The Atacama Rover Astrobiology Drilling Studies (ARADS) Project.

With advances in commercial space launch capabilities and reduced costs to orbit, humans may arrive on Mars within a decade. Both to preserve any signs of past (and extant) martian life and to protect the health of human crews (and Earth's biosphere), it will be necessary to assess the risk of cross-contamination on the surface, in blown dust, and into the near-subsurface (where exploration and resource-harvesting can be reasonably anticipated). Thus, evaluating for the presence of life and biosignatures may become a critical-path Mars exploration precursor in the not-so-far future, circa 2030. This Special Collection of papers from the Atacama Rover Astrobiology Drilling Studies (ARADS) project describes many of the scientific, technological, and operational issues associated with searching for and identifying biosignatures in an extreme hyperarid region in Chile's Atacama Desert, a well-studied terrestrial Mars analog environment. This paper provides an overview of the ARADS project and discusses in context the five other papers in the ARADS Special Collection, as well as prior ARADS project results.

Frequentist rules for regulatory approval of subgroups in phase III trials: A fresh look at an old problem.

BACKGROUND: The number of Phase III trials that include a biomarker in design and analysis has increased due to interest in personalised medicine. For genetic mutations and other predictive biomarkers, the trial sample comprises two subgroups, one of which, say B+ is known or suspected to achieve a larger treatment effect than the other B-. Despite treatment effect heterogeneity, trials often draw patients from both subgroups, since the lower responding B- subgroup may also gain benefit from the intervention. In this case, regulators/commissioners must decide what constitutes sufficient evidence to approve the drug in the B- population. METHODS AND RESULTS: Assuming trial analysis can be completed using generalised linear models, we define and evaluate three frequentist decision rules for approval. For rule one, the significance of the average treatment effect in B- should exceed a pre-defined minimum value, say ZB->L. For rule two, the data from the low-responding group B- should increase statistical significance. For rule three, the subgroup-treatment interaction should be non-significant, using type I error chosen to ensure that estimated difference between the two subgroup effects is acceptable. Rules are evaluated based on conditional power, given that there is an overall significant treatment effect. We show how different rules perform according to the distribution of patients across the two subgroups and when analyses include additional (stratification) covariates in the analysis, thereby conferring correlation between subgroup effects. CONCLUSIONS: When additional conditions are required for approval of a new treatment in a lower response subgroup, easily applied rules based on minimum effect sizes and relaxed interaction tests are available. Choice of rule is influenced by the proportion of patients sampled from the two subgroups but less so by the correlation between subgroup effects.

Declining grouper spawning aggregations in Western Province, Solomon Islands, signal the need for a modified management approach.

Globally, groupers (Epinephelidae) that form fish spawning aggregations (FSAs) are highly vulnerable to overfishing and often require site-specific approaches to management. Over 5-years (2009-2013), we conducted underwater visual censuses (UVC) at a well-known spawning site at Njari Island, Gizo, Western Province, Solomon Islands, that supports aggregations of squaretail coralgrouper (Plectropomus areolatus), camouflage grouper (Epinephelus polyphekadion) and brown-marbled grouper (E. fuscoguttatus). Findings show that while there were species-specific variations in the duration and timing of the spawning season, aggregation densities peaked from March to June, representing the main spawning season for all three species. For P. areolatus, gonad analysis from samples taken from 2008 to 2011 confirmed reproductive activity in support of density trends observed through UVC. Over the 5-year UVC monitoring period, FSA densities declined for P. areolatus and E. polyphekadion. Conversely, following the first year of monitoring, E. fuscoguttatus densities increased. These inter-specific differences may reflect variable responses to fishing as shown elsewhere, or for example, differences in recruitment success. In response to known declines in FSAs of these species, in 2018 the Solomon Islands government placed a nationwide ban on these species' harvest and sale between October and January. As this study shows, this ban does not encompass the peak aggregation period at Njari and will offer limited protection to other FSAs of these species that are known to vary in reproductive seasonality across the Solomon Islands. A more biologically meaningful and practical management strategy would be to implement a nationwide ban on the harvest and sale of these groupers each month between full and new moons when these FSAs form consistently throughout the country. Since effective management of FSAs typically requires a combined approach, spatial management that protects both spawning sites and reproductive migratory corridors is warranted.

Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

A Qualitative Investigation of the Impact of Home-Based Primary Care on Family Caregivers.

