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Background: Previous research suggests that a proportion of children experiencing reading and listening difficulties may have an underlying primary deficit in the way that the central auditory nervous system analyses the perceptually important, rapidly varying, formant frequency components of speech., Purpose: The Phoneme Identification Test (PIT) was developed to investigate the ability of children to use spectro-temporal cues to perceptually categorize speech sounds based on their rapidly changing formant frequencies. The PIT uses an adaptive two-alternative forced-choice procedure whereby the participant identifies a synthesized consonant-vowel (CV) (/ba/ or /da/) syllable. CV syllables differed only in the second formant (F2) frequency along an 11-step continuum (between 0% and 100%-representing an ideal /ba/ and /da/, respectively). The CV syllables were presented in either quiet (PIT Q) or noise at a 0 dB signal-to-noise ratio (PIT N)., Research Design: Development of the PIT stimuli and test protocols, and collection of normative and test-retest reliability data., Study Sample: Twelve adults (aged 23 yr 10 mo to 50 yr 9 mo, mean 32 yr 5 mo) and 137 typically developing, primary-school children (aged 6 yr 0 mo to 12 yr 4 mo, mean 9 yr 3 mo). There were 73 males and 76 females., Data Collection and Analysis: Data were collected using a touchscreen computer. Psychometric functions were automatically fit to individual data by the PIT software. Performance was determined by the width of the continuum for which responses were neither clearly /ba/ nor /da/ (referred to as the uncertainty region [UR]). A shallower psychometric function slope reflected greater uncertainty. Age effects were determined based on raw scores. Z scores were calculated to account for the effect of age on performance. Outliers, and individual data for which the confidence interval of the UR exceeded a maximum allowable value, were removed. Nonparametric tests were used as the data were skewed toward negative performance., Results: Across participants, the median value of the F2 range that resulted in uncertain responses was 33% in quiet and 40% in noise. There was a significant effect of age on the width of this UR (p < 0.00001) in both quiet and noise, with performance becoming adult like by age 9 on the PIT Q and age 10 on the PIT N. A skewed distribution toward negative performance occurred in both quiet (p = 0.01) and noise (p = 0.006). Median UR scores were significantly wider in noise than in quiet (T = 2041, p < 0.0000001). Performance (z scores) across the two tests was significantly correlated (r = 0.36, p = 0.000009). Test-retest z scores were significantly correlated in both quiet and noise (r = 0.4 and 0.37, respectively, p < 0.0001)., Conclusions: The PIT normative data show that the ability to identify phonemes based on changes in formant transitions improves with age, and that some children in the general population have performance much worse than their age peers. In children, uncertainty increases when the stimuli are presented in noise. The test is suitable for use in planned studies in a clinical population., (American Academy of Audiology)

Social cognition includes a range of cognitive processes that help individuals to understand how others think and feel. There is emerging evidence that social cognitive deficits may represent a transdiagnostic issue, potentially serving as a marker of neurological abnormality. We performed an electronic database search in order to identify published, peer-reviewed meta-analyses that compared facial emotion recognition or theory of mind task performance between individuals meeting clinical criteria for a psychiatric, neurological or developmental condition against healthy controls. We identified 31 meta-analyses eligible for inclusion that examined performance across relevant tasks among 30 different clinical populations. The results suggest that social cognitive deficits appear to be a core cognitive phenotype of many clinical conditions. Across the clinical groups, deficits in social cognitive domains were broadly similar in magnitude to those previously reported for more established aspects of cognition, such as memory and executive function. There is a need to clarify the 'real world' impact of these deficits, and to develop effective transdiagnostic interventions for those individuals that are adversely affected., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Primary care nurse-led prediabetes interventions are seldom reported. We examined the implementation and feasibility of a 6-month multilevel primary care nurse-led prediabetes lifestyle intervention compared with current practice in patients with prediabetes, with weight and glycated haemoglobin (HbA1c) as outcomes., Methods: This study used a convergent mixed methods design involving a 6-month pragmatic non-randomised pilot study with a qualitative process evaluation, and was conducted in two neighbouring provincial cities in New Zealand, with indigenous Māori populations comprising 18.2% and 23.0%, respectively. Participants were non-pregnant adults aged ≤ 70 years with newly diagnosed prediabetes (HbA1c 41-49 mmol/mol), body mass index (BMI) ≥ 25 kg/m 2 and not prescribed Metformin. A structured dietary intervention tool delivered by primary care nurses with visits at baseline, 2-3 weeks, 3 months and 6 months was implemented in four intervention practices. Four control practices continued to provide usual care. Primary quantitative outcome measures were weight and HbA1c. Linear and quantile regression models were used to compare each outcome between the two groups at follow-up. Qualitative data included: observations of nurse training sessions and steering group meetings; document review; semi-structured interviews with a purposive sample of key informants (n = 17) and intervention patients (n = 20). Thematic analysis was used., Results: One hundred fifty-seven patients with prediabetes enrolled (85 intervention, 72 control), 47.8% female and 31.2% Māori. Co-morbidities were common, particularly hypertension (49.7%), dyslipidaemia (40.1%) and gout (15.9%). Baseline and 6 month measures were available for 91% control and 79% intervention participants. After adjustment, the intervention group lost a mean 1.3 kg more than the control group (p < 0.001). Mean HbA1c, BMI and waist circumference decreased in the intervention group and increased in the control group, but differences were not statistically significant. Implementation fidelity was high, and it was feasible to implement the intervention in busy general practice settings. The intervention was highly acceptable to both patients and key stakeholders, especially primary care nurses., Conclusions: Study findings confirm the feasibility and acceptability of primary care nurses providing structured dietary advice to patients with prediabetes in busy general practice settings. The small but potentially beneficial mean weight loss among the intervention group supports further investigation., Trial Registration: ANZCTR ACTRN12615000806561 . Registered 3 August 2015 (Retrospectively registered).

