Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

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.

Galactose metabolic genes in yeast respond to a ratio of galactose and glucose.

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.

The Distribution of Road Salt in Private Drinking Water Wells in a Southeastern New York Suburban Township.

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 was >30 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.

Controlled Measurement and Comparative Analysis of Cellular Components in E. coli Reveals Broad Regulatory Changes in Response to Glucose Starvation.

How do bacteria regulate their cellular physiology in response to starvation? Here, we present a detailed characterization of Escherichia coli growth and starvation over a time-course lasting two weeks. We have measured multiple cellular components, including RNA and proteins at deep genomic coverage, as well as lipid modifications and flux through central metabolism. Our study focuses on the physiological response of E. coli in stationary phase as a result of being starved for glucose, not on the genetic adaptation of E. coli to utilize alternative nutrients. In our analysis, we have taken advantage of the temporal correlations within and among RNA and protein abundances to identify systematic trends in gene regulation. Specifically, we have developed a general computational strategy for classifying expression-profile time courses into distinct categories in an unbiased manner. We have also developed, from dynamic models of gene expression, a framework to characterize protein degradation patterns based on the observed temporal relationships between mRNA and protein abundances. By comparing and contrasting our transcriptomic and proteomic data, we have identified several broad physiological trends in the E. coli starvation response. Strikingly, mRNAs are widely down-regulated in response to glucose starvation, presumably as a strategy for reducing new protein synthesis. By contrast, protein abundances display more varied responses. The abundances of many proteins involved in energy-intensive processes mirror the corresponding mRNA profiles while proteins involved in nutrient metabolism remain abundant even though their corresponding mRNAs are down-regulated.

Infrared images of the transiting disk in the epsilon Aurigae system.

Epsilon Aurigae (epsilon Aur) is a visually bright, eclipsing binary star system with a period of 27.1 years. The cause of each 18-month-long eclipse has been a subject of controversy for nearly 190 years because the companion has hitherto been undetectable. The orbital elements imply that the opaque object has roughly the same mass as the visible component, which for much of the last century was thought to be an F-type supergiant star with a mass of approximately 15M[symbol:see text] (M[symbol:see text], mass of the Sun). The high mass-to-luminosity ratio of the hidden object was originally explained by supposing it to be a hyperextended infrared star or, later, a black hole with an accretion disk, although the preferred interpretation was as a disk of opaque material at a temperature of approximately 500 K, tilted to the line of sight and with a central opening. Recent work implies that the system consists of a low-mass (2.2M[symbol:see text]-3.3M[symbol:see text]) visible F-type star, with a disk at 550 K that enshrouds a single B5V-type star. Here we report interferometric images that show the eclipsing body moving in front of the F star. The body is an opaque disk and appears tilted as predicted. Adopting a mass of 5.9M[symbol:see text] for the B star, we derive a mass of approximately (3.6 +/- 0.7)M[symbol:see text] for the F star. The disk mass is dynamically negligible; we estimate it to contain approximately 0.07M[symbol:see text] (M[symbol:see text], mass of the Earth) if it consists purely of dust.

Modulating the innate immune response by combinatorial engineering of endotoxin.

Despite its highly inflammatory nature, LPS is a molecule with remarkable therapeutic potential. Lipid A is a glycolipid that serves as the hydrophobic anchor of LPS and constitutes a potent ligand of the Toll-like receptor (TLR)4/myeloid differentiation factor 2 receptor of the innate immune system. A less toxic mixture of monophosphorylated lipid A species (MPL) recently became the first new Food and Drug Administration-approved adjuvant in over 70 y. Whereas wild-type Escherichia coli LPS provokes strong inflammatory MyD88 (myeloid differentiation primary response gene 88)-mediated TLR4 signaling, MPL preferentially induces less inflammatory TRIF (TIR-domain-containing adaptor-inducing IFN-ß)-mediated responses. Here, we developed a system for combinatorial structural diversification of E. coli lipid A, yielding a spectrum of bioactive variants that display distinct TLR4 agonist activities and cytokine induction. Mice immunized with engineered lipid A/antigen emulsions exhibited robust IgG titers, indicating the efficacy of these molecules as adjuvants. This approach demonstrates how combinatorial engineering of lipid A can be exploited to generate a spectrum of immunostimulatory molecules for vaccine and therapeutics development.