BACKGROUND: Home-based primary care (HBPC) provides team-based clinical care for homebound patients who have difficulty accessing typical outpatient care. Interdisciplinary team members also provide social and emotional support and serve as a resource for family caregivers, who often experience significant emotional stress. OBJECTIVES: This qualitative study explores the impact of HBPC on family caregivers to identify aspects of the program that caregivers find most helpful and meaningful as well as areas for improvement. DESIGN: Semi structured recorded interviews were conducted with family caregivers of frail, elderly homebound patients. Interviews included the following topics: overall program satisfaction and suggestions for improvement. SETTING: A HBPC program serving patients in Queens, Nassau and Suffolk counties in New York. PARTICIPANTS: Nineteen family caregivers: 13 women, 6 men; 10 were adult children; 6 were spouses, and 3 were other family members of patients in a HBPC program. MEASUREMENTS: Thematic coding of all recorded transcribed interviews was prepared by 3 qualitative coders. Interrater reliability was conducted to ensure reliability across coders before themes were disseminated and discussed until consensus was achieved with the larger group of investigators. RESULTS: Three main themes were identified: the importance of staff emotional support; the burden of caring for homebound patients; and the need for a broader range of home-based services. Multiple family members noted that the program not only had saved their loved one's life, but had also metaphorically saved their own. CONCLUSIONS: Family caregivers value the communication and accessibility of HBPC and report that the program has a positive impact on their stress and mental health. Results can inform key aspects that need to be retained or enhanced with the expansion in HBPC programs.

Dynamic genetic regulation of gene expression during cellular differentiation.

Genetic regulation of gene expression is dynamic, as transcription can change during cell differentiation and across cell types. We mapped expression quantitative trait loci (eQTLs) throughout differentiation to elucidate the dynamics of genetic effects on cell type-specific gene expression. We generated time-series RNA sequencing data, capturing 16 time points during the differentiation of induced pluripotent stem cells to cardiomyocytes, in 19 human cell lines. We identified hundreds of dynamic eQTLs that change over time, with enrichment in enhancers of relevant cell types. We also found nonlinear dynamic eQTLs, which affect only intermediate stages of differentiation and cannot be found by using data from mature tissues. These fleeting genetic associations with gene regulation may explain some of the components of complex traits and disease. We highlight one example of a nonlinear eQTL that is associated with body mass index.

Computationally efficient methods for fitting mixed models to electronic health records data.

Motivated by two case studies using primary care records from the Clinical Practice Research Datalink, we describe statistical methods that facilitate the analysis of tall data, with very large numbers of observations. Our focus is on investigating the association between patient characteristics and an outcome of interest, while allowing for variation among general practices. We explore ways to fit mixed-effects models to tall data, including predictors of interest and confounding factors as covariates, and including random intercepts to allow for heterogeneity in outcome among practices. We introduce (1) weighted regression and (2) meta-analysis of estimated regression coefficients from each practice. Both methods reduce the size of the dataset, thus decreasing the time required for statistical analysis. We compare the methods to an existing subsampling approach. All methods give similar point estimates, and weighted regression and meta-analysis give similar standard errors for point estimates to analysis of the entire dataset, but the subsampling method gives larger standard errors. Where all data are discrete, weighted regression is equivalent to fitting the mixed model to the entire dataset. In the presence of a continuous covariate, meta-analysis is useful. Both methods are easy to implement in standard statistical software.

Label-invariant models for the analysis of meta-epidemiological data.

Rich meta-epidemiological data sets have been collected to explore associations between intervention effect estimates and study-level characteristics. Welton et al proposed models for the analysis of meta-epidemiological data, but these models are restrictive because they force heterogeneity among studies with a particular characteristic to be at least as large as that among studies without the characteristic. In this paper we present alternative models that are invariant to the labels defining the 2 categories of studies. To exemplify the methods, we use a collection of meta-analyses in which the Cochrane Risk of Bias tool has been implemented. We first investigate the influence of small trial sample sizes (less than 100 participants), before investigating the influence of multiple methodological flaws (inadequate or unclear sequence generation, allocation concealment, and blinding). We fit both the Welton et al model and our proposed label-invariant model and compare the results. Estimates of mean bias associated with the trial characteristics and of between-trial variances are not very sensitive to the choice of model. Results from fitting a univariable model show that heterogeneity variance is, on average, 88% greater among trials with less than 100 participants. On the basis of a multivariable model, heterogeneity variance is, on average, 25% greater among trials with inadequate/unclear sequence generation, 51% greater among trials with inadequate/unclear blinding, and 23% lower among trials with inadequate/unclear allocation concealment, although the 95% intervals for these ratios are very wide. Our proposed label-invariant models for meta-epidemiological data analysis facilitate investigations of between-study heterogeneity attributable to certain study characteristics.

