particularly with respect to Facebook. Four of these studies surveyed residents about their social network behavior with respect to their patients, while the rest explored how program directors use it to monitor residents' unprofessional online behavior. The effect of social media platforms on residency education, recruitment, and professionalism is mixed, and the quality of existing studies is modest at best.


Central nervous system complications and management in sickle cell disease.
With advances in brain imaging and completion of randomized clinical trials (RCTs) for primary and secondary stroke prevention, the natural history of central nervous system (CNS) complications in sickle cell disease (SCD) is evolving. In order of current prevalence, the primary CNS complications include silent cerebral infarcts (39% by 18 years), headache (both acute and chronic: 36% in children with sickle cell anemia [SCA]), ischemic stroke (as low as 1% in children with SCA with effective screening and prophylaxis, but ∼11% in children with SCA without screening), and hemorrhagic stroke in children and adults with SCA (3% and 10%, respectively). In high-income countries, RCTs (Stroke Prevention in Sickle Cell Anemia [STOP], STOP II) have demonstrated that regular blood transfusion therapy (typically monthly) achieves primary stroke prevention in children with SCA and high transcranial Doppler (TCD) velocities; after at least a year, hydroxycarbamide may be substituted (TCD With Transfusions Changing to Hydroxyurea [TWiTCH]). Also in high-income countries, RCTs have demonstrated that regular blood transfusion is the optimal current therapy for secondary prevention of infarcts for children with SCA and strokes (Stroke With Transfusions Changing to Hydroxyurea [SWiTCH]) or silent cerebral infarcts (Silent Infarct Transfusion [SIT] Trial). For adults with SCD, CNS complications continue to be a major cause of morbidity and mortality, with no evidence-based strategy for prevention.


Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer.
Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer. mRNA microarray data from breast cancer cell lines were used to identify bimodal genes-those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes. LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basal-like subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P = 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006). Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy.


Costs and usage of healthcare services before and after open bariatric surgery.
Morbidly obese individuals are major consumers of healthcare services, with high associated costs. Bariatric surgery is an alternative for improving these individuals' comorbidities. There are no studies comparing costs before and after bariatric surgery in Brazil. The aim here was to analyze results relating to healthcare usage and direct costs among morbidly obese patients undergoing bariatric surgery. Historical cohort study on patients receiving healthcare through a private health plan in Belo Horizonte, Minas Gerais. All healthcare services and their associated costs were included in the analysis: hospitalization, hospital stay, elective outpatient consultations, emergency service usage and examinations. The analyses were treated as total when including the whole years before and after surgery, or partial when excluding the three-month periods adjacent to the operation. For 382 obese patients who underwent open bariatric operations, there were 53 hospitalizations one year before and 95 one year after surgery (P = 0.013). Gastrointestinal complications were the main indications for post-procedure hospitalizations. The partial average cost almost doubled after the operation (US$ 391.96 versus US$ 678.31). In subgroup analysis, the costs from patients with gastrointestinal complications were almost four times greater after bariatric surgery. Even in the subgroup without complications, the partial average cost remained significantly higher. Although bariatric surgery is the only path towards sustained weight loss for morbidly obese patients, the direct costs over the first year after the procedure are greater. Further studies, with longer follow-up, might elucidate whether long-term reversal of this trend would occur.