A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Origin and insertion of the medial patellofemoral ligament: a systematic review of anatomy.

PURPOSE: The medial patellofemoral ligament (MPFL) is the major medial soft-tissue stabiliser of the patella, originating from the medial femoral condyle and inserting onto the medial patella. The exact position reported in the literature varies. Understanding the true anatomical origin and insertion of the MPFL is critical to successful reconstruction. The purpose of this systematic review was to determine these locations. METHODS: A systematic search of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed and Cochrane Library) and unpublished literature databases was conducted from their inception to the 3 February 2016. All papers investigating the anatomy of the MPFL were eligible. Methodological quality was assessed using a modified CASP tool. A narrative analysis approach was adopted to synthesise the findings. RESULTS: After screening and review of 2045 papers, a total of 67 studies investigating the relevant anatomy were included. From this, the origin appears to be from an area rather than (as previously reported) a single point on the medial femoral condyle. The weighted average length was 56 mm with an 'hourglass' shape, fanning out at both ligament ends. CONCLUSION: The MPFL is an hourglass-shaped structure running from a triangular space between the adductor tubercle, medial femoral epicondyle and gastrocnemius tubercle and inserts onto the superomedial aspect of the patella. Awareness of anatomy is critical for assessment, anatomical repair and successful surgical patellar stabilisation. LEVEL OF EVIDENCE: Systematic review of anatomical dissections and imaging studies, Level IV

Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery A Randomized Clinical Trial and Systematic Review

Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm.Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm.Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014.Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366).Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay.Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]).Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rate

Transcribing "Le Pèlerinage de Damoiselle Sapience": Scholarly Editing Covid19-Style

This article describes a methodological experiment conducted during the 13th Annual (Virtual) Schoenberg Symposium on Manuscript Studies in the Digital Age, hosted by the University of Pennsylvania, November 18–20, 2020. The experiment consisted of a “relay style” event in which three teams transcribed, revised, and prepared for submission to this journal a full edition of the “Le Pèlerinage de Damoiselle Sapience” and other texts from UPenn Ms Codex 660, ff. 86r–95v within the three-day timespan of the conference. The project used methods typical of crowdsourcing and drew participants from all over the world and from all different stages of their careers. After one group completed its work, the results were passed into the hands of the next. The final result—in the form of a finished manuscript edition, ready for submission to Digital Medievalist—was presented on the last day of the conference. The main purpose of this experiment was to demonstrate how the work of the transcriber and editor might be structured as a short-term digital event that relied wholly on virtual interactions with both the source materials and among collaborators. This method also reveals the positive aspects of the many challenges posed by working simultaneously, remotely, and globally

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Development Of An Automatic Image Analysis Approach To Determine Particle Distribution For Deep Learning Dataset

This study aims to develop a computer algorithm to determine the particle distribution/homogeneity in a powder mixture from microscopic images. This is an intermediate step for a quick and automatic image segmentation process (typically manual and laborious) using deep learning and will contribute to fast pharmaceutical drug product development through image-based mixture analysis. In this study, microscopic images of binary particles (Ibuprofen or Ciprofloxacin as drug and Microcrystalline cellulose as functional excipient) was integrated with the computer algorithm using Quantum Geographic Information System (QGIS) program (typically used for geographic information system application), Python, and SciPy. A 60:40 (drug: MCC) mixture was prepared experimentally, and obtained ratio from automatic image analysis is 58.5: 41.5, which can be improved further. The efficacy of current research is critical to creating a ground truth microscopic training image dataset for quick and auto determination of particle distribution using deep learning

Design of a mooring system for an inertia tube wave energy collector

The dynamics of a point absorber wave energy collector (WEC) were investigated using the University of New Hampshire (UNH) developed finite element computer program Aqua-FE and tank testing. The WEC design considered here makes use of a buoy rigidly connected to a long, vertical inertia tube which is open at the top and bottom. A piston-rod assembly is enclosed and connected to the power take-off (PTO) mechanism. Due to inertia of water within the tube, relative motion between the piston and buoy-inertia tube structure occurs, and this drives the PTO. The Aqua-FE model was then used to design a slack mooring system sufficient for holding the WEC on station while minimizing interference with its energy absorption function. The Aqua-FE model was created and validated by comparison to wave tank measurements made using a 1/9.4 scale physical model in experiments conducted in the UNH 36.6 m long by 3.66 m wide by 2.44 m deep wave tank. The mathematical model was then applied to predict full scale response to seas representing extreme storms expected at UNH\u27s offshore test site south of the Isles of Shoals, NH. Predicted mooring loads were used to specify mooring system hardware. The Aqua-FE model for this system was evaluated using scale model results for free-release tests in heave (vertical displacement), pitch (angular motion), as well as heave in a series of single frequency waves. Wave periods, Froude-scaled to full size, spanned the range of periods observed at the UNH site