Goldspotted spinefoot Siganus punctatus (Siganidae) age-based reproductive life history and fisheries vulnerability.

Between February 2015 and 2016, samples of the Indo-Pacific goldspotted spinefoot Siganus punctatus were taken from local fish markets, feeding sites and nursery grounds on the main island of Pohnpei, Micronesia, to ascertain sexual pattern, reproductive seasonality, age, growth and mortality. Microscopic examinations of gonads identified two seasonal peaks in reproduction: February to May and September to December, with evidence of some spawning activity in most months. Ripe females were observed 4 days on either side of the new moon. Females first matured at c. 180 mm fork length (LF ) and 1 year of age, which coincides with their entry into the fishery. Ninety five per cent of individuals were less than 3 years and the oldest fish were 8 years. To examine the species vulnerability to fishing, a tag-and-recapture study was conducted over 4 months in 2015 in a locally managed marine area and at an unprotected site. Findings suggest high residency and high vulnerability to fishing at shallow-water feeding sites and restricted migration overall. The placement of marine protected areas within critical habitat appears to be an effective conservation strategy for this species, particularly when combined with gear and seasonal market restrictions during vulnerable life-history phases.

The frequency of acute kidney injury in patients with chronic hepatitis C virus infection treated with sofosbuvir-based regimens.

BACKGROUND: Guidelines recommend withholding sofosbuvir (SOF) in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min. AIM: To assess the risk of acute kidney injury (AKI) in patients with no renal contraindications for SOF-based treatment. METHODS: This multicenter retrospective observational study included all consecutive patients that were treated with SOF-based or telaprevir/boceprevir (TVR/BOC)-based regimens at two tertiary university centers in North America. AKI was defined as an increase of ≥0.3 mg/dL (≥26.5 µmol/L) in serum creatinine level. Multivariable logistic regression analysis was used to identify risk factors for the occurrence of AKI. RESULTS: In total, 426 patients were included and treated with a SOF-based regimen (n=233, 54.7%) or TVR/BOC-based regimen (n=193, 45.3%). Among patients treated with a TVR/BOC-based regimen 34 (18%) of 193 patients experienced AKI compared to 26 (11%) of 233 patients treated with SOF-based regimens (P=.056). Multivariable logistic regression analysis showed that the presence of ascites (OR: 4.44, 95%CI: 1.46-13.54, P=.009) and the use of NSAIDs (OR: 4.47, 95%CI: 1.32-15.19, P=.016) were associated with a risk of AKI during SOF-based antiviral therapy. Creatinine levels returned to normal at end of follow-up in 23 (88%) of the 26 patients who experienced AKI with a SOF-based regimen and had a creatinine level available during follow-up. CONCLUSIONS: Although the risk for AKI was lower than for patients treated with TVR/BOC-based regimens, AKI was seen during 11% of SOF-based regimens and was mostly reversible. Patients with ascites and patients using NSAIDs have an increased risk for AKI during SOF-based antiviral therapy.

Growth and reproduction of the highfin grouper Epinephelus maculatus.

Highfin grouper Epinephelus maculatus sampled in Chuuk, Micronesia, exhibited a moderate growth rate and a relatively short life span compared to other epinephelids of a similar size. Combined gonad and otolith analysis provide preliminary evidence that the species conforms to a protogynous sexual pattern. Mean total length at maturity for females was 308 mm with first age at maturity 2·8 years for females and 4 years for males, which differs from other regional studies. Based on the gonado-somatic index and microscopic analysis of gonads, E. maculatus in Chuuk have a 4 month spawning season (January to April) that corresponds with seasonal lows in sea surface water temperature and overlaps with that of other aggregating epinephelids. The estimated von Bertalanffy growth factor (K) was 0·51 year(-1) , while total mortality was 0·34 year(-1) . Current management for E. maculatus in Chuuk includes a January to May catch, sale and export ban, which overlaps with its reproductive season. The effectiveness of these arrangements will require on-going monitoring to determine whether alternative management strategies are required to ensure population persistence.

Is Achenbach's syndrome a surgical emergency? A systematic review.

