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Purpose Microvascular surgery requires highly specialized and individualized training; most surgical residency training programs are not equipped with microsurgery teaching expertise and/or facilities. The aim of this manuscript was to describe the methodology and clinical effectiveness of an international microsurgery course, currently taught year-round in eight countries.Methods In the 5-day microsurgery course trainees perform arterial and venous end-to-end, end-to-side, one-way-up, and continuous suture anastomoses and vein graft techniques in live animals, supported by video demonstrations and hands-on guidance by a full-time instructor. To assess and monitor each trainee's progress, the course's effectiveness is evaluated using "in-course" evaluations, and participant satisfaction and clinical relevance are assessed using a "post-course" survey.Results Between 2007 and 2017, more than 600 trainees participated in the microsurgery course. "In-course" evaluations of patency rates revealed 80.3% (arterial) and 39% (venous) performed in end-to-end, 82.7% in end-to-side, 72.6% in continuous suture, and 89.5% (arterial) and 62.5% (venous) one-way-up anastomoses, and 58.1% in vein graft technique. "Post-course" survey results indicated that participants considered the most important components of the microcourse to be "practicing on live animals", followed by "the presence of a full-time instructor". In addition, almost all respondents indicated that they were more confident performing clinical microsurgery cases after completing the course.Conclusions Microvascular surgery requires highly specialized and individualized training to achieve the competences required to perform and master the delicate fine motor skills necessary to successfully handle and anastomose very small and delicate microvascular structures. The ever-expanding clinical applications of microvascular procedures has led to an increased demand for training opportunities. By teaching time-tested basic motor skills that form the foundation of microsurgical technique this international microsurgery-teaching course is helping to meet this demand.

We have a much better understanding of the dynamics and ontology of physics than we do of consciousness. I consider ways in which intrinsically mental aspects of fundamental ontology might induce modifications of the known laws of physics, or whether they could be relevant to accounting for consciousness if no such modifications exist. I suggest that our current knowledge of physics should make us sceptical of hypothetical modifications of the known rules, and that without such modifications it's hard to imagine how intrinsically mental aspects could play a useful explanatory role.

Attempts to solve the problem have led to a number of well-defined competing theories. Choosing between them might be crucial for progress in fundamental physics.

Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF.This prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin.Twenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm.Topical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months.ClinicalTrials.gov identifier, NCT03380026.

We study the conservation of energy, or lack thereof, when measurements are performed in quantum mechanics. The expectation value of the Hamiltonian of a system can clearly change when wave functions collapse in accordance with the standard textbook (Copenhagen) treatment of quantum measurement, but one might imagine that the change in energy is compensated by the measuring apparatus or environment. We show that this is not true; the change in the energy of a state after measurement can be arbitrarily large, independent of the physical measurement process. In Everettian quantum theory, while the expectation value of the Hamiltonian is conserved for the wave function of the universe (including all the branches), it is not constant within individual worlds. It should therefore be possible to experimentally measure violations of conservation of energy, and we suggest an experimental protocol for doing so., Comment: 11 pages

The true origins of space-time, the backdrop to reality, are hidden in the quantum realm, writes physicist Sean Carroll

Introduction It is well established that America is in the midst of an opioid crisis with 46 people dying every day from overdoses involving prescription opioids. In the last 2 years, multiple articles have been published indicating that the amount of opioid pain medication needed after discharge from thyroid and parathyroid surgery is low.Objective To objectively examine the amount of opioid pain medication required by patients in our practice after thyroid surgery.Methods Patients were given a standardized discharge prescription of 30 pills with a combination of 7.5 mg of hydrocodone and 325 mg of acetaminophen after thyroid surgery. They were asked to log the number of pills consumed per day and the level of pain per day using the Wong-Baker faces pain scale. We used in-office pill counts to ensure accuracy of the logs.Results While reaching a similar conclusion, the present study is the first to objectively examine the quantity of opioid pain medication consumed between postoperative discharge and office follow-up. Our study objectively demonstrates that 85% of patients consumed less than 75.0 morphine milligram equivalent (MME) after thyroid surgery using in-office pill counts.Conclusion Recent multimodality anesthesia research appears promising to dramatically reduce or even eliminate the need for opioid prescriptions upon postoperative discharge.