The range of imaging depth in optical resolution photoacoustic microscopy (PAM) is limited by the short depth of focus of high-numerical aperture objective lenses. In this paper, focus tunable lens modulation has been employed at the resonant frequency of focus tunable lenses in order to enhance both the range of imaging depth and the scanning speed. By electrically controlling the focal length in the axial direction of the sample, the range of imaging depth was extended approximately 1.22 times and the scanning speed was enhanced by approximately 7.40 times, in comparison to corresponding values of conventional PAM systems.

Purpose: Internists and primary care providers play a growing role in cancer care. We therefore evaluated the awareness of radiation therapy in general and specifically the clinical utility of stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) among current US internal medicine residents., Methods and Materials: A web-based institutional review board-approved multi-institutional survey was distributed to US internal medicine residency programs. The survey evaluated trainee demographic characteristics, baseline radiation oncology awareness, knowledge of the role of SBRT for early-stage NSCLC, and whether the survey successfully improved awareness., Results: Thirty US internal medicine programs participated, with an overall participant response rate of 46% (1177 of 2551). Of the trainees, 93% (n=1076) reported no radiation oncology education in their residency, 39% (n=452) reported confidence in knowing when to consult radiation oncology in an oncologic emergency, and 26% (n=293) reported confidence in knowing when to consult radiation oncology in the setting of a newly diagnosed cancer. Of the participants, 76% (n=850) correctly identified that surgical resection is the standard treatment in operable early-stage NSCLC, but only 50% (n=559) of participants would recommend SBRT to a medically inoperable patient, followed by 31% of participants (n=347) who were unsure of the most appropriate treatment, and 10% (n=117) who recommended waiting to offer palliative therapy. Ninety percent of participants (n=1029) agreed that they would benefit from further training on when to consult radiation oncology. Overall, 96% (n=1072) indicated that the survey increased their knowledge and awareness of the role of SBRT., Conclusions: The majority of participating trainees received no education in radiation oncology in their residency, reported a lack of confidence regarding when to consult radiation oncology, and overwhelmingly agreed that they would benefit from further training. These findings should serve as a call to increase the educational collaboration between internal medicine and radiation oncology departments to ensure optimal cancer care., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Lipid supplementation is a promising strategy for methane mitigation in cattle and has been evaluated using several different lipid sources. However, limited studies have assessed the effect of temperature on methane emissions from cattle and changes in incubation temperature have also not been extensively evaluated. The aim of this study was to evaluate the combined effect of pequi oil (high in unsaturated fatty acids) and incubation temperature on fermentation characteristics and microbial communities using the rumen simulation technique. A completely randomized experiment was conducted over a 28-day period using a Rusitec system. The experiment was divided into four periods of 7 days each, the first of which was a 7-day adaptation period followed by three experimental periods. The two treatments consisted of a control diet (no pequi oil inclusion) and a diet supplemented with pequi oil (1.5 mL/day) which increased the dietary fat content to 6% (dry matter, DM-basis). Three fermenter vessels (i.e., replicates) were allocated to each treatment. In the first experimental period, the incubation temperature was maintained at 39°C, decreased to 35°C in the second experimental period and then increased again to 39°C in the third. Pequi oil was continuously supplemented during the experiment. Microbial communities were assessed using high-throughput sequencing of the archaeal and bacterial 16S rRNA gene. Methane production was reduced by 57% following a 4°C decrease in incubation temperature. Supplementation with pequi oil increased the dietary fat content to 6% (DM-basis) but did not affect methane production. Analysis of the microbiota revealed that decreasing incubation temperature to 35°C affected the archaeal and bacterial diversity and richness of liquid-associated microbes, but lipid supplementation did not change microbial diversity.

In spring dairy cows are often gradually transitioned from a silage- and concentrate-based ration (total mixed ration, TMR) to pasture. Rumen microbiota adaptability is a key feature of ruminant survival strategy. However, only little is known on the temporal and spatial microbial alterations involved. This study aims to investigate how the rumen liquid (LAAB), particle (PAAB), and epithelium (EAAB) associated archaea and bacteria are influenced by this nutritional change. A 10-wk trial was performed, including 10 rumen-fistulated dairy cows, equally divided into a pasture- and a confinement- group (PG and CG). The CG stayed on a TMR-based ration, while the PG was gradually transitioned from TMR to pasture (wk 1: TMR-only, wk 2: 3 h/day on pasture, wk 3 & 4: 12 h/day on pasture, wk 5-10: pasture-only). In wk 1, wk 5, and wk 10 samples of solid and liquid rumen contents, and papillae biopsies were collected. The DNA was isolated, and PCR-SSCP and 16S rRNA gene amplicon sequencing analysis were performed. Cluster analysis revealed a higher similarity between LAAB and PAAB, compared to the EAAB, characterized by higher species diversity. At all three locations the microbiota was significantly influenced by the ration change, opposite the generally acknowledged hypothesis that the EAAB remain more consistent throughout dietary changes. Even though the animals in the PG were already on a full-grazing ration for 4-6 days in wk 5, the microbiota at all three locations was significantly different compared to wk 10, suggesting an adaptation period of several days to weeks. This is in line with observations made on animal level, showing a required time for adaptation of 2-3 weeks for production and metabolic variables. A large part of the rumen prokaryote species remained unaltered upon transition to pasture and exhibited a strong host influence, supporting the hypothesis that the rumen microbiota consists of a core and a variable microbiota. For the effect of the location as well as the ration change either very similar or opposite trends among member species of common taxa were observed, demonstrating that microbes that are phylogenetically close may still exhibit substantially different phenotypes and functions.