AIM: The aim of this study is to establish the nature (urgent vs. non-urgent), demographics, presentation and management of Achenbach's syndrome and to formulate an algorithmic approach for their diagnosis and management. MATERIALS AND METHODS: A systematic review and met-aggregation of literature from 1944 to 2015 in English language in MedLine, Embase and Cochrane database were conducted. RESULTS: Achenbach's syndrome is a female-dominant disease with median age of 49.5 years (range 22-76) (age ≤60, n = 11/12, 91 %). It presents with unilateral volar discoloration of a finger (100 %). It is associated with pain (n = 7/12, 58. %), edema (n = 7/12, 58 %), and paresthesia (n = 3/12, 25 %). The median time to resolution of symptoms without any intervention was 4 days (range 2-14). CONCLUSION: AS is self-limiting and a non-urgent surgical condition. It can be differentiated from other pathologies by clinical spectrum, patient demographics and in doubtful circumstances (acute limb ischemia) by Doppler sonography. An algorithmic approach can avoid hospital admissions, partially unnecessary investigation and assist in patient assurance.

Blunt abdominal trauma and mesenteric avulsion: a systematic review.

PURPOSE: The aim of this study is to establish the biomechanics, presentation and diagnosis of mesenteric avulsions following blunt abdominal trauma and reach a consensus on their overall management. MATERIALS AND METHODS: A systematic review of literature in MedLine, Embase, Scopus and CINHAL in English language from 1951 to November 2014 was performed. A total of 20 reported cases were identified. Variables including patient's demographics, signs and symptoms, mechanism of injury, investigative modality, management, length of stay, follow-up and outcomes were reviewed and analyzed. RESULTS: The median age of the cohort was 28.5 years (range 10-58 years), with a male-to-female ratio of 3:1. The commonest mechanism of injury was road traffic accident due to seat belt restraint (n = 12, 60 %). The commonest presentation was diffuse abdominal tenderness (n = 10, 45 %) followed by ecchymosis/bruising (n = 9, 40 %). Computed tomography (CT) remained the investigative modality of choice (n = 9, 45 %). All cases had an emergency exploratory laparotomy (n = 18, 90 %) within the initial 24 h and the median length of stay was 19 days (range 4-90 days). The overall mortality was 15 % (n = 3). CONCLUSION: Mesenteric avulsion is rare and has a complex and vague presentation. Due to its potential mortality and morbidity, emergency physicians should keep a high index of suspicion in individuals with blunt abdominal trauma from any mechanism of injury.

The effect of thermal variance on the phenotype of marine turtle offspring.

Temperature can have a profound effect on the phenotype of reptilian offspring, yet the bulk of current research considers the effects of constant incubation temperatures on offspring morphology, with few studies examining the natural thermal variance that occurs in the wild. Over two consecutive nesting seasons, we placed temperature data loggers in 57 naturally incubating clutches of loggerhead sea turtles Caretta caretta and found that greater diel thermal variance during incubation significantly reduced offspring mass, potentially reducing survival of hatchlings during their journey from the nest to offshore waters and beyond. With predicted scenarios of climate change, behavioral plasticity in nest site selection may be key for the survival of ectothermic species, particularly those with temperature-dependent sex determination.

Age-based demographic and reproductive assessment of orangespine Naso lituratus and bluespine Naso unicornis unicornfishes.

Bluespine unicornfish Naso unicornis and orangespine unicornfish Naso lituratus were sampled in Pohnpei and Guam, Micronesia, over 13 months to identify reproductive and age-based demographic features necessary for informed management. Age and reproductive information were derived from analysis of sagittal otoliths and gonads. Both species had moderate life spans [maximum ages of 23 (N. unicornis) and 14 years (N. lituratus)] compared with published estimates of conspecifics from other locations (>30 years) and of other Naso species. Length at maturation for N. unicornis was similar between Pohnpei and Guam while females consistently matured at a larger size [c. 30 cm fork length (LF )] than males (c. 27 cm LF ). This sex-specific pattern was reversed in N. lituratus for which estimates of maturation length (females: 15 cm LF ; males: 18 cm LF ) were only obtained from Guam. Developmental patterns in female gonads of both species suggested that initiation of maturation occurs very early. Growth patterns of N. lituratus displayed rapid asymptotic growth compared with N. unicornis and other congeners as well as slight sex-specific patterns of length-at-age. Results highlight the considerable spatial variation that may occur in the population biology of these species across various scales. Additionally, proper management remains complicated without improved knowledge of fishery trends and reproductive behaviour in unicornfishes, species that are prime fishery targets in Micronesia and elsewhere.

Reproductive biology of squaretail coralgrouper Plectropomus areolatus using age-based techniques.

