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Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter-individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver-reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. LAY SUMMARY: In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.

Introduction Adolescents and young adults who overemphasize the social values placed on an attractive appearance may develop body dysmorphic symptoms (BDS), defined as over-preoccupation with perceived appearance flaws and repetitive behaviors to conceal the flaws. Further, research has found that a heightened expectation of judgement and rejection by others because of appearance (i.e., appearance-based rejection sensitivity [appearance-RS]) is both a maintaining and an aggravating factor in BDS. This study focused on emotion regulation (ER), appearance-related support from others and self-acceptance, expecting they would buffer the negative impact of appearance-RS on BDS. Methods Participants included 782 Australian high school and young university students, aged 14–28 years (M = 17.94 years, 40% male) who completed a survey to report their BDS, appearance-RS, ER, appearance-related support from others and self-acceptance. Results Multiple regression analyses revealed that youth reported more BDS when they were higher in appearance-RS but reported less self-acceptance, ER, and support from others. Further, the association between appearance-RS and BDS was weaker when young people reported higher (relative to lower) ER and support from others. However, when three-way interactions with gender were tested, these buffering effects were only significant for young men. Conclusion Findings suggest that ER and appearance-related support from important others are promising targets for intervention, given they could mitigate the risk of appearance-RS in young men. However, further research is needed to consider additional factors that buffer against the negative effects of appearance-RS on BDS for young women.

Social motivation is a foundational construct with regard to the etiology, neurobiology, and phenotype of autism spectrum disorder (ASD). Multiple theories suggest that early emerging alterations to social motivation underlie a developmental cascade of social and communication deficits across the lifespan. Despite this significance, methods to measure social motivation vary widely, with little data to date as to how different measures might compare. In this study, we explore three existing caregiver-report measures that have been proposed to quantify social motivation among school-age children with ASD (n = 18; all male) and without ASD (n = 36; 50% female), with the broad goal of characterizing social motivation across measures and specific aims of investigating (a) diagnostic and sex differences in social motivation, (b) correspondence between measures, and (c) relationships between social motivation and broader social outcomes. Across all three measures, individuals with ASD had lower social motivation by caregiver-report. However, they did display individual differences in the degree of social motivation reported. There were no differences in social motivation between males and females without ASD on any of the three measures. For the full sample, measures of social motivation correlated with one another as anticipated, and stronger social motivation was associated with stronger social skills and fewer social difficulties. Our data suggest that social motivation among children with ASD may be best conceptualized as an individual difference that is diminished on average relative to peers but which varies among children and adolescents with ASD, rather than as an absolute absence or uniform deficit. LAY SUMMARY: Several theories suggest that children with autism spectrum disorder (ASD) experience less social motivation than their peers without ASD, contributing to difficulties in social skills. Based on multiple caregiver-report questionnaires, social motivation was reduced on average for school-age children with ASD but also varied among children with ASD. Stronger social motivation was related to stronger social skills and fewer social problems. Future work should include more girls with ASD, consider social motivation across age groups, and include first-hand perspectives from people with ASD.

To investigate how remotely induced changes in ligand folding might affect catalysis by organometallic complexes, dynamic α-amino-iso-butyric acid (Aib) peptide foldamers bearing rhodium(I) N-heterocyclic carbene (NHC) complexes have been synthesised and studied. X-ray crystallography of a foldamer with an N-terminal azide and a C-terminal Rh(NHC)(Cl)(diene) complex showed a racemate with a chiral axis in the Rh(NHC) complex and a distorted 310 helical body. Replacing the azide with either one or two chiral Lα-methylvaline (L-αMeVal) residues gave diastereoisomeric foldamers that each possessed point, helical and axial chirality. NMR spectroscopy revealed an unequal ratio of diastereoisomers for some foldamers, indicating that the chiral conformational preference of the N-terminal residue(s) was relayed down the 1 nm helical body to the axially chiral Rh(NHC) complex. Although the remote chiral residue(s) did not affect the stereoselectivity of hydrosilylation reactions catalysed by these foldamers, these studies suggest a potential pathway towards remote conformational control of organometallic catalysts.