Some modern cosmological models predict the appearance of Boltzmann Brains: observers who randomly fluctuate out of a thermal bath rather than naturally evolving from a low-entropy Big Bang. A theory in which most observers are of the Boltzmann Brain type is generally thought to be unacceptable, although opinions differ. I argue that such theories are indeed unacceptable: the real problem is with fluctuations into observers who are locally identical to ordinary observers, and their existence cannot be swept under the rug by a choice of probability distributions over observers. The issue is not that the existence of such observers is ruled out by data, but that the theories that predict them are cognitively unstable: they cannot simultaneously be true and justifiably believed.

INTRODUCTION: AXA1665 is a novel investigational amino acid (AA) composition specifically designed to impact AA imbalance, ammoniagenesis, and dysregulated anabolic activity associated with cirrhosis. METHODS: This 2-part study examined AXA1665 effects on safety, tolerability, and hepatic/muscle physiology in subjects with Child–Pugh A and B cirrhosis. Part 1 established plasma ammonia and AA concentration baselines with a standardized protein supplement. Part 2 included two 15-day domiciled periods separated by a 14-day washout. In period 1, subjects were randomly distributed to 2 groups: AXA1665 14.7 g t.i.d. (group 1) or control t.i.d. (group 2). In period 2, subjects from group 1 crossed over to control and those in group 2 crossed over to AXA1665 4.9 g t.i.d. All subjects were maintained on standard of care (standardized meals; 30-minute daily, supervised, mandatory physical activity; and daily late-evening snack). RESULTS: In parts 1 and 2, 23 and 17 participants were enrolled, respectively. Dose-dependent increases were observed in plasma concentrations of AXA1665-constituent AAs. Fasted branched-chain AA-to-aromatic AA and valine-to-phenylalanine ratios were both increased (AXA1665 14.7 g t.i.d. control-adjusted change: 44.3% ± 2.7% and 47.2% ± 3.9%, respectively; P < 0.0001). Despite provision of additional nitrogen, mean fasted plasma ammonia concentration at day 15 numerically decreased (−21.1% in AXA1665 14.7 g t.i.d. vs −3.8% in control; P > 0.05). AXA1665 14.7 g t.i.d. produced a leaner body composition and significantly decreased Liver Frailty Index at day 15 vs control (−0.70 ± 0.15 vs −0.14 ± 0.17; P < 0.05). AXA1665 was safe and well tolerated. DISCUSSION: AXA1665 has potential to mitigate core metabolic derangements associated with cirrhosis.

Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for vaccine development and most protective antibodies studied to date interact with the central NANP repeat region of PfCSP. However, it remains unclear what structural and functional characteristics correlate with better protection by one antibody over another. Binding to the junctional region between the N-terminal domain and central NANP repeats has been proposed to result in superior protection: this region initiates with the only NPDP sequence followed immediately by NANP. Here, we isolated antibodies in Kymab mice immunized with full-length recombinant PfCSP and two protective antibodies were selected for further study with reactivity against the junctional region. X-ray and EM structures of two monoclonal antibodies, mAb667 and mAb668, shed light on their differential affinity and specificity for the junctional region. Importantly, these antibodies also bind to the NANP repeat region with equal or better affinity. A comparison with an NANP-only binding antibody (mAb317) revealed roughly similar but statistically distinct levels of protection against sporozoite challenge in mouse liver burden models, suggesting that junctional antibody protection might relate to the ability to also cross-react with the NANP repeat region. Our findings indicate that additional efforts are necessary to isolate a true junctional antibody with no or much reduced affinity to the NANP region to elucidate the role of the junctional epitope in protection., Author summary The circumsporozoite protein (CSP) of Plasmodium falciparum malaria has been the foundation for the design of transmission blocking malaria vaccines. To date, the most promising CSP-based vaccine candidate is RTS,S, which consists of the central repeating NANP amino-acid sequence and the C-terminal domain of CSP fused to hepatitis B surface antigen that assembles into virus-like particles. Potential shortcomings of RTS,S includes the lack of other potential CSP epitopes such as the junctional epitope, which is located between the N-terminal domain of CSP and the start of the NANP repeat region. Here, we elicited antibodies against full-length CSP and screened for junctional epitope binding. We then used an array of biophysical techniques to elucidate the nature of the binding and tested the level of two protective antibodies in a mouse challenge model. Although the antibodies were able to bind both junctional and NANP epitopes, the in vivo data showed distinct levels of protection between themselves and also to an NANP-only binder. Our data suggest that their protection ability may be related to the strong cross-reactivity with NANP epitopes. Since all reported junctional antibodies to date have dual-specificity, we suggest that a true junctional binder with no or very low NANP affinity, if one can be found, is essential to evaluate the contribution of the junctional epitope to protection.