Aim To explore the preferences of residents with dementia for their end of life care, and nurses' perceptions of these preferences. Method Residents' preferences were compared with nurses' perceptions of their preferences in a qualitatively designed study in which the nominal group technique was adopted for data collection. Findings Some of the residents' preferences for their end of life care matched nurses' perceptions of their preferences, but differences were identified. Residents emphasised comfort, family presence, familiar staff and surroundings; nurses thought that residents would want good communication, pain management, advance care planning, being cared for by knowledgeable staff and the inclusion of their families. Conclusion End of life care needs are individual and a generic approach is not a sufficient standard of care for people with dementia. Patients should be included in studies about their needs and preferences for future care to provide a holistic approach to end of life care, and to develop evidence-based standards.

Background: A significant proportion of children in the social care system in England present with mental health problems, with the majority experiencing some form of emotional and behavioural difficulties. The most effective treatments for these children are currently unknown, partly due to a lack of robust, controlled studies. Researchers have identified a number of obstacles to conducting well-designed research with this population, making the need to test the feasibility of a randomised controlled trial especially important., Methods/design: This protocol outlines a two-arm, randomised control feasibility trial to explore the acceptability and credibility of mentalization-based treatment (MBT) as a treatment for reducing emotional and behavioural difficulties in looked after children and to test the possibility of addressing a number of methodological challenges to conducting high-quality research with this population. MBT is a relatively new intervention which, in the adaptation of the model tested here, includes many of the features of therapy identified in NICE guidelines as necessary to support children in care. The two arms are MBT and usual clinical care (UCC). The study will take place in Hertfordshire Partnership University NHS Foundation Trust with follow-up at 12 and 24 weeks., Discussion: This study will aim to ascertain whether it is worthwhile and feasible to progress to testing the intervention in a full-scale definitive randomised controlled trial (RCT). This study therefore has the potential to improve our understanding of the obstacles to conducting high-quality research with this very vulnerable population, and in the medium term, could help to improve the stability of foster placements and the emotional well-being of children in care., Trial Registration: ISRCTN90349442.

Kaede, an analogue of green fluorescent protein (GFP), is a green-to-red photoconvertible fluorescent protein used as an in vivo "optical highlighter" in bioimaging. The fluorescence quantum yield of the red Kaede protein is lower than that of GFP, suggesting that increasing the conjugation modifies the electronic relaxation pathway. Using a combination of anion photoelectron spectroscopy and electronic structure calculations, we find that the isolated red Kaede protein chromophore in the gas phase is deprotonated at the imidazole ring, unlike the GFP chromophore that is deprotonated at the phenol ring. We find evidence of an efficient electronic relaxation pathway from higher-lying electronically excited states to the S 1 state of the red Kaede chromophore that is not accessible in the GFP chromophore. Rapid autodetachment from high-lying vibrational states of S 1 is found to compete efficiently with internal conversion to the ground electronic state.

Objectives: We report single-institution clinical outcomes of women treated with stereotactic ablative radiotherapy (SABR) for oligometastatic or progressive gynecological malignancies., Materials and Methods: From 2009 to 2015, 47 lesions from 28 patients were treated with SABR and retrospectively analyzed. All patients had oligometastatic (93%) or oligoprogressive (7%) disease. Primary cancer diagnoses were 15 ovarian, 8 endometrial, 2 cervical, 2 vaginal, and 1 uterine carcinosarcoma. Treatment was delivered using a median of 5 fractions to a median total dose of 40 Gy. Targets were grouped by treatment site and assessed for response using Response Evaluation Criteria in Solid Tumors v1.1. Mean biologically effective dose and pre-SABR tumor size were compared with response. Progression-free survival (PFS) was determined using Kaplan-Meier analysis, and toxicity outcomes were graded using Common Terminology Criteria for Adverse Events version 4.03., Results: Median follow-up was 12.8 months. Target locations were 17% liver, 21% lung, 17% paraaortic node, 26% other node, and 19% pelvic soft tissue. After treatment, 34% of targets were stable (SD), 32% had a partial response (PR), 17% had a complete response (CR), and 17% had progressive disease (PD). No failures occurred in lung or nodal targets. Mean ± standard deviation pre-SABR tumor diameter was 24 ± 22 mm. There was a significant difference in mean size between lesions that had a favorable (SD, PR, and CR) versus unfavorable response (PD) (17.2 vs 57.6 mm, P = 0.0044). Lesions that responded favorably were also more likely to have received a higher biologically effective dose (79.0 vs 59.6 Gy, P = 0.027). Median PFS was 10.8 months, and 1 patient experienced grade 3 toxicity., Conclusions: The SABR is a safe and effective local treatment modality in patients with oligometastatic gynecological disease. Distant progression remains the primary mode of failure in this patient population. In carefully selected patients, a combination of systemic treatment and SABR may offer long-term PFS.

Introduction Body dysmorphic disorder (BDD) is a debilitating disorder, characterized by obsessions and compulsions relating specifically to perceived appearance, and which has been newly classified within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Obsessive-Compulsive and Related Disorders grouping. Until now, little research has been conducted into the cognitive profile of this disorder., Methods: Participants with BDD (n=12) and participants without BDD (n=16) were tested using a computerized neurocognitive battery investigating attentional set-shifting (Intra/Extra Dimensional Set Shift Task), decision-making (Cambridge Gamble Task), motor response-inhibition (Stop-Signal Reaction Time Task), and affective processing (Affective Go-No Go Task). The groups were matched for age, IQ, and education., Results: In comparison to controls, patients with BDD showed significantly impaired attentional set-shifting, abnormal decision-making, impaired response inhibition, and greater omission and commission errors on the emotional processing task., Conclusion: Despite the modest sample size, our results showed that individuals with BDD performed poorly compared to healthy controls on tests of cognitive flexibility, reward and motor impulsivity, and affective processing. Results from separate studies in OCD patients suggest similar cognitive dysfunction. Therefore, these findings are consistent with the reclassification of BDD alongside OCD. These data also hint at additional areas of decision-making abnormalities that might contribute specifically to the psychopathology of BDD.

