On cooperative libertines and wicked puritans.

We agree with Fitouchi et al. that self-denial is sometimes moralized to signal capacity for cooperation, but propose that a person's cooperative character is more precisely judged by willingness to follow cultural, group, and interpersonal goals, for which many rules can serve as proxies, including rules about abstention. But asceticism is not a moral signal if its aims are destructive, while indulging impulses in a culturally approved way can also signal cooperation.

Inferring Population Histories for Ancient Genomes Using Genome-Wide Genealogies.

Ancient genomes anchor genealogies in directly observed historical genetic variation and contextualize ancestral lineages with archaeological insights into their geography and cultural associations. However, the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies. Here, we present a fast and scalable method, Colate, the first approach for inferring ancestral relationships through time between low-coverage genomes without requiring phasing or imputation. Our approach leverages sharing patterns of mutations dated using a genealogy to infer coalescence rates. For deeply sequenced ancient genomes, we additionally introduce an extension of the Relate algorithm for joint inference of genealogies incorporating such genomes. Application to 278 present-day and 430 ancient DNA samples of >0.5x mean coverage allows us to identify dynamic population structure and directional gene flow between early farmer and European hunter-gatherer groups. We further show that the previously reported, but still unexplained, increase in the TCC/TTC mutation rate, which is strongest in West Eurasia today, was already present at similar strength and widespread in the Late Glacial Period ~10k-15k years ago, but is not observed in samples >30k years old. It is strongest in Neolithic farmers, and highly correlated with recent coalescence rates between other genomes and a 10,000-year-old Anatolian hunter-gatherer. This suggests gene-flow among ancient peoples postdating the last glacial maximum as widespread and localizes the driver of this mutational signal in both time and geography in that region. Our approach should be widely applicable in future for addressing other evolutionary questions, and in other species.

Altering the Binding Properties of PRDM9 Partially Restores Fertility across the Species Boundary.

Sterility or subfertility of male hybrid offspring is commonly observed. This phenomenon contributes to reproductive barriers between the parental populations, an early step in the process of speciation. One frequent cause of such infertility is a failure of proper chromosome pairing during male meiosis. In subspecies of the house mouse, the likelihood of successful chromosome synapsis is improved by the binding of the histone methyltransferase PRDM9 to both chromosome homologs at matching positions. Using genetic manipulation, we altered PRDM9 binding to occur more often at matched sites, and find that chromosome pairing defects can be rescued, not only in an intersubspecific cross, but also between distinct species. Using different engineered variants, we demonstrate a quantitative link between the degree of matched homolog binding, chromosome synapsis, and rescue of fertility in hybrids between Mus musculus and Mus spretus. The resulting partial restoration of fertility reveals additional mechanisms at play that act to lock-in the reproductive isolation between these two species.

Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice.

The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.

The fine-scale genetic structure of the British population.

Fine-scale genetic variation between human populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo-Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post-Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population.

Enhanced Recovery Pathways for Flap-Based Reconstruction: Systematic Review and Meta-Analysis.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways are known to improve patient outcomes after surgery. In recent years, there have been growing interest in ERAS for reconstructive surgery. OBJECTIVES: To systematically review and summarise literature on the key components and outcomes of ERAS pathways for autologous flap-based reconstruction. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform and reference lists of relevant studies. INCLUSION CRITERIA: All primary studies of ERAS pathways for free and pedicled flap-based reconstructions reported in the English language. OUTCOME MEASURES: The primary outcome measure was length of stay. Secondary outcomes were complication rates including total flap loss, partial flap loss, unplanned reoperation within 30 days, readmission to hospital within 30 days, surgical site infections and medical complications. RESULTS: Sixteen studies were included. Eleven studies describe ERAS pathways for autologous breast reconstructions and five for autologous head and neck reconstructions. Length of stay was lower in ERAS groups compared to control groups (mean reduction, 1.57 days; 95% CI, - 2.15 to - 0.99). Total flap loss, partial flap loss, unplanned reoperations, readmissions, surgical site infections and medical complication rates were similar between both groups. Compliance rates were poorly reported. CONCLUSION: ERAS pathways for flap-based reconstruction reduce length of stay without increasing complication rates. ERAS pathways should be adapted to each institution according to their needs, resources and caseload. There is potential for the development of ERAS pathways for chest wall, perineum and lower limb reconstruction. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Fractional radiofrequency in the treatment of skin aging: an evidence-based treatment protocol.