We study the question of how to decompose Hilbert space into a preferred tensor-product factorization without any pre-existing structure other than a Hamiltonian operator, in particular the case of a bipartite decomposition into "system" and "environment." Such a decomposition can be defined by looking for subsystems that exhibit quasi-classical behavior. The correct decomposition is one in which pointer states of the system are relatively robust against environmental monitoring (their entanglement with the environment does not continually and dramatically increase) and remain localized around approximately-classical trajectories. We present an in-principle algorithm for finding such a decomposition by minimizing a combination of entanglement growth and internal spreading of the system. Both of these properties are related to locality in different ways. This formalism could be relevant to the emergence of spacetime from quantum entanglement., Comment: 40 pages, 6 figures. v3 contains version accepted by Phys. Rev. A

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

Obtaining lines of evidence indicating that contamination in sediment environments is degrading and being transformed to less toxic forms is an important component of building support for a monitored natural recovery remedy for contaminated sediments. This project was a field demonstration of manufactured gas plant contaminant degradation in river sediments using metabolic gas flux and was performed in an urban area section of a river in northeastern Indiana. CO2 sorbent traps were deployed to measure CO2 flux from the river sediments. Sediment samples were collected and analyzed for polycyclic aromatic hydrocarbon (PAH) concentrations and for microbial community composition using molecular techniques. The results showed that the deployment was successful, measuring CO2 flux at all sediment locations and demonstrating that microbial contaminant degrading activity was occurring in the sediments. Radio carbon dating showed a significant portion of the CO2 being generated (approximately 19–27 percent) was the result of fossil fuel degradation. Molecular results showed that the microbial community consisted of phylotypes known to be associated with monocyclic aromatic and PAH degradation. ©2017 Wiley Periodicals, Inc.

To the best of our current understanding, quantum mechanics is part of the most fundamental picture of the universe. It is natural to ask how pure and minimal this fundamental quantum description can be. The simplest quantum ontology is that of the Everett or Many-Worlds interpretation, based on a vector in Hilbert space and a Hamiltonian. Typically one also relies on some classical structure, such as space and local configuration variables within it, which then gets promoted to an algebra of preferred observables. We argue that even such an algebra is unnecessary, and the most basic description of the world is given by the spectrum of the Hamiltonian (a list of energy eigenvalues) and the components of some particular vector in Hilbert space. Everything else - including space and fields propagating on it - is emergent from these minimal elements.