Covering: 2013 up to the end of 2015This review covers the isolation and structure of new pyrrolizidines; pyrrolizidine biosynthesis; biological activity, including the occurrence of pyrrolizidines as toxic components or contaminants in foods and beverages; and formal and total syntheses of naturally-occurring pyrrolizidine alkaloids and closely related non-natural analogues.

Aseptic loosening due to peri-prosthetic osteolysis is one of the primary causes for failure of artificial joint replacements. Implant-derived wear particles, often ultra-high molecular weight polyethylene (UHMWPE) microparticles, initiate an inflammatory cascade upon phagocytosis by macrophages, which leads to osteoclast recruitment and activation, ultimately resulting in osteolysis. Investigation into integrin receptors, involved in cellular interactions with biomaterial-adsorbed adhesive proteins, is of interest to understand and modulate inflammatory processes. In this work, we investigate the role of macrophage integrins Mac-1 and RGD-binding integrins in response to UHMWPE wear particles. Using integrin knockout mice as well as integrin blocking techniques, reduction in macrophage phagocytosis and inflammatory cytokine secretion is demonstrated when these receptors are either absent or blocked. Along this line, various opsonizing proteins are shown to differentially modulate microparticle uptake and macrophage secretion of inflammatory cytokines. Furthermore, using a calvarial osteolysis model it is demonstrated that both Mac-1 integrin and RGD-binding integrins modulate the particle induced osteolysis response to UHMWPE microparticles, with a 40% decrease in the area of osteolysis by the absence or blocking of these integrins, in vivo. Altogether, these findings indicate Mac-1 and RGD-binding integrins are involved in macrophage-directed inflammatory responses to UHMWPE and may serve as therapeutic targets to mitigate wear particle induced peri-prosthetic osteolysis for improved performance of implanted joints., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Negative (or a lack of positive) interpretation of ambiguous social situations has been hypothesised to maintain social anxiety disorder in children, yet there is currently limited evidence to support this. Cognitive Bias Modification of Interpretation (CBM-I) provides a means to explore the causal influence of interpretation bias on social anxiety disorder, and has been associated with a reduction in social anxiety symptoms in adults. Seven to twelve year old children with a diagnosis of social anxiety disorder completed CBM-I training, adapted from materials designed for socially anxious children in the community, or no training. Effects on interpretation bias and social anxiety were assessed. The adapted CBM-I training was not associated with significant changes in benign or negative interpretation. Unsurprisingly given the lack of successful interpretation training, there were no significant changes in child or parent reported social anxiety symptoms, clinician-rated severity or diagnoses and change in interpretation was not significantly associated with change in social anxiety. These findings contrast with some studies with community populations although it is possible that more intensive CBM-I training is required to fully test this hypothesis among clinical groups., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite a large focus on the use of vitrification to cryopreserve embryos in recent years, there are still arguments for the use of slow freezing for the cleavage-stage embryo. Having said this, there are lessons to be learned from the process of vitrification that could be applied to slow freezing to improve post-thaw survival and ultimately clinical pregnancy rates. Specifically, increasing the concentration of sucrose in the freezing solution from 0.1 to 0.2 M and subsequently increasing the sucrose concentrations in thawing solutions could prove beneficial. The use of vitrification warming solutions in the thawing of slow-frozen embryos may also be an option that not only improves survival but also streamlines product purchasing and protocols within the laboratory.

Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The Synthetic Biology Open Language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.1 of SBOL that builds upon version 2.0 published in last year&rsquo;s JIB special issue. In particular, SBOL 2.1 includes improved rules for what constitutes a valid SBOL document, new role fields to simplify the expression of sequence features and how components are used in context, and new best practices descriptions to improve the exchange of basic sequence topology information and the description of genetic design provenance, as well as miscellaneous other minor improvements.

Motivation: Model simulation exchange has been standardized with the Simulation Experiment Description Markup Language (SED-ML), but specialized software is needed to generate simulations in this format. Text-based languages allow researchers to create and modify experimental protocols quickly and easily, and export them to a common machine-readable format., Results: phraSED-ML language allows modelers to use simple text commands to encode various elements of SED-ML (models, tasks, simulations, and results) in a format easy to read and modify. The library can translate this script to SED-ML for use in other softwares., Availability: phraSED-ML language specification, libphrasedml library, and source code are available under BSD license from http://phrasedml.sourceforge.net/ .

Background: In most countries the coverage of seasonal influenza vaccination in pregnant women is low. We investigated the acceptance, reasons for rejection and professional involvement related to vaccine information in pregnant women in Valencia, Spain., Methods: Observational retrospective study in 200 pregnant women, 100 vaccinated and 100 unvaccinated, were interviewed during the 2014/2015 vaccination campaign. Electronic medical records, immunization registry and telephone interviews were used to determine reasons for vaccination and immunization rejection., Results: 40.5% of pregnant women in the health department were vaccinated. The midwife was identified as source of information for 89% of women. The vaccine was rejected due to low perceptions of risk of influenza infection (23%), lack of information (19%), considering the vaccine as superfluous (16%), close proximity of delivery date (13%) and fear of side effects (12%)., Conclusion: Pregnant women in Spain declined to be vaccinated due to under-estimation of the risk of contracting or being harmed by influenza, and lack of information. Interventions aiming to optimize vaccination coverage should include information addressing the safety and effectiveness of the current vaccine together with improved professional training and motivation.