How to Recover a Qubit That Has Fallen into a Black Hole.

We demonstrate an algorithm for the retrieval of a qubit, encoded in spin angular momentum, that has been dropped into a no-firewall black hole. Retrieval is achieved analogously to quantum teleportation by collecting Hawking radiation and performing measurements on the black hole. Importantly, these methods require only the ability to perform measurements from outside the event horizon.

An Analysis of the "Classic" Papers in Aesthetic Surgery.

INTRODUCTION: 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. METHODS: 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. RESULTS: Six journals contributed to the top 50 papers in aesthetic surgery with Plastic and Reconstructive Surgery contributing the most with 31 papers.

An objective evaluation of a multi-component, competitive, selection process for admitting surgeons into higher surgical training in a national setting.

BACKGROUND: Changing work practices make it imperative that surgery selects candidates for training who demonstrate the spectrum of abilities that best facilitate learning and development of attributes that, by the end of their training, approximate the characteristics of a consultant surgeon. AIMS: The aim of our study was to determine the relative merits of components of a program used for competitive selection of trainees into higher surgical training (HST) in general surgery. METHODS: Applicants (N = 98, males 69, mean age 31 years [range 29-40]) to the Royal College of Surgeons in Ireland program for HST in general surgery between 2006 and 2008 were assessed. Clinical, basic surgical training, logbook, research performance, and reference scores were evaluated. A total of 51 candidates were shortlisted and completed a further objective assessment of their technical skills and interview performances. RESULTS: Shortlisted candidates performed better (p < 0.003) on all assessed parameters. Compared with candidates who were not selected for HST, those who were selected (N = 31) significantly outperformed on individual assessments and overall (p < 0.0001). Logistic regression analysis showed that clinical, technical skills, and research assessments, but not interview, predicted (92.2 %) HST selection outcomes. CONCLUSIONS: Candidates selected for the national HST program in Ireland consistently outperformed those who were not. The assessments reliably and consistently distinguished between candidates, and all of the assessed parameters (except interview) contributed to a highly predictive selection model. This is the largest reported dataset from an objective, transparent, and fair assessment program for selection of the next generation of surgeons.

Intensive hands-on microsurgery course provides a solid foundation for performing clinical microvascular surgery.

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.

Is our Universe natural?

It goes without saying that we are stuck with the Universe we have. Nevertheless, we would like to go beyond simply describing our observed Universe, and try to understand why it is that way rather than some other way. When considering both the state in which we find our current Universe, and the laws of physics it obeys, we discover features that seem remarkably unnatural to us. Physicists and cosmologists have been exploring increasingly ambitious ideas in an attempt to explain how surprising aspects of our Universe can arise from simple dynamical principles.

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03380026.

Surgical reconstruction of pressure ulcer defects: a single- or two-stage procedure?

BACKGROUND: The surgical management of pressure ulcers traditionally involved staged procedures, with initial debridement of necrotic or infected material followed by reconstruction at a later date when the wound was deemed viable and free of gross infection. However, over the past decade, it has been suggested that a single-stage procedure, combining initial debridement and definitive reconstruction, may provide advantages over staged surgery. We present our experience with the staged approach and review the current evidence for both methods. SUBJECTS AND SETTINGS: : We reviewed medical records of all patients referred to our service for pressure ulcer management between October 2001 and October 2007. The National Rehabilitation Hospital is the national center in Ireland for primary rehabilitation of adults and children suffering from spinal and brain injury, serving patients locally and from around the country. METHODS: All subjects who were managed surgically underwent a 2-stage procedure, with initial debridement and subsequent reconstruction. The main outcome measures were length of hospital stay, postoperative morbidity and mortality, and time to complete ulcer healing. RESULTS: Forty-one of 108 patients with 58 pressure ulcers were managed surgically. All patients underwent initial surgical debridement and 20 patients underwent subsequent pressure ulcer reconstruction. Postreconstructive complications occurred in 5 patients (20%). The mean time to complete ulcer healing was 17.4 weeks. Partial flap necrosis occurred in 3 patients, but there were no episodes of flap failure. CONCLUSIONS: We achieved favorable results with a 2-stage reconstruction technique and suggest that the paucity of evidence related to single-stage procedures does not support a change in surgical management.