Background: The application of evidence-based medicine (EBM) to the practice of hand surgery has been limited. Production of high-quality research is an integral component of EBM. With considerable improvements in the quality evidence in both orthopedic and plastic and reconstructive surgery, it is imperative that hand surgery research emulates this trend. Methods: A systematic review was performed on all hand surgery articles published in 6 journals over a 20-year period. The journals included Plastic and Reconstruction Surgery, Journal of Plastic, Reconstructive and Aesthetic Surgery, Journal of Hand Surgery–European Volume, Journal of Hand Surgery–American Volume, Journal of Bone & Joint Surgery, and the Bone & Joint Journal. The level of evidence of each article was determined using the Oxford level of evidence. The quality of methodology of randomized controlled trials (RCTs) was assessed using Jadad scale. Statistical analysis involved chi-squares and Student t test ( P < .05). Results: A total of 972 original hand surgery research articles were reviewed. There was a significant increase in the average level of evidence of articles published between1993 and 2013. High-quality evidence only accounted for 11.2% of evidence published, with a significant increase over the study period ( P = 0.001). Quantitative evaluation of the 26 published RCTs, using Jadad scale, revealed a progressive improvement in study design from 0.3 in 1993 to 3.33 in 2013. Conclusions: Hand surgery research has mirrored trends seen in other surgical specialties, with a significant increase in quality of evidence over time. Yet, high-quality evidence still remains infrequent.

Aesthetic surgery is a rapidly evolving sub-speciality, both technologically and conceptually. It is therefore critical that plastic surgery training coincides with this rapid evolution. Recent fiscal limitations in public health provision and trainee working-time legislation may impact the delivery of high quality aesthetic surgery training. There is an urgent need to address the delivery of aesthetic training in current training paradigms in Ireland and we propose a number of strategies to obliterate the learning curve.

We used a GIS analysis of sodium and chloride concentrations in private water wells in a southeastern New York township to describe the pattern of distribution of road salt in aquifers tapped for drinking water. The primary source of road salt was sodium chloride, and sodium and chloride concentrations were significantly correlated ( = 0.80,0.01). Chloride concentrations in wells increased as the percentage of impervious surface cover (ISC) within a 250-m radius around wells increased ( = 0.87,0.01) and declined with increasing distance to the nearest road ( = 0.76,0.01). Wells that were located lower in elevation than the nearest road had higher concentrations of chloride than wells that were higher than the nearest road, but this occurred only when the nearest road was30 m from the wells (0.01). Chloride concentrations were not affected by well depth or adjacent road type (major or minor roads). Surface geology and hydrologic soil class had significant effects (0.01) on chloride concentrations in wells, with porous surface geology types and well-drained soils having higher concentrations; these effects may be confounded by the fact that ISC was more likely to occur on these permeable surface geology and soil types. Hot and cold spot analysis revealed substantial unevenness in chloride concentrations. Results for sodium were similar to those for chloride. Overall, these results indicate that road salt contamination of groundwater is unevenly distributed and is affected by landscape factors that can be used to guide well testing and best management practices of deicing salt distribution.

A longstanding issue in attempts to understand the Everett (Many-Worlds) approach to quantum mechanics is the origin of the Born rule: why is the probability given by the square of the amplitude? Following Vaidman, we note that observers are in a position of self-locating uncertainty during the period between the branches of the wave function splitting via decoherence and the observer registering the outcome of the measurement. In this period it is tempting to regard each branch as equiprobable, but we argue that the temptation should be resisted. Applying lessons from this analysis, we demonstrate (using methods similar to those of Zurek's envariance-based derivation) that the Born rule is the uniquely rational way of apportioning credence in Everettian quantum mechanics. In doing so, we rely on a single key principle: changes purely to the environment do not affect the probabilities one ought to assign to measurement outcomes in a local subsystem. We arrive at a method for assigning probabilities in cases that involve both classical and quantum self-locating uncertainty. This method provides unique answers to quantum Sleeping Beauty problems, as well as a well-defined procedure for calculating probabilities in quantum cosmological multiverses with multiple similar observers., Comment: 44 pages, 2 figures

Sean M. Carroll notes that, despite popular stereotypes of existential “philosophers sitting in cafes, smoking cigarettes and drinking apricot cocktails” and neuroscientists decked out in lab coats, there is an undeniable connection between existentialism and science. This is perhaps easy to see with biology and neuroscience, but the connection goes beyond this. Carroll maintains that, “An honest grappling with the questions of purpose and freedom in the universe must also involve ideas from physics and cosmology.” He goes on to argue that if we want to create purpose and meaning at the scale of individual human lives, we must understand the nature of the larger universe of which we are a part. After discussing what modern physics can tell us about determinism, quantum mechanics, the arrow of time, and emergence, Carroll concludes by exploring the existential implications of these insights for freedom and meaning.