Here we describe Tellurium, a Python based platform for supporting the development of reproducible models in systems biology. The tool exploits a number of available standards, including SBML, SED-ML and COMBINE archives to achieve its goal.

Following cognitive behavioural therapy for child anxiety a significant minority of children fail to lose their diagnosis status. One potential barrier is high parental anxiety. We designed a pilot RCT to test claims that parental intolerance of the child's negative emotions may impact treatment outcomes. Parents of 60 children with an anxiety disorder, who were themselves highly anxious, received either brief parent-delivered treatment for child anxiety or the same treatment with strategies specifically targeting parental tolerance of their child's negative emotions. Consistent with predictions, parental tolerance of the child's negative emotions significantly improved from pre- to post-treatment. However, there was no evidence to inform the direction of this association as improvements were substantial in both groups. Moreover, while there were significant improvements in child anxiety in both conditions, there was little evidence that this was associated with the improvement in parental tolerance. Nevertheless, findings provide important clinical insight, including that parent-led treatments are appropriate even when the parent is highly anxious and that it may not be necessary to adjust interventions for many families., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To compare dosimetric characteristics with multiparametric magnetic resonance imaging-identified imaging tumor volume (gross tumor volume, GTV), prostate clinical target volume and planning target volume, and organs at risk (OARs) for 2 treatment techniques representing 2 arms of an institutional phase 3 randomized trial of hypofractionated external beam image guided highly targeted radiation therapy., Methods and Materials: Group 1 (n=20) patients were treated before the trial inception with the standard dose prescription. Each patient had an additional treatment plan generated per the experimental arm. A total of 40 treatment plans were compared (20 plans for each technique). Group 2 (n=15) consists of patients currently accrued to the hypofractionated external beam image guided highly targeted radiation therapy trial. Plans were created as per the treatment arm, with additional plans for 5 of the group 2 experimental arm with a 3-mm expansion in the imaging GTV., Results: For all plans in both patient groups, planning target volume coverage ranged from 95% to 100%; GTV coverage of 89.3 Gy for the experimental treatment plans ranged from 95.2% to 99.8%. For both groups 1 and 2, the percent volumes of rectum/anus and bladder receiving 40 Gy, 65 Gy, and 80 Gy were smaller in the experimental plans than in the standard plans. The percent volume at 1 Gy per fraction and 1.625 Gy per fraction were compared between the standard and the experimental arms, and these were found to be equivalent., Conclusions: The dose per fraction to the OARs can be made equal even when giving a large simultaneous integrated boost to the GTV. The data suggest that a GTV margin may be added without significant dose effects on the OARs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Issue addressed Alcohol-related harm is an issue of concern for African migrant communities living in Australia. However, there has been little information available to guide workers in developing culturally sensitive health promotion strategies. Methods A three-step approach, comprising a literature review, community consultations and an external review, was undertaken to develop a guide to assist organisations and health promotion groups working with African migrant communities to address alcohol-related harms. Discussion There was a high level of agreement between the three steps. Addressing alcohol harms with African migrant communities requires approaches that are sensitive to the needs, structures and experiences of communities. The process should incorporate targeted approaches that enable communities to achieve their resettlement goals as well as strengthening mainstream health promotion efforts. Conclusions The resource produced guides alcohol harm prevention coalitions and workers from the first steps of understanding the influences of acculturation and resettlement on alcohol consumption, through to planning, developing and evaluating an intervention in partnership with communities. So what? This paper advances knowledge by providing a precise summary of Australian African migrant focused alcohol and other drug research to date. It also describes a three-step approach that aimed to incorporate a diversity of community views in the creation of a health promotion and community capacity-building resource.

Context: Primary care physicians are well placed to identify patients in need of advance care planning (ACP) and initiate ACP in advance of an acute situation., Objectives: This study aimed to understand Australian general practitioner (GP) clinical decision making relating to a patient's "need for ACP" and the likelihood of initiating ACP., Methods: An experimental vignette study pseudorandomly manipulated factors thought to influence decision making regarding ACP. Patient-level factors included gender, age, type of disease, medical severity, openness to ACP, doctor-patient relationship, and family support. An accompanying demographic survey assessed health professional-level factors, including gender, years of experience, place of training, place of practice, caseload of patients with ACP, direct personal experience in ACP, and self-reported attitudes toward ACP. Seventy GPs were recruited, and each completed six unique vignettes, providing ratings of patient need for ACP, importance of initiating ACP in the coming months, and likelihood of initiating ACP at the next consultation., Results: Older patients, with malignant or cardiovascular disease, severe clinical presentations, good doctor-patient relationship, female gender, and poor family support were more likely to receive prompt ACP. Positive GP attitudes toward ACP were associated with greater likelihood of initiating ACP promptly., Conclusion: Patients with presentations suggesting higher mortality risk were identified as being in need of ACP; however, the likelihood of initiating ACP was sensitive to GP attitudes and psychosocial aspects of the doctor-patient interaction. Training materials aimed at encouraging GP involvement in ACP should target attitudes toward ACP and communication skills, rather than focusing solely on prognostic risk., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Interleukin-27 (IL-27) is a heterodimeric regulatory cytokine of the IL-12 family, which is produced by macrophages, dendritic cells, and B cells upon stimulation through innate immune receptors. Here, we described regulatory CD4(+) T cells that produce IL-27 in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-27-dependent manner. IL-27-producing CD4(+) T cells were Foxp3(-)CD11a(+)CD49d(+) malaria antigen-specific CD4(+) T cells and were distinct from interferon-γ (IFN-γ) producing Th1 or IL-10 producing Tr1 cells. In mice lacking IL-27 in T cells, IL-2 production was restored and clonal expansion and IFN-γ production by specific CD4(+) T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-27 producing regulatory CD4(+) T cells and their critical role in the regulation of the protective immune response against malaria parasites., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We encountered a case of uterine leiomyosarcoma with multiple lung metastases. The patient was a 52-year-old woman who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by chemotherapy with gemcitabine and docetaxel. After 1 cycle of chemotherapy, the lung metastasis was reduced, but at the same time, she developed bilateral pneumothorax. Chemical pleurodesis using talc was performed. The lungs were expanded and stabilized in 7 days. After 5 cycles of chemotherapy were administered, no recurrence of pneumothorax and adverse effects were observed.