The squaretail coralgrouper Plectropomus areolatus was identified as a fast-growing, early maturing and relatively short-lived aggregation-spawning epinephelid. Examinations of sectioned otoliths found females and males first maturing at 2 and 3 years, respectively, suggesting protogynous hermaphroditism; however, no transitionals were observed in samples. Age distribution for the two sexes was similar and both were represented in the oldest age class; however, significant sex-specific differences in size-at-age were identified. Both sexes fully recruit into the fishery at age 4 years and reach 90% of asymptotic length by age 3 years. Underwater visual assessments, combined with the gonado-somatic indices, revealed a 5 month reproductive season, with interannual variability observed in the month of highest density within the spawning aggregation. Catch restrictions on adults during spawning times and at reproductive sites, combined with gear-based management and enhanced enforcement, are recommended to maintain spawning stocks. Based on the available evidence, the sexual pattern for this species is unresolved.

The effect of pistachio shells as a visual cue in reducing caloric consumption.

UNLABELLED: It was hypothesized that pistachio shells left in sight as visual cues of consumption will cause individuals to consume less. A convenience sample of faculty and staff at a mid-western university (n=118) were recruited as subjects for the study. The subjects were told they were going to evaluate a variety of brands of pistachios and were surveyed at the end of each day to determine their fullness and satisfaction. The subjects were offered pistachios on their desks for an 8-h period on two separate days and were able to consume the pistachios at their leisure during that time. Subjects began each day with a sixteen ounce bowl filled with four ounces of pistachios in the shell. They were also provided with a second sixteen ounce bowl, in which they were instructed to place the empty shells from the pistachios they consumed. Every 2 h throughout the day pistachios were added in two ounce increments. In condition one, the shells remained in the bowls until the end of the day, whereas in condition two, the shell bowls were emptied every 2 h throughout the day. In condition one, subjects consumed an average of 216 calories. In condition two, subjects consumed an average of 264 calories, a difference of 48 calories. Subjects in condition one consumed significantly (p≤.05) fewer calories, yet fullness and satisfaction ratings were not significantly (p≥.05) different between conditions. Leaving pistachio shells as a visual cue to consumption may help consumers consume fewer calories. LEARNING OUTCOMES: Individuals will be aware of the impact of visual cues of dietary intake on total food consumption.

gammadeltaT cell-mediated regulation of chemokine producing macrophages during Listeria monocytogenes infection-induced inflammation.

Infection of gammadeltaT cell-deficient (TcRdelta-/-) mice with the intracellular bacterium Listeria monocytogenes (Lm) results in an exacerbated inflammatory response characterized by the accumulation of activated macrophages and necrotic liver lesions. Here we investigated whether changes in chemokine production by Lm-elicited macrophages contribute to this abnormal inflammatory response. In response to Lm infection, activated macrophages accumulate in the primary sites of infection in TcRdelta-/- mice and express high amounts of mRNA encoding the chemokines CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CXCL2 (MIP-2) and CXCL10 (IP-10). In the infected tissues of TcRdelta-/- the number of chemokine-synthesizing macrophages was higher than in wild-type (WT) mice, with the amount of MIP-1alpha and MIP-1beta secreted by individual macrophages in the spleen of TcRdelta-/- mice also being significantly higher than in WT mice. By contrast, protease activity and NO production in individual splenic macrophages of Lm-infected TcRdelta-/- and WT mice were comparable. Pathogen-elicited macrophages in TcRdelta-/- mice also expressed high levels of the CCL3 and CCL4 receptor, CCR5. In macrophage-gammadeltaT cell co-cultures, chemokine-producing macrophages were killed by cytotoxic Vgamma1+ T cells in a Fas-FasL-dependent manner consistent with the high levels of chemokine-producing macrophages seen in infected TcRdelta-/- mice being due to the absence of Vgamma1+ T cells. Together these findings highlight the importance of gammadeltaT cells in regulating macrophage anti-microbial responses.

Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy.

Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of 2-3 weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE.

Cancer Care Ontario Colonoscopy Standards: standards and evidentiary base.

Colorectal cancer (CRC) is the most common cause of non-tobacco-related cancer deaths in Canadian men and women, accounting for 10% of all cancer deaths. An estimated 7800 men and women will be diagnosed with CRC, and 3250 will die from the disease in Ontario in 2007. Given that CRC incidence and mortality rates in Ontario are among the highest in the world, the best opportunity to reduce this burden of disease would be through screening. The present report describes the findings and recommendations of Cancer Care Ontario's Colonoscopy Standards Expert Panel, which was convened in March 2006 by the Program in Evidence-Based Care. The recommendations will form the basis of the quality assurance program for colonoscopy delivered in support of Ontario's CRC screening program.