Fractional radiofrequency (FRF) has recently emerged for the treatment of scars, cellulite and skin rejuvenation. The aim of this paper was to investigate the evidence behind its use in skin aging and evaluate efficacy, safety, and standardization of protocols. The literature was systematically searched and finally 25 full-text articles were included. Two were randomized controlled trials, 3 were comparative studies, and 20 were case series. Most studies were underpowered with low methodological quality. The participants had skin phototype I-VI with variable baseline severity of signs. Fractional radiofrequency using microneedles or electrode pins was performed on the face, neck, and décolletage. There was heterogeneity in outcomes measurement, but the efficacy of FRF was confirmed in all relevant studies. Mainly, the improvement of rhytides and skin tightening were reported. Mild to moderate pain, transient erythema and edema were the commonest adverse events. Hyperpigmentation was also noted in some cases. There was no consistency in the protocols used and in the description of procedures. A clinical impact score was created to assess the studies and to aid the generation of an evidence-based protocol for minimally invasive radiofrequency procedures. However, there is a need for large scale, well-designed trials to better investigate the efficacy and safety of FRF and to produce clear guidelines.

Great ape genetic diversity and population history.

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

Economy of Hand Motion During Cleft Palate Surgery Using a High-Fidelity Cleft Palate Simulator.

OBJECTIVE: The objectives of this study were to assess economy of hand motion of residents, fellows, and staff surgeons using a high-fidelity cleft palate simulator to (1) stratify performance for the purpose of simulator validation and (2) to estimate the learning curve. DESIGN: Two residents, 2 fellows, and 2 staff surgeons performed cleft palate surgery on a high-fidelity cleft palate simulator while their hand motion was tracked using an electromagnetic hand sensor. The time, number of hand movements, and path length of their hands were determined for 10 steps of the procedure. The magnitude of these metrics was compared among the 3 groups of participants and utilized to estimate the learning curve using curve-fitting analysis. RESULTS: The residents required the most time, number of hand movements, and path length to complete the procedure. Although the number of hand movements was closely matched between the fellows and staff, the overall total path length was shorter for the staff. Inverse curves were fit to the data to represent the learning curve and 25 and 113 simulation sessions are required to reach within 5% and 1% of the expert level, respectively. CONCLUSION: The simulator successfully stratified performance using economy of hand motion. Path length is better matched to previous level of experience compared to time or number of hand movements.

A Critical Review of Botulinum Toxin Type A in the Prophylactic Treatment of Chronic Migraine in Adults.

BACKGROUND: Migraine is a severe, disabling condition, ranked by World Health Organization as the sixth highest cause of disability worldwide. It greatly affects patients' quality of life, functionality, and physical and mental health. The financial burden of migraine on the UK economy is conservatively estimated at £3.42 billion per year. OBJECTIVES: The authors sought to perform an evidence-based literature review of the safety and efficacy of botulinum toxin type A (onaBoNTA) in the prophylactic treatment of adult patients suffering with chronic migraine (CM) compared to placebo. After the best evidence is identified, it will be utilized to formulate a protocol for doctors managing CM in their aesthetic clinic. METHODS: A comprehensive search of the current literature on the topic was performed by H.M. using Pubmed MEDLINE electronic database on March 1, 2018. All articles up to and inclusive of this date were included. Articles were limited to human studies and those in the English language. In vitro and animal studies were excluded. RESULTS: A total of 260 articles were identified. Of these, the excellent-quality, high-strength (level 1A) trials were short-listed to answer the research question. CONCLUSIONS: There is high-quality, level 1A evidence to support onaBoNTA treatment in adults with CM is well tolerated and considered safe. However, it is associated with increased risk of adverse events and still some uncertainty exists associated with the degree onaBoNTA improves outcome measures compared to placebo. These data have been used to formulate The London Aesthetic Migraine Protocol (LAMP) to provide safe, evidence-based guidance for appropriately trained and experienced aesthetic practitioners to manage CM in their aesthetic clinics.

Semitransparent bandages based on chitosan and extracellular matrix for photochemical tissue bonding.

BACKGROUND: Extracellular matrices (ECMs) are often used in reconstructive surgery to enhance tissue regeneration and remodeling. Sutures and staples are currently used to fix ECMs to tissue although they can be invasive devices. Other sutureless and less invasive techniques, such as photochemical tissue bonding, cannot be coupled to ECMs because of their intrinsic opacity to light. RESULTS: We succeeded in fabricating a biocompatible and adhesive device that is based on ovine forestomach matrix (OFM) and a chitosan adhesive. The natural opacity of the OFM has been overcome by adding the adhesive into the matrix that allows for the light to effectively penetrate through it. The OFM-chitosan device is semitransparent (attenuation length ~ 106 µm) and can be photoactivated by green light to bond to tissue. This device does not require sutures or staples and guarantees a bonding strength of ~ 23 kPa. CONCLUSIONS: A new semitransparent and biocompatible bandage has been successfully fabricated and characterized for sutureless tissue bonding.