Saccharomyces cerevisiae is a genetically facile organism, yet multiple CRISPR/Cas9 techniques are widely used to edit its genome more efficiently and cost effectively than conventional methods. The absence of selective markers makes CRISPR/Cas9 editing particularly useful when making mutations within genes or regulatory sequences. Heterozygous mutations within genes frequently arise in the winners of evolution experiments. The genetic dissection of heterozygous alleles can be important to understanding gene structure and function. Unfortunately, the high efficiency of genome cutting and repair makes the introduction of heterozygous alleles by standard CRISPR/Cas9 technique impossible. To be able to quickly and reliably determine the individual phenotypes of the thousands of heterozygous mutations that can occur during directed evolutions is of particular interest to industrial strain improvement research. In this report, we describe a CRISPR/Cas9 method that introduces specific heterozygous mutations into the S. cerevisiae genome. This method relies upon creating silent point mutations in the protospacer adjacent motif site or removing the protospacer adjacent motif site entirely to stop the multiple rounds of genome editing that prevent heterozygous alleles from being generated. This technique should be able to create heterozygous alleles in other diploid yeasts and different allelic copy numbers in polyploid cells.

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF).METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap.RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap.CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

Objective To determine the effect of the length of incision and of the number of suture lines on the load to failure of incisional gastropexy in an ex vivo model. Study design Ex vivo study. Sample population Thirty-six hound-mix fresh canine cadavers. Methods Specimens were randomly divided into four groups of incisional gastropexies varying in length of incision (2 or 4 cm) and number of suture lines (one or two). Load to failure was measured. Number of suture bites on each side of the gastropexy and number of inadvertent full thickness gastric suture bites were recorded. Results Incisional gastropexies performed with one or two suture lines sustained loads to failure of 53.80 ± 12.10 N and 53.30 ± 10.60 N (P = .887), respectively. Loads to failure equal to 49.70 ± 10.80 N and 57.30 ± 10.60 N (P = .048) were measured on incisional gastropexies performed with 2- or 4-cm-suture lines, respectively. There was no interaction between the length of the incision and the number of suture lines (P = .634). Conclusion Length of incision but not number of suture lines influenced the biomechanical properties of gastropexies in this acute cadaveric model. Clinical significance According to this acute in vitro experiment, gastropexy can be performed with either one or two suture lines.

Background The 2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines provide information for managing abnormal cervical cancer screening tests and cancer precursors. According to these guidelines for Pap smear diagnosis of Atypical squamous cells of undetermined significance, reflex high risk (HR) human papilloma virus (HPV) genotyping is required among women 21 years of age or older. Whereas, in women of 30 to 65 years of age, HR-HPV can be ordered by the clinicians as part of co-testing with any diagnosis and every 5 years with a negative Cervico-Vaginal Pap test (CVPT). Methods A retrospective review of the CoPath database of the Pathology Department at the University of Florida, College of Medicine Jacksonville, FL, was performed to identify North Florida (NF) women who underwent CVPT and HR-HPV testing between 2006 and 2014. The women were stratified by race and age, respectively. Results The study included 19,933 CVPTs. Significant differences in the outcomes' distributions were found among age and race groups, respectively. Highest prevalence of HPV positivity was found in African American women, and in 14- to 20-year-old women, respectively. Twenty- to 30-year-old women had the highest percentage (59%) of epithelial abnormality. The most common HR-HPV genotypic distribution was other HR-HPV. Conclusions This study underscores the importance of using both HR-HPV and CVPT for screening for cervical cancer, and confirms the need for special focus on managing high-risk populations subgroups, such as African American women, and women of ages 14 to 20 years especially in high-risk populations.

