Reproductive phenology and behaviour of endangered redside dace (Clinostomus elongatus) in urban streams.

Investigation of the reproductive phenology and spawning behaviour of imperilled species in relation to environmental variability is needed to understand a critical component of species life history. In this study, we used redside dace (Clinostomus elongatus), a freshwater leuciscid listed as Endangered under Canada's Species at Risk Act, to model spawning phenology and make predictions about spawning initiation using historical and climate change projected thermal cues (measured as cumulative growing degree days), and provide an ethological description of spawning behaviour. Logistic regression models applied to 4 years of average daily stream water temperature data and field behavioural observations of the onset of spawning activity indicated a 50% probability of spawning initiation when cumulative growing degree days reached 214°C days and a 95% probability of spawning initiation at 288°C days. Using two climate change scenarios (i.e., a mid-century 1.6°C increase and an end of century 3.6°C increase), spawning initiation was predicted to advance 3 days by the year 2050 and 7 days by the year 2100. Underwater video cameras placed at two sites within an urban stream captured 73 unique spawning events revealing that redside dace spawn in pairs as well as in dense, tightly packed groups (more than 20 individuals). Moreover, there is evidence of redside dace having a polygynandrous mating system, as female redside dace spawned with multiple males in 45.2% of the total spawning events recorded. Taken together, this study provides important insights into redside dace spawning initiation and behaviour, key life-history traits having conservation implications for future reproductive success and, ultimately, population dynamics.

Comparative population genomics: power and principles for the inference of functionality.

The availability of sequenced genomes from multiple related organisms allows the detection and localization of functional genomic elements based on the idea that such elements evolve more slowly than neutral sequences. Although such comparative genomics methods have proven useful in discovering functional elements and ascertaining levels of functional constraint in the genome as a whole, here we outline limitations intrinsic to this approach that cannot be overcome by sequencing more species. We argue that it is essential to supplement comparative genomics with ultra-deep sampling of populations from closely related species to enable substantially more powerful genomic scans for functional elements. The convergence of sequencing technology and population genetics theory has made such projects feasible and has exciting implications for functional genomics.

Strong purifying selection at synonymous sites in D. melanogaster.

Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in Drosophila melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated.

Dorsal Wrist Ganglion: Pilot for Randomized Control Trial Comparing Aspiration Alone or Combined with Injection of Platelet-Rich Plasma.

This pilot study assessed the feasibility of performing a randomized control trial (RCT) investigating injection with platelet-rich plasma (PRP) for dorsal wrist ganglion (DWG). Aspiration alone was compared with aspiration plus injection of PRP. Seventeen patients were enrolled. Nine patients received PRP and eight aspiration alone. Patients were followed up at 6 weeks and 1 year; recurrence of the ganglion and Patient Evaluation Measure scores were measured. At 6 weeks seven patients in the aspiration group had a recurrence and five in the PRP group, but by 1 year, this has increased to seven out of eight in the PRP group whereas in the aspiration group four had resolved leaving three out of eight patients with a ganglion still present. From the basis of our work an RCT would require a minimum of 46 patients per group; however, it is unlikely that PRP will be a panacea for ganglia. This is a Level II study.

Orf virus infection of the hand in a Scottish sheep farmer. A case report to increase awareness to avoid misdiagnosis.

Awareness of infections which are transmitted between animals and humans have been given prominence following the (COVID-19) pandemic. The Orf infection in humans is rare. Recognition of Orf lesions avoids misdiagnosing and incorrect treatment. We present a case of a Scottish-farmer with pain and discomfort from a lesion on her finger.

Pervasive Strong Selection at the Level of Codon Usage Bias in Drosophila melanogaster.

Codon usage bias (CUB), where certain codons are used more frequently than expected by chance, is a ubiquitous phenomenon and occurs across the tree of life. The dominant paradigm is that the proportion of preferred codons is set by weak selection. While experimental changes in codon usage have at times shown large phenotypic effects in contrast to this paradigm, genome-wide population genetic estimates have supported the weak selection model. Here we use deep genomic population sequencing of two Drosophila melanogaster populations to measure selection on synonymous sites in a way that allowed us to estimate the prevalence of both weak and strong purifying selection. We find that selection in favor of preferred codons ranges from weak (|Nes| ∼ 1) to strong (|Nes| > 10), with strong selection acting on 10-20% of synonymous sites in preferred codons. While previous studies indicated that selection at synonymous sites could be strong, this is the first study to detect and quantify strong selection specifically at the level of CUB. Further, we find that CUB-associated polymorphism accounts for the majority of strong selection on synonymous sites, with secondary contributions of splicing (selection on alternatively spliced genes, splice junctions, and spliceosome-bound sites) and transcription factor binding. Our findings support a new model of CUB and indicate that the functional importance of CUB, as well as synonymous sites in general, have been underestimated.

Radiation exposure of patients during mini C-arm use: an audit in 2032 procedures.