Background The plastic surgery literature is vast, consisting of a plethora of diverse articles written by a myriad of illustrious authors. Despite this considerable archive of published material, it remains nebulous as to which precise papers have had the greatest impact on our specialty. The aim of this study was to identify the most cited papers in the plastic surgery literature and perform a citation analysis paying particular attention to the evidence levels of the clinical studies. Methods We identified the 50 most cited papers published in the 20 highest impact plastic surgery journals through the Web of Science. The articles were ranked in order of number of citations acquired and level of evidence assessed. Results The top 50 cited papers were published in six different journals between the years 1957 and 2007. Forty-two of the papers in the top 50 were considered as level IV or V evidence. No level I or II evidence was present in the top 50 list. The average level of evidence of the top 50 papers was 4.28. Conclusions In the plastic surgery literature, no positive correlation exists between a high number of citations and a high level of evidence. Anatomical reconstructive challenges tend to be the main focus of plastic surgery rather than pathologic diseases and consequently, papers with lower levels of evidence are relatively more valuable in plastic surgery than many other specialties.

Bioengineering holds great promise to provide fast and efficient biocatalysts for methanol-based biotechnology, but necessitates proven methods to optimize physiology in engineered strains. Here, we highlight experimental evolution as an effective means for optimizing an engineered Methylobacterium extorquens AM1. Replacement of the native formaldehyde oxidation pathway with a functional analog substantially decreased growth in an engineered Methylobacterium, but growth rapidly recovered after six hundred generations of evolution on methanol. We used whole-genome sequencing to identify the basis of adaptation in eight replicate evolved strains, and examined genomic changes in light of other growth and physiological data. We observed great variety in the numbers and types of mutations that occurred, including instances of parallel mutations at targets that may have been “rationalized” by the bioengineer, plus other “illogical” mutations that demonstrate the ability of evolution to expose unforeseen optimization solutions. Notably, we investigated mutations to RNA polymerase, which provided a massive growth benefit but are linked to highly aberrant transcriptional profiles. Overall, we highlight the power of experimental evolution to present genetic and physiological solutions for strain optimization, particularly in systems where the challenges of engineering are too many or too difficult to overcome via traditional engineering methods.

Natural environments are filled with multiple, often competing, signals. In contrast, biological systems are often studied in "well-controlled" environments where only a single input is varied, potentially missing important interactions between signals. Catabolite repression of galactose by glucose is one of the best-studied eukaryotic signal integration systems. In this system, it is believed that galactose metabolic (GAL) genes are induced only when glucose levels drop below a threshold. In contrast, we show that GAL gene induction occurs at a constant external galactose:glucose ratio across a wide range of sugar concentrations. We systematically perturbed the components of the canonical galactose/glucose signaling pathways and found that these components do not account for ratio sensing. Instead we provide evidence that ratio sensing occurs upstream of the canonical signaling pathway and results from the competitive binding of the two sugars to hexose transporters. We show that a mutant that behaves as the classical model expects (i.e., cannot use galactose above a glucose threshold) has a fitness disadvantage compared with wild type. A number of common biological signaling motifs can give rise to ratio sensing, typically through negative interactions between opposing signaling molecules. We therefore suspect that this previously unidentified nutrient sensing paradigm may be common and overlooked in biology.