This case report describes the successful orthodontic tooth movement through the maxillary sinus in an adult patient. A 41-year-old Asian woman had severe lip protrusion and multiple missing posterior teeth. Her orthodontic treatment included the extraction of two teeth, maximum retraction of the incisors using the extraction spaces and the existing spaces from the missing molars, and closure of all remaining spaces. Even though the treatment time was extended because of the anatomic and biologic challenges associated with moving posterior teeth over a long distance through the maxillary sinus, a successful outcome was obtained, with significant bone modeling of the maxillary sinus. The results demonstrate that a carefully selected force system can overcome the anatomic limitations of moving tooth against the cortical bone of the maxillary sinus wall in adult patients., (© EDP Sciences, SFODF, 2015.)

Objective: Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS., Participants and Methods: We examined multiunit and single-unit muscle SNS activity (by microneurography), HRV (time and frequency domain analysis) and endothelial function [ischaemic reactive hyperaemia index (RHI) using the EndoPAT device] in 19 overweight/obese women with PCOS (BMI: 31·3 ± 1·5 kg/m(2), age: 31·3 ± 1·6 years) and compared them with 21 control overweight/obese women (BMI: 33·0 ± 1·4 kg/m(2), age: 28·2 ± 1·6 years) presenting a similar metabolic profile (fasting total, HDL and LDL cholesterol, glucose, triglycerides, insulin sensitivity and blood pressure)., Results: Women with PCOS had elevated multiunit muscle SNS activity (41 ± 2 vs 33 ± 3 bursts per 100 heartbeats, P < 0·05). Single-unit analysis showed that vasoconstrictor neurons were characterized by elevated firing rate and probability and incidence of multiple spikes (P < 0·01 for all parameters). Women with PCOS also had impaired endothelial function (RHI: 1·77 ± 0·14 vs 2·18 ± 0·14, P < 0·05). HRV did not differ between the groups., Conclusion: Women with PCOS have increased sympathetic drive and impaired endothelial function independent of obesity and metabolic disturbances. Sympathetic activation and endothelial dysfunction may confer greater cardiovascular risk in women with PCOS., (© 2015 John Wiley & Sons Ltd.)

Background: Obsessive compulsive personality disorder (OCPD) is characterized by perfectionism, need for control, and cognitive rigidity. Currently, little neuropsychological data exist on this condition, though emerging evidence does suggest that disorders marked by compulsivity, including obsessive-compulsive disorder (OCD), are associated with impairment in cognitive flexibility and executive planning on neurocognitive tasks., Aim: The current study investigated the neurocognitive profile in a nonclinical community-based sample of people fulfilling diagnostic criteria for OCPD in the absence of major psychiatric comorbidity., Method: Twenty-one nonclinical subjects who fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for OCPD were compared with 15 healthy controls on selected clinical and neurocognitive tasks. OCPD was measured using the Compulsive Personality Assessment Scale (CPAS). Participants completed tests from the Cambridge Automated Neuropsychological Test Battery including tests of set shifting (Intra-Extra Dimensional [IED] Set Shifting) executive planning (Stockings of Cambridge [SOC]), and decision making (Cambridge Gamble Task [CGT])., Results: The OCPD group made significantly more IED-ED shift errors and total shift errors, and also showed longer mean initial thinking time on the SOC at moderate levels of difficulty. No differences emerged on the CGT., Conclusions: Nonclinical cases of OCPD showed significant cognitive inflexibility coupled with executive planning deficits, whereas decision-making remained intact. This profile of impairment overlaps with that of OCD and implies that common neuropsychological changes affect individuals with these disorders.

Aims: To estimate current and future specialist neurologist demand and supply to assist with health sector planning., Methods: Current demand for the neurology workforce in New Zealand was assessed using neuroepidemiological data. To assess current supply, all New Zealand neurology departments were surveyed to determine current workforce and estimate average neurologist productivity. Projections were made based on current neurologists anticipated retirement rates and addition of new neurologists based on current training positions. We explored several models to address the supply-demand gap., Results: The current supply of neurologists in New Zealand is 36 full-time equivalents (FTE), insufficient to meet current demand of 74 FTE. Demand will grow over time and if status quo is maintained the gap will widen., Conclusions: Pressures on healthcare dollars are ever increasing and we cannot expect to address the identified service gap by immediately doubling the number of neurologists. Instead we propose a 12-year strategic approach with investments to enhance service productivity, strengthen collaborative efforts between specialists and general service providers, moderately increase the number of neurologists and neurology training positions, and develop highly skilled non-specialists including trained.