This study aimed to audit large quantities of mini C-arm data used in hand and wrist surgery and to analyse what effect the type and anatomical location of procedures had on screening time and dose area product. Of a total of 2032 procedures, the median screening time was 11 seconds and median dose area product was 0.75 cGycm2. The third quartile value for screening time was 23 seconds and dose area product was 1.62 cGycm2. The median screening time for closed procedures was 7 seconds and the dose area product was 0.57 cGycm2. The median screening time for open surgery was 23 seconds with a median dose area product of 1.45 cGycm2. The data for steroid injection procedures were similar to those of the closed procedures, with a median screening time of 7 seconds and dose area product of 0.45 cGycm2. We found no significant differences in the screening time or dose area product between procedures on the wrist and forearm compared with the hand and digits. Level of evidence: III.

Accelerating Wright-Fisher Forward Simulations on the Graphics Processing Unit.

Forward Wright-Fisher simulations are powerful in their ability to model complex demography and selection scenarios, but suffer from slow execution on the Central Processor Unit (CPU), thus limiting their usefulness. However, the single-locus Wright-Fisher forward algorithm is exceedingly parallelizable, with many steps that are so-called "embarrassingly parallel," consisting of a vast number of individual computations that are all independent of each other and thus capable of being performed concurrently. The rise of modern Graphics Processing Units (GPUs) and programming languages designed to leverage the inherent parallel nature of these processors have allowed researchers to dramatically speed up many programs that have such high arithmetic intensity and intrinsic concurrency. The presented GPU Optimized Wright-Fisher simulation, or "GO Fish" for short, can be used to simulate arbitrary selection and demographic scenarios while running over 250-fold faster than its serial counterpart on the CPU. Even modest GPU hardware can achieve an impressive speedup of over two orders of magnitude. With simulations so accelerated, one can not only do quick parametric bootstrapping of previously estimated parameters, but also use simulated results to calculate the likelihoods and summary statistics of demographic and selection models against real polymorphism data, all without restricting the demographic and selection scenarios that can be modeled or requiring approximations to the single-locus forward algorithm for efficiency. Further, as many of the parallel programming techniques used in this simulation can be applied to other computationally intensive algorithms important in population genetics, GO Fish serves as an exciting template for future research into accelerating computation in evolution. GO Fish is part of the Parallel PopGen Package available at: http://dl42.github.io/ParallelPopGen/.

Translating natural genetic variation to gene expression in a computational model of the Drosophila gap gene regulatory network.

Annotating the genotype-phenotype relationship, and developing a proper quantitative description of the relationship, requires understanding the impact of natural genomic variation on gene expression. We apply a sequence-level model of gap gene expression in the early development of Drosophila to analyze single nucleotide polymorphisms (SNPs) in a panel of natural sequenced D. melanogaster lines. Using a thermodynamic modeling framework, we provide both analytical and computational descriptions of how single-nucleotide variants affect gene expression. The analysis reveals that the sequence variants increase (decrease) gene expression if located within binding sites of repressors (activators). We show that the sign of SNP influence (activation or repression) may change in time and space and elucidate the origin of this change in specific examples. The thermodynamic modeling approach predicts non-local and non-linear effects arising from SNPs, and combinations of SNPs, in individual fly genotypes. Simulation of individual fly genotypes using our model reveals that this non-linearity reduces to almost additive inputs from multiple SNPs. Further, we see signatures of the action of purifying selection in the gap gene regulatory regions. To infer the specific targets of purifying selection, we analyze the patterns of polymorphism in the data at two phenotypic levels: the strengths of binding and expression. We find that combinations of SNPs show evidence of being under selective pressure, while individual SNPs do not. The model predicts that SNPs appear to accumulate in the genotypes of the natural population in a way biased towards small increases in activating action on the expression pattern. Taken together, these results provide a systems-level view of how genetic variation translates to the level of gene regulatory networks via combinatorial SNP effects.

Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation.