Emerging infectious diseases threaten the persistence of biodiversity globally. The amphibian chytrid fungus, Batrachochytrium dendrobatidis, is one of the most widespread and damaging pathogens to biodiversity. New Guinea hosts 6% of the world's frogs and is the largest landmass where B. dendrobatidis remains undetected despite being largely climatically suitable for its persistence. We surveyed for B. dendrobatidis in Papua New Guinea, by swabbing live frogs in the Gulf Province and Eastern Highlands Province and by examining museum specimens from a range of sites and elevations. Here, we show that over a large geographical range, all 442 samples were negative for B. dendrobatidis. The spread of B. dendrobatidis to Papua New Guinea may have been thus far prevented by the remoteness of New Guinea and the hotter climate in its lowlands, which surrounds a more climatically suitable zone for B. dendrobatidis in the highlands. Alternatively, B. dendrobatidis may be present in isolated patches or at low levels and remain undetected, to date. Papua New Guinea remains at risk and would benefit from a national disease surveillance program for chytrid fungi and pre‐emptive actions, designed to reduce the risk of pathogen transmission. Measures should include improved biosecurity protocols for trade and travel and continued disease surveillance in areas of probable entry and spread.

Background Because both diarrhea due to other causes and gastrointestinal colonization with toxigenic Clostridioides difficile are common in HSCT, there is a possibility of false-positive diagnoses of C difficile infections (CDI). Methods We estimated the probability of a patient being colonized by toxigenic C difficile by testing non-diarrheal surveillance stools from 223 HSCT recipients and the probability that a specimen submitted for C difficile testing was not CDI by determining the number of clinical tests that returned negative from this cohort. The number of expected false-positive CDI was estimated using these probabilities and compared with observed clinical test results. Results The expected false-positive and the observed numbers of positive clinical results were similar. The 20 patients diagnosed with CDI were also similar to 142 patients with diarrhea and C difficile-negative stools in number of stools on day of testing, associated symptoms, and the recorded number of days to formed stools. C difficile colonization was most commonly detected during the first week and CDI during the second. Retrospective analysis of 837 patients showed that 18 stools were submitted for each diagnosis of CDI. Ribotyping of the surveillance samples showed 17 ribotypes. Conclusions Although several assumptions could impact the accuracy of our false-positive CDI estimates, it appears that many HSCT recipients diagnosed with CDI may actually represent colonized status and an alternative cause of diarrhea. Diagnostic stewardship, including limiting CDI diagnoses to patients with positive toxin and restricting stool submissions to patients with more severe symptoms, may decrease the number of false-positive diagnoses.

A great diversity of parasites, from viruses and bacteria to a range of remarkable eukaryotic organisms, exploit reptile and amphibian hosts. Recent increases in the emergence of infectious disease have revealed the importance of understanding the effects of interactions between hosts and their parasites. Here we review the effects of parasite infection on a range of demographic, behavioural, genomic and physiological factors in reptile and amphibian species. Reviewing these parasite roles collectively, and prioritising areas for research, advances our ecological understanding and guides direction for conservation in a time of rapid species decline. Poorly resolved systems include Gymnophionan amphibians and Crocodilian hosts, in addition to viral and bacterial parasites. Future research should seek to understand processes enabling population recovery and examining synergistic interactions of parasites with fragmentation, climate change and other processes that threaten species persistence.

AIMS: The aims of the present study were to explore whether a long‐term intervention with dietary nitrate [(NO(3) (−)), a potential tolerance‐free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS: A subsample of participants in our double‐blind, randomized, factorial‐design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent‐to‐treat. RESULTS: Nitrate‐containing juice (n = 40) decreased left ventricular (LV) end‐diastolic volume {−6.3 [95% confidence interval (CI) –11.1, –1.6] ml} and end‐systolic volume [−3.2 (95% CI −5.9, –0.5) ml], and increased end‐diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [−0.01 (95% CI −0.02, –0.00)]. Although spironolactone reduced LV mass index relative to baseline [−1.48 (95% CI −2.08, –0.88) g m(–2.7)], there was no difference vs. doxazosin [−0.85 (95% CI −1.76, 0.05) g m(–2.7)]. Spironolactone also decreased the E/A ratio [−0.12 (95% CI −0.19, –0.04)] and increased S′ (a tissue‐Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s(–1). BP did not differ between the juices, or between the drugs. CONCLUSIONS: Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP‐independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic–diastolic function, although confirmatory, were independent of BP.