Intracellular protein copy numbers show significant cell-to-cell variability within an isogenic population due to the random nature of biological reactions. Here we show how the variability in copy number can be controlled by perturbing gene expression. Depending on the genetic network and host, different perturbations can be applied to control variability. To understand more fully how noise propagates and behaves in biochemical networks we developed stochastic control analysis (SCA) which is a sensitivity-based analysis framework for the study of noise control. Here we apply SCA to synthetic gene expression systems encoded on plasmids that are transformed into Escherichia coli. We show that (1) dual control of transcription and translation efficiencies provides the most efficient way of noise-versus-mean control. (2) The expressed proteins follow the gamma distribution function as found in chromosomal proteins. (3) One of the major sources of noise, leading to the cell-to-cell variability in protein copy numbers, is related to bursty translation. (4) By taking into account stochastic fluctuations in autofluorescence, the correct scaling relationship between the noise and mean levels of the protein copy numbers was recovered for the case of weak fluorescence signals.

The objective of the current study is to evaluate the association between fatty acid composition and fatty acid synthase gene polymorphisms as responsible mutations. For this purpose, we selected seven previously reported single nucleotide polymorphisms (SNPs) in FASN gene, including one within promoter region (g.841G>C) and six non-synonymous SNPs (g.8805C>T, g.13126C>T, g.15532A>C, g.16024A>G, g.16039C>T, g.17924A>G), and genotyped them in Japanese Black cattle. Genotyping results revealed that g.8805 C>T and g.17924 A>G were monomorphic loci. Genome-wide association analysis including the other five SNPs revealed that only g.841G>C showed significant associations with the percentages of C14:0, C14:1, C16:1 and C18:1 at 5% genome-wide significance level. In order to further evaluate the effect, we genotyped g.841G>C using additional three populations, including two Japanese Black populations and a Holstein cattle population. g.16024A>G was also genotyped and included in the analysis because it has been reported to be associated with fatty acid composition in Japanese Black cattle. In the result of analysis of variance, g.841G>C showed stronger effects on fatty acid percentage than those of g.16024A>G in all populations. These results suggested that g.841G>C would be a responsible mutation for fatty acid composition and contribute to production of high-grade beef as a selection marker in beef cattle., (© 2015 Japanese Society of Animal Science.)

A 53-year-old patient with recurrent ovarian clear cell adenocarcinoma developed fever (39°C) and cough on day 28 of liposomal doxorubicin chemotherapy, the 4th cycle of the 4th regimen since initial treatment. Drug-induced interstitial pneumonia was suspected from a chest CT image showing diffuse ground-glass opacities; however, we deduced pneumocystis pneumonia from the elevated serum beta-D-glucan levels. After effective treatment with sulfamethoxazole and amphotericin B, the patient's symptoms and radiological findings improved. Pneumocystis pneumonia is an opportunistic infection that poses a risk not only for patients undergoing aggressive immunosuppressive therapy, those infected with HIV, and those with transplants, but also for patients undergoing chemotherapy. When pneumonia is diagnosed during chemotherapy, it is essential to consider the possibility of pneumocystis pneumonia.

Background: The efficacy of focal continuous low dose-rate brachytherapy (CLDR-BT) for prostate cancer requires that appropriate margins are applied to ensure robust target coverage. In this study we propose a method to establish such margins by emulating a focal treatment in patients treated with CLDR-BT to the entire gland., Material and Methods: In 15 patients with localized prostate cancer, prostate volumes and dominant intra-prostatic lesions were delineated on pre-treatment magnetic resonance imaging (MRI). Delineations and MRI were registered to trans-rectal ultrasound images in the operating theater. The patients received CLDR-BT treatment to the total prostate volume. The implantation consisted of two parts: an experimental focal plan covering the dominant intra-prostatic lesion (F-GTV), followed by a plan containing additional seeds to achieve entire prostate coverage. Isodose surfaces were reconstructed using follow-up computed tomography (CT). The focal dose was emulated by reconstructing seeds from the focal plan only. The distance to agreement between planned and delivered isodose surfaces and F-GTV coverage was determined to calculate the margin required for robust treatment., Results: If patients had been treated only focally, the target volume would have been reduced from an average of 40.9 cm3 for the entire prostate to 5.8 cm3 for the focal plan. The D90 for the F-GTV in the focal plan was 195±60 Gy, the V100 was 94% [range 71-100%]. The maximum distance (cd95) between the planned and delivered isodose contours was 0.48 cm., Conclusions: This study provides an estimate of 0.5 cm for the margin required for robust coverage of a focal target volume prior to actually implementing a focal treatment protocol.

Background and Purpose: Prostate biopsy positivity after radiotherapy (RT) is a significant determinant of eventual biochemical failure. We mapped pre- and post-treatment tumor locations to determine if residual disease is location-dependent., Materials and Methods: There were 303 patients treated on a randomized hypofractionation trial. Of these, 125 underwent prostate biopsy 2-years post-RT. Biopsy cores were mapped to a sextant template, and 86 patients with both pre-/post-treatment systematic sextant biopsies were analyzed., Results: The pretreatment distribution of positive biopsy cores was not significantly related to prostate region (base, mid, apex; p=0.723). Whereas all regions post-RT had reduced positive biopsies, the base was reduced to the greatest degree and the apex the least (p=0.045). In 38 patients who had a positive post-treatment biopsy, there was change in the rate of apical positivity before and after treatment (76 vs. 71%; p=0.774), while significant reductions were seen in the mid and base., Conclusion: In our experience, persistence of prostate tumor cells after RT increases going from the base to apex. MRI was used in planning and image guidance was performed daily during treatment, so geographic miss of the apex is unlikely. Nonetheless, the pattern observed suggests that attention to apex dosimetry is a priority., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

The great demand for long-wavelength and high signal-to-noise Ca(2+) indicators has led us to develop CaRuby-Nano, a new functionalizable red calcium indicator with nanomolar affinity for use in cell biology and neuroscience research. In addition, we generated CaRuby-Nano dextran conjugates and an AM-ester variant for bulk loading of tissue. We tested the new indicator using in vitro and in vivo experiments demonstrating the high sensitivity of CaRuby-Nano as well as its power in dual color imaging experiments.

Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of α-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated α-syn by inducing autophagic clearance of α-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-β-cyclodextrin promotes autophagic clearance of aggregated α-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of α-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of α-syn aggregates.

Enhanced neuronal activity in the brain triggers a local increase in blood flow, termed functional hyperemia, via several mechanisms, including calcium (Ca(2+)) signaling in astrocytes. However, recent in vivo studies have questioned the role of astrocytes in functional hyperemia because of the slow and sparse dynamics of their somatic Ca(2+) signals and the absence of glutamate metabotropic receptor 5 in adults. Here, we reexamined their role in neurovascular coupling by selectively expressing a genetically encoded Ca(2+) sensor in astrocytes of the olfactory bulb. We show that in anesthetized mice, the physiological activation of olfactory sensory neuron (OSN) terminals reliably triggers Ca(2+) increases in astrocyte processes but not in somata. These Ca(2+) increases systematically precede the onset of functional hyperemia by 1-2 s, reestablishing astrocytes as potential regulators of neurovascular coupling.

Background: The way that information is presented is well known to induce a range of biases in human decision tasks. Little research exists on framing effects in psychiatric decision making, but it is reasonable to assume that psychiatrists are not immune and, if so, there may be implications for the welfare of patients, staff and the general public., Aims: To investigate whether presentation of risk information in different formats (frequency, percentage and semantic) influences inpatient admission decisions by psychiatrists., Methods: Six-hundred seventy-eight general adult psychiatrists read a short clinical vignette presenting a case scenario of a patient presenting for inpatient admission. One of four condition questions followed the vignette, incorporating either numerical or percentage probabilities and the semantic labels "high" and "low" risk. In each condition, the actual risk was identical, but the way it was presented varied. The decision to admit the patient or not was recorded and compared across conditions., Results: More individuals chose to admit the patient when risk information was presented in numerical form (X2 = 7.43, p = 0.006) and with the semantic label "high" (X2 = 7.27, p = 0.007)., Conclusions: Presentation of risk information may influence decision making in psychiatrists. This has important implications for mental health clinical practice where clinicians are required to interpret probabilistic information within their daily work.

An important key to clinical management of prostate cancer patients is to determine early those who will benefit from primary treatment and are not good candidates for active surveillance (AS). We describe a 67-year-old gentleman with a long history of stable prostate-specific antigen (PSA) levels and a negative biopsy. After slight PSA rise and low volume Gleason score 6 biopsy, the patient was considered for primary treatment or AS. A multiparametric (MP)-MRI exam revealed a suspicious lesion in the anterior apex of the prostate. Biopsies were carried out on a 3D-ultrasound prostate biopsy system with MRI-fusion. The location of the target area was challenging and could have been missed using standard 12-core biopsy template. The pathology determined Gleason 3 + 4 disease in 30% of the core from this region. Consequently, the patient underwent radiotherapy (RT). MP-MRI was also used to follow the changes from pre- to post-RT.

Twelve personal narratives address the challenges, benefits, and pitfalls of genetic testing. Three commentary articles explore these stories and suggest lessons that can be learned from them. The commentators come from backgrounds that include bioethics, public health, psychology, and philosophy.

This review covers pyrrolizidine alkaloids isolated from natural sources. Topics include: aspects of structure, isolation, and biological/pharmacological studies; total syntheses of necic acids, necine bases and closely-related non-natural analogues.

Aziridines formed upon treatment of allylic carbamates and homoallylic sulfamates with Rh(II) carboxylate catalysts under oxidative conditions are trapped by suitably-disposed hydroxyl groups to give functionalised tetrahydrofurans.

This case report describes the successful orthodontic tooth movement through the maxillary sinus in an adult patient. A 41-year-old Asian woman had severe lip protrusion and multiple missing posterior teeth. Her orthodontic treatment included the extraction of 2 teeth, maximum retraction of the incisors using the extraction spaces and the existing spaces from the missing molars, and closure of all remaining spaces. Even though the treatment time was extended because of the anatomic and biologic challenges associated with moving posterior teeth over a long distance through the maxillary sinus, a successful outcome was obtained, with significant bone modeling of the maxillary sinus. The results demonstrate that a carefully selected force system can overcome the anatomic limitations of moving tooth against the cortical bone of the maxillary sinus wall in adult patients., (Copyright © 2014 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

The echolocation behavior of Pipistrellus abramus during exposure to artificial jamming sounds during flight was investigated. Echolocation pulses emitted by the bats were recorded using a telemetry microphone mounted on the bats' backs, and their adaptation based on acoustic characteristics of emitted pulses was assessed in terms of jamming-avoidance responses (JARs). In experiment 1, frequency-modulated jamming sounds (3 ms duration) mimicking echolocation pulses of P. abramus were prepared. All bats showed significant increases in the terminal frequency of the frequency-modulated pulse by an average of 2.1-4.5 kHz when the terminal frequency of the jamming sounds was lower than the bats' own pulses. This frequency shift was not observed using jamming frequencies that overlapped with or were higher than the bats' own pulses. These findings suggest that JARs in P. abramus are sensitive to the terminal frequency of jamming pulses and that the bats' response pattern was dependent on the slight difference in stimulus frequency. In experiment 2, when bats were repeatedly exposed to a band-limited noise of 70 ms duration, the bats in flight more frequently emitted pulses during silent periods between jamming sounds, suggesting that the bats could actively change the timing of pulse emissions, even during flight, to avoid temporal overlap with jamming sounds. Our findings demonstrate that bats could adjust their vocalized frequency and emission timing during flight in response to acoustic jamming stimuli., (© 2014. Published by The Company of Biologists Ltd.)