BACKGROUND: Dupuytren's disease is a slowly progressive condition of the hand, characterised by the formation of nodules in the palm that gradually develop into fibrotic cords. Contracture of the cords produces deformities of the fingers. Surgery is recommended for moderate and severe contractures, but complications and/or recurrences are frequent. Collagenase clostridium histolyticum (CCH) has been developed as a minimally invasive alternative to surgery for some patients. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of collagenase as an alternative to surgery for adults with Dupuytren's contracture with a palpable cord. DATA SOURCES: We searched all major electronic databases from 1990 to February 2014. REVIEW METHODS: Randomised controlled trials (RCTs), non-randomised comparative studies and observational studies involving collagenase and/or surgical interventions were considered. Two reviewers independently extracted data and assessed risk of bias of included studies. A de novo Markov model was developed to assess cost-effectiveness of collagenase, percutaneous needle fasciotomy (PNF) and limited fasciectomy (LF). Results were reported as incremental cost per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty. RESULTS: Five RCTs comparing collagenase with placebo (493 participants), three RCTs comparing surgical techniques (334 participants), two non-randomised studies comparing collagenase and surgery (105 participants), five non-randomised comparative studies assessing various surgical procedures (3571 participants) and 15 collagenase case series (3154 participants) were included. Meta-analyses of RCTs assessing CCH versus placebo were performed. Joints randomised to collagenase were more likely to achieve clinical success. Collagenase-treated participants experienced significant reduction in contracture and an increased range of motion compared with placebo-treated participants. Participants treated with collagenase also experienced significantly more adverse events, most of which were mild or moderate. Four serious adverse events were observed in the collagenase group: two tendon ruptures, one pulley rupture and one complex regional pain syndrome. Two tendon ruptures were also reported in two collagenase case series. Non-randomised studies comparing collagenase with surgery produced variable results and were at high risk of bias. Serious adverse events across surgery studies were low. Recurrence rates ranged from 0% (at 90 days) to 100% (at 8 years) for collagenase and from 0% (at 2.7 years for fasciectomy) to 85% (at 5 years for PNF) for surgery. The results of the de novo economic analysis show that PNF was the cheapest treatment option, whereas LF generated the greatest QALY gains. Collagenase was more costly and generated fewer QALYs compared with LF. LF was £1199 more costly and generated an additional 0.11 QALYs in comparison with PNF. The incremental cost-effectiveness ratio was £10,871 per QALY gained. Two subgroup analyses were conducted for a population of patients with moderate and severe disease and up to two joints affected. In both subgroup analyses, collagenase remained dominated. LIMITATIONS: The main limitation of the review was the lack of head-to-head RCTs comparing collagenase with surgery and the limited evidence base for estimating the effects of specific surgical procedures (fasciectomy and PNF). Substantial differences across studies further limited the comparability of available evidence. The economic model was derived from a naive indirect comparison and was hindered by a lack of suitable data. In addition, there was considerable uncertainty about the appropriateness of many assumptions and parameters used in the model. CONCLUSIONS: Collagenase was significantly better than placebo. There was no evidence that collagenase was clinically better or worse than surgical treatments. LF was the most cost-effective choice to treat moderate to severe contractures, whereas collagenase was not. However, the results of the cost-utility analysis are based on a naive indirect comparison of clinical effectiveness, and a RCT is required to confirm or refute these findings. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006248. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Faster than neutral evolution of constrained sequences: the complex interplay of mutational biases and weak selection.

Comparative genomics has become widely accepted as the major framework for the ascertainment of functionally important regions in genomes. The underlying paradigm of this approach is that most of the functional regions are assumed to be under selective constraint, which in turn reduces the rate of evolution relative to neutrality. This assumption allows detection of functional regions through sequence conservation. However, constraint does not always lead to sequence conservation. When purifying selection is weak and mutation is biased, constrained regions can even evolve faster than neutral sequences and thus can appear to be under positive selection. Moreover, conservation estimates depend also on the orientation of selection relative to mutational biases and can vary over time. In the light of recent data of the ubiquity of mutational biases and weak selective forces, these effects should reduce the power of conservation analyses to define functional regions using comparative genomics data. We argue that the estimation of true mutational biases and the use of explicit evolutionary models are essential to improve methods inferring the action of natural selection and functionality in genome sequences.

Neisseria meningitidis sequence type and risk for death, Iceland.

Invasive meningococcal infections are hyperendemic in Iceland, a relatively isolated country in the mid-Atlantic. We performed a nationwide study on all viable meningococcal strains (N = 362) from 1977 to 2004. We analyzed the association of patient's age and sex, meningococcal serogroups, and sequence types (STs) with outcomes. Overall, 59 different STs were identified, 19 of which were unique to Iceland. The most common STs were 32 (24.6%), 11 (19.9%), and 10 (10.2%). The unique ST-3492 ranked fourth (7.7%). The most common serogroups were B (56.4%), C (39.8%), and A (2.2%). Age (p < 0.001) and infection with a unique ST (p = 0.011) were independently associated with increased death rates, whereas isolation of meningococci from cerebrospinal fluid only was associated with lower death rates (p = 0.046). This study shows evolutionary trends of meningococcal isolates in a relatively isolated community and highlights an association between unique STs and poor outcome.

Insertion of tantalum beads in RSA of the hip: variations in incidence of extra-osseous beads with insertion site.

Radiostereometric analysis (RSA) is a technique that can be used to measure the in-vivo micro-motion of the components of hip arthroplasty. It requires the insertion of tantalum beads into the bone permitting analysis of the radiographs. Extra-osseous beads reduce the usable bead pattern and previous studies have reported their incidence in the proximal femur as between 11% and 13% of all inserted beads. We reviewed the relative incidence of extra-osseous beads by examining 1038 radiographs of 97 patients who were part of an ongoing RSA hip study. Extra-osseous beads were seen in 44% of our patients with most having a single extra-osseous bead. The relative incidence of extra-osseous beads was 2% and 6% in the femur and pelvis, respectively. We observed a reduction in the incidence of the femoral beads with time, but not of the pelvis, which suggests that experience in the insertion technique improves the insertion rates at least of the femur. Our findings indicate that the incidence of extra-osseous beads is lower than previously reported. However, care should be taken in the design of studies to ensure that an adequate number of beads are placed in locations which are both surgically achievable and technically useful.