Paracetamol (acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years, the benefits of paracetamol use in chronic conditions has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long-term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas as well. The evidence base for the adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomized controlled trials, many of which contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg) increase in systolic blood pressure are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. The present review summarizes the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.

Helical α-aminoisobutyric acid (Aib) foldamers show great potential as devices for the communication of conformational information across phospholipid bilayers, but determining their conformation in bilayers remains a challenge. In the present study, Raman, Raman optical activity (ROA), infrared (IR) and vibrational circular dichroism (VCD) spectroscopies have been used to analyze the conformational preferences of Aib foldamers in solution and when interacting with bilayers. A 310 -helix marker band at 1665-1668 cm-1 in Raman spectra was used to show that net helical content increased strongly with oligomer length. ROA and VCD spectra of chiral Aib foldamers provided the chiroptical signature for both left- and right-handed 310 -helices in organic solvents, with VCD establishing that foldamer screw-sense was preserved when the foldamers became embedded within bilayers. However, the population distribution between different secondary structures was perturbed by the chiral phospholipid. These studies indicate that ROA and VCD spectroscopies are valuable tools for the study of biomimetic structures, such as artificial signal transduction molecules, in phospholipid bilayers.

Theoretical and empirical studies suggest that the total energy available in natural communities influences body size as well as patterns of abundance and diversity. But the precise mechanisms underlying relationships or how these three ecological properties relate remain elusive. We identify five hypotheses relating energy availability, body size distributions, abundance, and species richness within communities, and we use experimental deep sea wood fall communities to test their predicted effects both on descriptors describing the species richness-body size distribution, and on trends in species richness within size classes over an energy gradient (size class-richness relationships). Invertebrate communities were taxonomically identified, weighed, and counted from 32 Acacia sp. logs ranging in size from 0.6 to 20.6 kg (corresponding to different levels of energy available) which were deployed at 3203 m in the Northeast Pacific Ocean for between 5 and 7 years. Trends in both the species richness-body size distribution and the size class-richness distribution with increasing wood fall size provide support for the Increased Packing hypothesis: species richness increases with increasing wood fall size but only in the modal size class. Furthermore, species richness of body size classes reflected the abundance of individuals in that size class. Thus, increases in richness in the modal size class with increasing energy were concordant with increases in abundance within that size class. The results suggest that increases in species richness occurring as energy availability increases may be isolated to specific niches, e.g. the body size classes, especially in communities developing on discrete and energetically isolated resources such as deep sea wood falls.

Objectives To assess the impact of nasal septal perforation on quality of life. Design Retrospective cohort study. Setting Rhinology clinics from two hospitals in Liverpool, United Kingdom. Participants Patients diagnosed with nasal septal perforation (NSP). Main outcome measures Patients (n=26) diagnosed with NSP completed the Sino-Nasal Outcome Test-22 (SNOT-22). The collated data was compared with SNOT-22 scores from a cohort of healthy volunteers (n=34) and a cohort of patients (n=30) diagnosed with chronic rhinosinusitis (CRS). Results The mean total SNOT-22 score of NSP and CRS cohorts were higher than that observed in healthy volunteers. The mean total SNOT-22 score in the CRS cohort (57.2, standard deviation SD 10.3) was the higher than NSP (50.2, SD 23.5), although this difference did not achieve statistical significance. The mean score for the rhinologic-specific domains (rhinologic symptoms, extra-nasal rhinologic symptoms), ear/facial symptoms and psychological dysfunction domain were higher in the CRS cohort compared to NSP, although statistical significance was only observed in the extranasal rhinologic symptoms domain (11.2, SD 2.4 vs. 6.4, SD 4.1). Conversely, the mean sleep dysfunction domain score for NSP (12.7, SD 7.5) was higher than CRS (10.0, SD 4.9 respectively) although this was not statistically significant. Conclusions The present study has assessed the clinimetric and psychometric properties of patients suffering with symptomatic NSP. Future reports should consider inclusion of SNOT-22 data but with the addition of perforation-specific symptoms (nasal crusting, epistaxis, whistling noise). This article is protected by copyright. All rights reserved.