Levels of Evidence in Plastic and Reconstructive Surgery Research: Have We Improved Over the Past 10 Years?

Levels of evidence (LOE) aid in the critical appraisal of evidence by ranking studies based on limitation of its design. Analyzing LOE provides insight into application of evidence-based medicine. The aim of this study is to determine if the quality of evidence in plastic surgery research has improved over the past 10 years. Systematic review of research published in Plastics and Reconstructive Surgery journal over the years, 10-year period (2008, 2013, 2018), was performed. LOE for each article was determined using the American Society of Plastic Surgeons (ASPS) guidelines. Each level was calculated as percentage of publications per year and compared yearly and between different topics. Eight hundred eighty-four studies were included in the final analysis. The LOE of the research improved over the study period. Level 4 evidence was the most frequent published (50.6%, 447/884), with a decline from 63.2% in 2008 to 41.3% in 2018. Level 1 evidence improved each year and accounted for 2.1% of all research in 2018. Aesthetic surgery was the most frequent published topic with upper limb research demonstrating an 18.5% increase in high-quality evidence over the study period. Increased awareness of evidence-based medicine has improved the quality of plastic surgery research over the past decade. It is vital this continues to provide gold standard patient care.

Aesthetic surgery training in a changing healthcare environment.

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.

ASCOT: Autologous Bone Marrow Stem Cell Use for Osteoarthritis of the Thumb-First Carpometacarpal Joint.

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 E. coli molecular phenotype under different growth conditions.

Modern systems biology requires extensive, carefully curated measurements of cellular components in response to different environmental conditions. While high-throughput methods have made transcriptomics and proteomics datasets widely accessible and relatively economical to generate, systematic measurements of both mRNA and protein abundances under a wide range of different conditions are still relatively rare. Here we present a detailed, genome-wide transcriptomics and proteomics dataset of E. coli grown under 34 different conditions. Additionally, we provide measurements of doubling times and in-vivo metabolic fluxes through the central carbon metabolism. We manipulate concentrations of sodium and magnesium in the growth media, and we consider four different carbon sources glucose, gluconate, lactate, and glycerol. Moreover, samples are taken both in exponential and stationary phase, and we include two extensive time-courses, with multiple samples taken between 3 hours and 2 weeks. We find that exponential-phase samples systematically differ from stationary-phase samples, in particular at the level of mRNA. Regulatory responses to different carbon sources or salt stresses are more moderate, but we find numerous differentially expressed genes for growth on gluconate and under salt and magnesium stress. Our data set provides a rich resource for future computational modeling of E. coli gene regulation, transcription, and translation.

Bayesian second law of thermodynamics.

We derive a generalization of the second law of thermodynamics that uses Bayesian updates to explicitly incorporate the effects of a measurement of a system at some point in its evolution. By allowing an experimenter's knowledge to be updated by the measurement process, this formulation resolves a tension between the fact that the entropy of a statistical system can sometimes fluctuate downward and the information-theoretic idea that knowledge of a stochastically evolving system degrades over time. The Bayesian second law can be written as ΔH(ρ_{m},ρ)+〈Q〉_{F|m}≥0, where ΔH(ρ_{m},ρ) is the change in the cross entropy between the original phase-space probability distribution ρ and the measurement-updated distribution ρ_{m} and 〈Q〉_{F|m} is the expectation value of a generalized heat flow out of the system. We also derive refined versions of the second law that bound the entropy increase from below by a non-negative number, as well as Bayesian versions of integral fluctuation theorems. We demonstrate the formalism using simple analytical and numerical examples.

Trends in the Level of Evidence in Clinical Hand Surgery Research.

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.