Background: Breast implants are high-risk devices that have been at the epicenter of much debate and controversy. In light of the Poly Implant Prothese crisis, data registries among 11 national societies around the world are cooperatively calling for the urgent need to establish robust national clinical quality registries based on international best practice within a framework of international collaboration. Methods: A survey was conducted on the historic and current status of national breast device registries. Eleven countries participated in the study, illustrating different data collection systems and registries around the world. Data collection was designed to illustrate the capabilities of current national registries, with particular focus on capture rate and outcome reporting mechanisms. Results: A study of national breast implant registries revealed that less than half of the participating countries had operational registries and that none of these had adequately high data capture to enable reliable outcome analysis. The study revealed that the two most common problems that discouraged participation are the complexity of data sets and the opt-in consent model. Conclusions: Recent implant crises have highlighted the need for robust registries. This article argues the importance of securing at least 90 percent data capture, which is achievable through the opt-out consent model. Since adopting this model, the Australian Breast Device Registry has increased data capture from 4 percent to over 97 percent. Simultaneously, it is important to foster international collaboration from the outset to avoid duplication of efforts and enable the development of effective international early warning systems.

We present a technique to coarse-grain quantum states in a finite-dimensional Hilbert space. Our method is distinguished from other approaches by not relying on structures such as a preferred factorization of Hilbert space or a preferred set of operators (local or otherwise) in an associated algebra. Rather, we use the data corresponding to a given set of states, either specified independently or constructed from a single state evolving in time. Our technique is based on principle component analysis (PCA), and the resulting coarse-grained quantum states live in a lower dimensional Hilbert space whose basis is defined using the underlying (isometric embedding) transformation of the set of fine-grained states we wish to coarse-grain. Physically, the transformation can be interpreted to be an "entanglement coarse-graining" scheme that retains most of the global, useful entanglement structure of each state, while needing fewer degrees of freedom for its reconstruction. This scheme could be useful for efficiently describing collections of states whose number is much smaller than the dimension of Hilbert space, or a single state evolving over time., 16 pages, 1 figure. Comments welcome. v2 includes additions following reviewer's comments

Background:. The first carpometacarpal joint (CMCJ) in the hand is a commonly affected joint by osteoarthritis. It causes significant thumb base pain, limiting functional capacity. Microfracturing and application of autologous stem cells has been performed on large joints such as the knee but has never been evaluated for use in the smaller joints in the hand. Our aim was to determine the potential benefit of microfracturing and autologous bone marrow stem cells for treatment of osteoarthritis of the first CMCJ in the hand. Methods:. All inclusion criteria were satisfied. Preoperative assessment by the surgeon, physiotherapist, and occupational therapist was performed. The first CMCJ was microfractured and the Bone Marrow Stem Cells were applied directly. Postoperatively, the patients were followed up for 1 year. Results:. Fifteen patients met inclusion criteria; however, 2 patients were excluded due to postoperative cellulitis and diagnosis of De Quervain's tenosynovitis. The mean scores of the 13-patient preoperative and 1 year follow-up assessments are visual analog score at rest of 3.23–1.69 (P = 0.0292), visual analog score on activity of 7.92–4.23 (P = 0.0019), range of motion 45.77o–55.15o (P = 0.0195), thumb opposition score 7.62–9.23 (P = 0.0154), Disability of the Arm, Shoulder and Hand score of 51.67–23.08 (P = 0.0065). Strength improved insignificantly from 4.7 kg preoperatively to 5.53 kg at 12 months (P = 0.1257). All patients had a positive Grind test preoperatively and a negative test after 12 months. Conclusions:. This innovative pilot study is a new approach to osteoarthritis of the thumb.

The origins of space and time are among the most mysterious and contentious topics in science. Our February 2017 article “Pop Goes the Universe” argues against the dominant idea that the early cosmos underwent an extremely rapid expansion called inflation. Its authors instead advocate for another scenario—that our universe began not with a bang but with a bounce from a previously contracting cosmos. In the letter below, a group of 33 physicists who study inflationary cosmology respond to that article. It is followed by a reply from the authors. In “Pop Goes the Universe,” by Anna Ijjas, Paul J. Steinhardt and Abraham Loeb, the authors (hereafter “IS&L”) make the case for a bouncing cosmology, as was proposed by Steinhardt and others in 2001. They close by making the extraordinary claim that inflationary cosmology “cannot be evaluated using the scientific method” and go on to assert that some scientists who accept inflation have proposed “discarding one of [science's] defining properties: empirical testability,” thereby “promoting the idea of some kind of nonempirical science.” We have no idea what scientists they are referring to. We disagree with a number of statements in their article, but in this letter, we will focus on our categorical disagreement with these statements about the testability of inflation.