Amphibian chytridiomycosis, caused by infection with Batrachochytrium dendrobatidis (Bd), is the most devastating vertebrate disease on record. Reservoir hosts are likely to be important in the Bd-amphibian system because many amphibian species can carry infections without experiencing mortality. However, while a variety of reservoirs have been proposed, few have been empirically demonstrated to act as competent reservoir hosts. In this study, we investigate whether the common eastern froglet, Crinia signifera, a non-declining species that is widespread in eastern Australia, is a reservoir host for Bd infection. We conducted a long-term, large-scale field survey to investigate disease dynamics in C. signifera at sites where four sympatric, threatened anuran species have severely declined. We also monitored Bd-infected C. signifera in the laboratory to determine susceptibility and survivorship. Finally, we assessed population age structure to investigate disease impact in the wild. We found that C. signifera is a competent reservoir host, maintaining high prevalence and infection intensities in the wild and in the laboratory, with no signs of sub-lethal effects or clinical disease. In the wild, the modal age is 4 years with individuals living up to 6 years, indicating that adults can survive across multiple years despite high infection prevalence and intensity. The occurrence of C. signifera at sites with remnant populations of threatened species likely contributes to ongoing disease impact in declining species decades after the arrival of Bd. The presence of C. signifera at sites where threatened species have become extinct inhibits effective reintroductions, and we recommend avoiding sites with high reservoir host abundance when planning reintroductions.

Perioperative leaders at our facility were struggling to meet efficiency targets for robotic surgery procedures while also maintaining the satisfaction of the surgical team. We developed a human resources time and motion study tool and used it in conjunction with the NASA Task Load Index to observe and analyze the required workload of personnel assigned to 25 robotic surgery procedures. The time and motion study identified opportunities to enlist the help of nonlicensed support personnel to ensure safe patient care and improve OR efficiency. Using the NASA Task Load Index demonstrated that high temporal, effort, and physical demands existed for personnel assisting with and performing robotic surgery. We believe that this process could be used to develop cost-effective staffing models, resulting in safe and efficient care for all surgical patients.

Soil temperatures from 1976 to 2010 are reported from two sites: Compton (UK) and Hohe Warte (Austria). Soil temperature at Compton significantly increased over the period 1976–2010; increases ranged between +0.04 degC and +0.08 degC year–1, depending on depth. Temperature increases were greater in winter. Mean annual temperature at Hohe Warte increased by around 0.03 degC year−1 from 1976 to 2010. Significant temperature increases were recorded at Hohe Warte in summer, but not in winter. These differences were attributed to greater snow cover at Hohe Warte insulating the soil in winter, and to the drier summers at Hohe Warte enabling more rapid soil warming.