Evidence for a Common Origin of Blacksmiths and Cultivators in the Ethiopian Ari within the Last 4500 Years: Lessons for Clustering-Based Inference.

The Ari peoples of Ethiopia are comprised of different occupational groups that can be distinguished genetically, with Ari Cultivators and the socially marginalised Ari Blacksmiths recently shown to have a similar level of genetic differentiation between them (FST ≈ 0.023 - 0.04) as that observed among multiple ethnic groups sampled throughout Ethiopia. Anthropologists have proposed two competing theories to explain the origins of the Ari Blacksmiths as (i) remnants of a population that inhabited Ethiopia prior to the arrival of agriculturists (e.g. Cultivators), or (ii) relatively recently related to the Cultivators but presently marginalized in the community due to their trade. Two recent studies by different groups analysed genome-wide DNA from samples of Ari Blacksmiths and Cultivators and suggested that genetic patterns between the two groups were more consistent with model (i) and subsequent assimilation of the indigenous peoples into the expanding agriculturalist community. We analysed the same samples using approaches designed to attenuate signals of genetic differentiation that are attributable to allelic drift within a population. By doing so, we provide evidence that the genetic differences between Ari Blacksmiths and Cultivators can be entirely explained by bottleneck effects consistent with hypothesis (ii). This finding serves as both a cautionary tale about interpreting results from unsupervised clustering algorithms, and suggests that social constructions are contributing directly to genetic differentiation over a relatively short time period among previously genetically similar groups.

Art or Science? An Evidence-Based Approach to Human Facial Beauty a Quantitative Analysis Towards an Informed Clinical Aesthetic Practice.

BACKGROUND: Patients often seek guidance from the aesthetic practitioners regarding treatments to enhance their 'beauty'. Is there a science behind the art of assessment and if so is it measurable? Through the centuries, this question has challenged scholars, artists and surgeons. AIMS AND OBJECTIVES: This study aims to undertake a review of the evidence behind quantitative facial measurements in assessing beauty to help the practitioner in everyday aesthetic practice. METHODS: A Medline, Embase search for beauty, facial features and quantitative analysis was undertaken. SELECTION CRITERIA: Inclusion criteria were studies on adults, and exclusions included studies undertaken for dental, cleft lip, oncology, burns or reconstructive surgeries. The abstracts and papers were appraised, and further studies excluded that were considered inappropriate. The data were extracted using a standardised table. The final dataset was appraised in accordance with the PRISMA checklist and Holland and Rees' critique tools. RESULTS: Of the 1253 studies screened, 1139 were excluded from abstracts and a further 70 excluded from full text articles. The remaining 44 were assessed qualitatively and quantitatively. It became evident that the datasets were not comparable. Nevertheless, common themes were obvious, and these were summarised. CONCLUSION: Despite measures of the beauty of individual components to the sum of all the parts, such as symmetry and the golden ratio, we are yet far from establishing what truly constitutes quantitative beauty. Perhaps beauty is truly in the 'eyes of the beholder' (and perhaps in the eyes of the subject too). LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Recombination in the human Pseudoautosomal region PAR1.

The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African-American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome.

A common sequence motif associated with recombination hot spots and genome instability in humans.

In humans, most meiotic crossover events are clustered into short regions of the genome known as recombination hot spots. We have previously identified DNA motifs that are enriched in hot spots, particularly the 7-mer CCTCCCT. Here we use the increased hot-spot resolution afforded by the Phase 2 HapMap and novel search methods to identify an extended family of motifs based around the degenerate 13-mer CCNCCNTNNCCNC, which is critical in recruiting crossover events to at least 40% of all human hot spots and which operates on diverse genetic backgrounds in both sexes. Furthermore, these motifs are found in hypervariable minisatellites and are clustered in the breakpoint regions of both disease-causing nonallelic homologous recombination hot spots and common mitochondrial deletion hot spots, implicating the motif as a driver of genome instability.

The Benslimane's Artistic Model for Females' Gaze Beauty: An Original Assessment Tool.