We construct a model in which the cosmological constant is canceled from the gravitational equations of motion. Our model relies on two key ingredients: a nonlocal constraint on the action, which forces the spacetime average of the Lagrangian density to vanish, and a dynamical way for this condition to be satisfied classically with arbitrary matter content. We implement the former condition with a spatially-constant Lagrange multiplier associated with the volume form and the latter by including a free four-form gauge field strength in the action. These two features are enough to remove the cosmological constant from the Einstein equation. The model is consistent with all cosmological and experimental bounds on modification of gravity and allows for both cosmic inflation and the present epoch of acceleration., Comment: 19 pages

In a wide class of cosmological models, a positive cosmological constant drives cosmological evolution toward an asymptotically de Sitter phase. Here we connect this behavior to the increase of entropy over time, based on the idea that de Sitter spacetime is a maximum-entropy state. We prove a cosmic no-hair theorem for Robertson-Walker and Bianchi I spacetimes that admit a Q-screen ("quantum" holographic screen) with certain entropic properties: If generalized entropy, in the sense of the cosmological version of the Generalized Second Law conjectured by Bousso and Engelhardt, increases up to a finite maximum value along the screen, then the spacetime is asymptotically de Sitter in the future. Moreover, the limiting value of generalized entropy coincides with the de Sitter horizon entropy. We do not use the Einstein field equations in our proof, nor do we assume the existence of a positive cosmological constant. As such, asymptotic relaxation to a de Sitter phase can, in a precise sense, be thought of as cosmological equilibration., 43 pages 12 figures, v2: added references, fixed typos; v3: added a corollary in sec III, reworked parts of sec IV according to referee comments, added App B; v4: small formatting changes, updated to reflect PRD

We consider the emergence from quantum entanglement of spacetime geometry in a bulk region. For certain classes of quantum states in an appropriately factorized Hilbert space, a spatial geometry can be defined by associating areas along codimension-one surfaces with the entanglement entropy between either side. We show how Radon transforms can be used to convert this data into a spatial metric. Under a particular set of assumptions, the time evolution of such a state traces out a four-dimensional spacetime geometry, and we argue using a modified version of Jacobson's "entanglement equilibrium" that the geometry should obey Einstein's equation in the weak-field limit. We also discuss how entanglement equilibrium is related to a generalization of the Ryu-Takayanagi formula in more general settings, and how quantum error correction can help specify the emergence map between the full quantum-gravity Hilbert space and the semiclassical limit of quantum fields propagating on a classical spacetime., Comment: 29 pages, 2 figures

Many modern cosmological scenarios feature large volumes of spacetime in a de Sitter vacuum phase. Such models are said to be faced with a "Boltzmann Brain problem" - the overwhelming majority of observers with fixed local conditions are random fluctuations in the de Sitter vacuum, rather than arising via thermodynamically sensible evolution from a low-entropy past. We argue that this worry can be straightforwardly avoided in the Many-Worlds (Everett) approach to quantum mechanics, as long as the underlying Hilbert space is infinite-dimensional. In that case, de Sitter settles into a truly stationary quantum vacuum state. While there would be a nonzero probability for observing Boltzmann-Brain-like fluctuations in such a state, "observation" refers to a specific kind of dynamical process that does not occur in the vacuum (which is, after all, time-independent). Observers are necessarily out-of-equilibrium physical systems, which are absent in the vacuum. Hence, the fact that projection operators corresponding to states with observers in them do not annihilate the vacuum does not imply that such observers actually come into existence. The Boltzmann Brain problem is therefore much less generic than has been supposed.