Recent emergences of fungal diseases have caused catastrophic global losses of biodiversity. Temperature is one of the most important factors influencing host–fungus associations but the effects of temperature variability on disease development are rarely examined. The chytrid pathogen Batrachochytrium dendrobatidis (Bd) has had severe effects on populations of hundreds of rainforest-endemic amphibian species but we know little about the effects of rainforest-specific host body temperature cycles on infection patterns. To address this challenge, we used body temperature regimes experienced in nature by frogs in the Australian Wet Tropics to guide a controlled experiment investigating the effects of body temperature fluctuations on infection patterns in a model host (Litoria spenceri), with emphasis on exposing frogs to realistic “heat pulses” that only marginally exceed the thermal optimum of the fungus. We then exposed cultured Bd to an expanded array of heat pulse treatments and measured parameters of population growth to help resolve the role of host immunity in our in vivo results. Infections developed more slowly in frogs exposed to daily 4-hr heat pulses of 26°C or 29°C than in frogs in constant temperature treatments without heat pulses (control). Frogs that experienced heat pulses were also less likely to exceed infection intensities at which morbidity and mortality become likely. Ten of 11 (91%) frogs from the daily 29°C heat pulse treatment even cleared their infections after approximately 9 weeks. Cultured Bd also grew more slowly when exposed to heat pulses than in constant-temperature control treatments, suggesting that mild heat pulses have direct negative effects on Bd growth in nature, but precluding us from determining whether there was a concurrent benefit of heat pulses to host immunity. Our results suggest that even in habitats where average temperatures may be suitable for fungal growth and reproduction, infection risk or the outcome of existing infections may be heavily influenced by short but frequent exposures to temperatures that only slightly exceed the optimum for the fungus. Our findings provide support for management interventions that promote warm microenvironments for hosts, such as small-scale removal of branches overhanging critical habitat or provision of artificial heat sources.

This is a joint statement from individual pharmacology and pharmaceutical professionals acting in their own capacity, including members of the Alliance for Clinical Research Excellence and Safety (ACRES) and the International Society of Pharmacovigilance (ISoP). By building on the extensive pharmacological and regulatory investigations that already take place, we are calling for a fuller and more robust systems‐based approach to the independent investigation of clinical research when serious incidents of harm occur, starting with first‐in‐human clinical trials. To complement existing activities and regulations, we propose an additional approach blending evidence derived from both pharmacological and organizational science, which addresses human factors and transparency, to enhance organizational learning and continuous improvement. As happens with investigations in other sectors of society, such as the chemical and aviation sector, this systems approach should be seen as an additional way to understand how problems occur and how they might be prevented in the future. We believe that repetition of potentially preventable and adverse outcomes during clinical research, by failing to identify and act upon all systematic vulnerabilities, is a situation that needs urgent change. As we will discuss further on, approaches based on applying systems theory and human factors are much more likely to improve objectivity and transparency, leading to better system design.

Aim The aim of this article is to test the hypothesis that remote ischaemic preconditioning (RIPC) increases circulating endogenous local and systemic plasma (nitrite) during RIPC and ischaemia-reperfusion (IR) as a potential protective mechanism against ischaemia-reperfusion injury (IRI). Methods Six healthy male volunteers (mean age 29.5 ± 7.6 years) were randomized in a crossover study to initially receive either RIPC (4 × 5 min cycles) to the left arm, or no RIPC (control), both followed by an ischaemia-reperfusion (IR) sequence (20 min cuff inflation to 200 mmHg, 20 min reperfusion) to the right arm. The volunteers returned at least 7 days later for the alternate intervention. The primary outcome was the effect of RIPC vs. control on local and systemic plasma (nitrite). Results RIPC did not significantly change plasma (nitrite) in either the left or the right arm during the RIPC sequence. However, compared to control, RIPC decreased plasma (nitrite) during the subsequent IR sequence by ~26% (from 118 ± 9 to 87 ± 5 nmol l-1 ) locally in the left arm (P = 0.008) overall, with an independent effect of -58.70 nmol l-1 (95% confidence intervals -116.1 to -1.33) at 15 min reperfusion, and by ~24% (from 109 ± 9 to 83 ± 7 nmol l-1 ) systemically in the right arm (P = 0.03). Conclusions RIPC had no effect on plasma (nitrite) during the RIPC sequence, but instead decreased plasma (nitrite) by ~25% during IR. This would likely counteract the protective mechanisms of RIPC, and contribute to RIPC's lack of efficacy, as observed in recent clinical trials. A combined approach of RIPC with nitrite administration may be required.