BACKGROUND: The aim of this paper is to analyze the aesthetic characteristics of the human females' gaze using anthropometry and to present an artistic model to represent it: "The Frame Concept." In this model, the eye fissure represents a painting, and the most peripheral shadows around it represent the frame of this painting. The narrower the frame, the more aesthetically pleasing and youthful the gaze appears. MATERIALS AND METHOD: This study included a literature review of the features that make the gaze appear attractive. Photographs of models with attractive gazes were examined, and old photographs of patients were compared to recent photographs. The frame ratio was defined by anthropometric measurements of modern portraits of twenty consecutive Miss World winners. The concept was then validated for age and attractiveness across centuries by analysis of modern female photographs and works of art acknowledged for portraying beautiful young and older women in classical paintings. RESULTS: The frame height inversely correlated with attractiveness in modern female portrait photographs. The eye fissure frame ratio of modern idealized female portraits was similar to that of beautiful female portraits idealized by classical artists. In contrast, the eye fissure frames of classical artists' mothers' portraits were significantly wider than those of beautiful younger women. CONCLUSION: The Frame Concept is a valid artistic tool that provides an understanding of both the aesthetic and aging characteristics of the female periorbital region, enabling the practitioner to plan appropriate aesthetic interventions. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A3 online Instructions to Authors. www.springer.com/00266 .

Twelve tips for postgraduate or undergraduate medics building a basic microsurgery simulation training course.

Microsurgery is used in a variety of surgical specialties, including Plastic Surgery, Maxillofacial Surgery, Ophthalmic Surgery, Otolaryngology and Neurosurgery. It is considered one of the most technically challenging fields of surgery. Microsurgical skills demand fine, precise and controlled movements, and microsurgical skill acquisition has a steep initial learning curve. Microsurgical simulation provides a safe environment for skill acquisition before operating clinically. The traditional starting point for anyone wanting to pursue microsurgery is a basic simulation training course. We present twelve tips for postgraduate and undergraduate medics on how to set up and run a basic ex-vivo microsurgery simulation training course suitable for their peers.

A new multipoint method for genome-wide association studies by imputation of genotypes.

Genome-wide association studies are set to become the method of choice for uncovering the genetic basis of human diseases. A central challenge in this area is the development of powerful multipoint methods that can detect causal variants that have not been directly genotyped. We propose a coherent analysis framework that treats the problem as one involving missing or uncertain genotypes. Central to our approach is a model-based imputation method for inferring genotypes at observed or unobserved SNPs, leading to improved power over existing methods for multipoint association mapping. Using real genome-wide association study data, we show that our approach (i) is accurate and well calibrated, (ii) provides detailed views of associated regions that facilitate follow-up studies and (iii) can be used to validate and correct data at genotyped markers. A notable future use of our method will be to boost power by combining data from genome-wide scans that use different SNP sets.

Multiple regions within 8q24 independently affect risk for prostate cancer.

After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

Anastomosis Lapse Index (ALI): A Validated End Product Assessment Tool for Simulation Microsurgery Training.

BACKGROUND: Over the last decade, simulation has become a principal training method in microsurgery. With an increasing move toward the use of nonliving models, there is a need to develop methods for assessment of microvascular anastomosis skill acquisition substituting traditional patency rate. The authors present and validate a novel method of microvascular anastomosis assessment tool for formative and summative skills competency assessment. METHODS: In this study, 29 trainees with varying levels of experience in microsurgery undertook a 5-day microsurgery course. Two consecutive end-to-end microvascular anastomoses of cryopreserved rat aortas performed on day 3 and day 5 of the course were longitudinally split and photographed for randomized blinded qualitative evaluation. Four consecutive anastomoses by two experienced microsurgeons were analyzed as expert controls. Errors potentially leading to anastomotic leak or thrombosis were identified and logged. Statistical analysis using the Kruskal-Wallis analysis of variance (ANOVA) and a two-way repeated measure ANOVA was used to measure construct and concurrent validity, respectively. RESULTS: A total of 128 microvascular anastomoses were analyzed for both student and control groups. Ten errors were identified and indexed. There was a statistically significant difference detected between average errors per anastomosis performed between groups (p < 0.05). Average errors per anastomosis was statistically decreased on day 5 of the course compared with day 3 (p < 0.001). CONCLUSION: Evaluation of anastomosis structural patency and quality in nonliving models is possible. The proposed error list showed construct and predictive validity. The anastomosis lapse index can serve as a formative and summative assessment tool during microvascular training.