We discuss the branching structure of the quantum-gravitational wave function that describes the evaporation of a black hole. A global wave function which initially describes a classical Schwarzschild geometry is continually decohered into distinct semiclassical branches by the emission of Hawking radiation. The laws of quantum mechanics dictate that the wave function evolves unitarily, but this unitary evolution is only manifest when considering the global description of the wave function; it is not implemented by time evolution on a single semiclassical branch. Conversely, geometric notions like the position or smoothness of a horizon only make sense on the level of individual branches. We consider the implications of this picture for probes of black holes by classical observers in definite geometries, like those involved in the AMPS construction. We argue that individual branches can describe semiclassical geometries free of firewalls, even as the global wave function evolves unitarily. We show that the pointer states of infalling detectors that are robust under Hamiltonian evolution are distinct from, and incompatible with, those of exterior detectors stationary with respect to the black hole horizon, in the sense that the pointer bases are related to each other via nontrivial transformations that mix the system, apparatus, and environment. This result describes a Hilbert-space version of black hole complementarity., Comment: 25 pages, 2 figures; v2 added citations; v3 fixed a typo in sec 2.5 + 1 citation; v4 expanded discussion in sec 2, more citations; v5 small typo fixes to reflect published version

We investigate the proposed connection between de Sitter spacetime and the MERA (Multiscale Entanglement Renormalization Ansatz) tensor network, and ask what can be learned via such a construction. We show that the quantum state obeys a cosmic no-hair theorem: the reduced density operator describing a causal patch of the MERA asymptotes to a fixed point of a quantum channel, just as spacetimes with a positive cosmological constant asymptote to de Sitter. The MERA is potentially compatible with a weak form of complementarity (local physics only describes single patches at a time, but the overall Hilbert space is infinite-dimensional) or, with certain specific modifications to the tensor structure, a strong form (the entire theory describes only a single patch plus its horizon, in a finite-dimensional Hilbert space). We also suggest that de Sitter evolution has an interpretation in terms of circuit complexity, as has been conjectured for anti-de Sitter space., Comment: 24 pages, 12 figures. Updated to be consistent with PRD version

Over the past 50 years, there has been a significant increase in published articles in the medical literature. The aesthetic surgery literature is vast, consisting of a plethora of diverse articles written by a myriad of illustrious authors. Despite this considerable archive of published material, it remains nebulous as to which precise papers have had the greatest impact on our specialty. The aim of our study was to identify and analyse the characteristics of the top 50 papers in the field of aesthetic surgery in the published literature. The 50 most cited papers were identified in several surgical journals through the Web of Science. The articles were ranked in order of the number of citations received. These classic 50 papers were analysed for article type, their journal distribution, level of evidence as well as geographic and institutional origin. Six journals contributed to the top 50 papers in aesthetic surgery with Plastic and Reconstructive Surgery contributing the most with 31 papers. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Background Proximal interphalangeal joint (PIPJ) dislocations represent a significant proportion of hand clinic visits and typically require frequent follow-ups for clinical assessment, orthotic adjustments, and physiotherapy. There are a large number of treatment options available for PIPJ dislocations, yet no prospective or controlled studies have been carried out, largely due to the diversity of the various types of injuries. Methods We retrospectively reviewed all the PIPJ dislocations in our institution over a five-year period and directly compared the different splinting techniques that we have used over this time frame. Results There were a total of 77 dislocations of the PIPJ (57 men and 20 women) that were included in our study. We found that our management has shifted gradually from complete immobilisation to controlled early mobilisation with figure-of-eight splints. Following treatment, the range of motion of the PIPJ in the figure-of-eight group was significantly greater than that in the other three methods (P Conclusions The treatment of PIPJ dislocations has undergone a significant evolution in our experience. Early controlled mobilisation has become increasingly important, and therefore, splints have had to be adapted to allow for this. The figure-of-eight splint has yielded excellent results in our experience. It should be considered for all PIPJ dislocations, but careful patient selection is required to achieve optimum results.