Facing the ever-growing demand for data storage will most probably require a new paradigm. Nanoscale magnetic skyrmions are anticipated to solve this issue as they are arguably the smallest spin ...textures in magnetic thin films in nature. We designed cobalt-based multilayered thin films in which the cobalt layer is sandwiched between two heavy metals and so provides additive interfacial Dzyaloshinskii-Moriya interactions (DMIs), which reach a value close to 2 mJ m(-2) in the case of the Ir|Co|Pt asymmetric multilayers. Using a magnetization-sensitive scanning X-ray transmission microscopy technique, we imaged small magnetic domains at very low fields in these multilayers. The study of their behaviour in a perpendicular magnetic field allows us to conclude that they are actually magnetic skyrmions stabilized by the large DMI. This discovery of stable sub-100 nm individual skyrmions at room temperature in a technologically relevant material opens the way for device applications in the near future.
Tendinopathy is a multifactorial spectrum of tendon disorders that affects different anatomical sites and is characterized by activity-related tendon pain. These disorders are common, account for a ...high proportion (∼30%) of referrals to musculoskeletal practitioners and confer a large socioeconomic burden of disease. Our incomplete understanding of the mechanisms underpinning tendon pathophysiology continues to hamper the development of targeted therapies, which have been successful in other areas of musculoskeletal medicine. Debate remains among clinicians about the role of an inflammatory process in tendinopathy owing to a lack of clinical correlation. The advent of modern molecular techniques has highlighted the presence of immune cells and inflammatory mechanisms throughout the spectrum of tendinopathy in both animal and human models of disease. Key inflammatory mediators - such as cytokines, nitric oxide, prostaglandins and lipoxins - play crucial parts in modulating changes in the extracellular matrix within tendinopathy. Understanding the links between inflammatory mechanisms, tendon homeostasis and resolution of tendon damage will be crucial in developing novel therapeutics for human tendon disease.
Summary
Breakthrough invasive fungal infections (IFIs) have emerged as a significant problem in patients receiving systemic antifungals; however, consensus criteria for defining breakthrough IFI are ...missing. This position paper establishes broadly applicable definitions of breakthrough IFI for clinical research. Representatives of the Mycoses Study Group Education and Research Consortium (MSG‐ERC) and the European Confederation of Medical Mycology (ECMM) reviewed the relevant English literature for definitions applied and published through 2018. A draft proposal for definitions was developed and circulated to all members of the two organisations for comment and suggestions. The authors addressed comments received and circulated the updated document for approval. Breakthrough IFI was defined as any IFI occurring during exposure to an antifungal drug, including fungi outside the spectrum of activity of an antifungal. The time of breakthrough IFI was defined as the first attributable clinical sign or symptom, mycological finding or radiological feature. The period defining breakthrough IFI depends on pharmacokinetic properties and extends at least until one dosing interval after drug discontinuation. Persistent IFI describes IFI that is unchanged/stable since treatment initiation with ongoing need for antifungal therapy. It is distinct from refractory IFI, defined as progression of disease and therefore similar to non‐response to treatment. Relapsed IFI occurs after treatment and is caused by the same pathogen at the same site, although dissemination can occur. These proposed definitions are intended to support the design of future clinical trials and epidemiological research in clinical mycology, with the ultimate goal of increasing the comparability of clinical trial results.
Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal ...risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We performed a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n = 334 968), using the PHESANT open-source phenome scan tool. A subset of identified associations were followed up with a formal two-stage instrumental variable analysis in UK Biobank, to estimate the causal effect of BMI on these phenotypes. Of the 22 922 tests performed, our MR-pheWAS identified 587 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate. These included many previously identified causal effects, for instance, an adverse effect of higher BMI on risk of diabetes and hypertension. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS in circa 115,000 UK Biobank participants and replicated in a different subset of circa 223,000 UK Biobank participants. Our comprehensive MR-pheWAS identified potential causal effects of BMI on a large and diverse set of phenotypes. This included both previously identified causal effects, and novel effects such as a protective effect of higher BMI on feelings of nervousness.
Timely perception of adverse environmental changes is critical for survival. Dynamic changes in gases are important cues for plants to sense environmental perturbations, such as submergence. In ...Arabidopsis thaliana, changes in oxygen and nitric oxide (NO) control the stability of ERFVII transcription factors. ERFVII proteolysis is regulated by the N-degron pathway and mediates adaptation to flooding-induced hypoxia. However, how plants detect and transduce early submergence signals remains elusive. Here we show that plants can rapidly detect submergence through passive ethylene entrapment and use this signal to pre-adapt to impending hypoxia. Ethylene can enhance ERFVII stability prior to hypoxia by increasing the NO-scavenger PHYTOGLOBIN1. This ethylene-mediated NO depletion and consequent ERFVII accumulation pre-adapts plants to survive subsequent hypoxia. Our results reveal the biological link between three gaseous signals for the regulation of flooding survival and identifies key regulatory targets for early stress perception that could be pivotal for developing flood-tolerant crops.
Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 ...(S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.
Background:
A number of surgical techniques for managing tennis elbow have been described. One of the most frequently performed involves excising the affected portion of the extensor carpi radialis ...brevis (ECRB). The results of this technique, as well as most other described surgical techniques for this condition, have been reported as excellent, yet none have been compared with placebo surgery.
Hypothesis:
The surgical excision of the degenerative portion of the ECRB offers no additional benefit over and above placebo surgery for the management of chronic tennis elbow.
Study Design:
Randomized controlled trial; Level of evidence, 2.
Methods:
This study investigated surgical excision of the macroscopically degenerated portion of the ECRB (surgery; n = 13) as compared with skin incision and exposure of the ECRB alone (sham; n = 13) to treat patients who had tennis elbow for >6 months and had failed at least 2 nonsurgical modalities. The primary outcome measure was defined as patient-rated frequency of elbow pain with activity at 6 months after surgery. Secondary outcome measures included patient-rated pain and functional outcomes, range of motion, epicondyle tenderness, and strength at 6 months and 2.5 years. All outcome measures up to and including the 6-month follow-up were measured in person; the longer-term questionnaire was conducted in person or over the phone.
Results:
The 2 groups, surgery and sham, were similar for age, sex, hand dominance, and duration of symptoms. Both procedures improved patient-rated pain frequency and severity, elbow stiffness, difficulty with picking up objects, difficulty with twisting motions, and overall elbow rating >6 months and at 2.5 years (P < .01). Both procedures also improved epicondyle tenderness, pronation-supination range, grip strength, and modified Orthopaedic Research Institute–Tennis Elbow Testing System at 6 months (P < .05). No significant difference was observed between the groups in any parameter at any stage. No side effects or complications were reported. The study was stopped before the calculated number of patients were enrolled (40 per group); yet, a post hoc futility analysis was conducted that showed, based on the magnitude of the differences between the groups, >6500 patients would need to be recruited per group to see a significant difference between the groups at 26 weeks in the primary outcome (patient-rated frequency of elbow pain with activity).
Conclusion:
With the number of available participants, this study failed to show additional benefit of the surgical excision of the degenerative portion of the ECRB over placebo surgery for the management of chronic tennis elbow.
Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their ...strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
The prevalence of rotator cuff tears increases with age, and many patients undergo surgical repair. Retears are not uncommon, with rates ranging between 9% and 36% in recent studies, and are a major ...concern. The aim of this study was to investigate the relationship between patient age and the chance of healing following rotator cuff repair.
This was a retrospective cohort study of patients who had undergone arthroscopic rotator cuff repair performed by a single surgeon. All patients had an ultrasound performed by a musculoskeletal sonographer 6 months after rotator cuff repair to assess the repair integrity.
The cohort of 1,600 patients was normally distributed in terms of age, with a mean age (and standard error of the mean) of 59 ± 0.3 years and a range of 15 to 91 years. The 212 patients (13%) who had a retear at 6 months were also normally distributed in terms of age, with a mean age of 65 ± 0.8 years and a range of 15 to 88 years. The retear rate in patients <50 years old was 5%. This increased to 10% in patients aged 50 to 59 years, 15% in those aged 60 to 69 years, 25% in those aged 70 to 79 years, and 34% in those aged ≥80 years. Multiple logistic regression analysis showed that patient age was an independent factor strongly associated with retears.
The rate of rotator cuff retears is low in patients <50 years of age. The relationship between age and rotator cuff retears is linear in patients 50 to 69 years of age, with an increase of 5% between decades, and increases substantially in patients ≥70 years old.
Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Factors Predicting Rotator Cuff Retears Le, Brian T.N.; Wu, Xiao L.; Lam, Patrick H. ...
The American journal of sports medicine,
05/2014, Letnik:
42, Številka:
5
Journal Article
Recenzirano
Background:
The rate of retears after rotator cuff repair varies from 11% to 94%. A retear is associated with poorer subjective and objective clinical outcomes than intact repair.
Purpose:
This study ...was designed to determine which preoperative and/or intraoperative factors held the greatest association with retears after arthroscopic rotator cuff repair.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
This study retrospectively evaluated 1000 consecutive patients who had undergone a primary rotator cuff repair by a single surgeon using an arthroscopic inverted-mattress knotless technique and who had undergone an ultrasound evaluation 6 months after surgery to assess repair integrity. Exclusion criteria included previous rotator cuff repair on the same shoulder, incomplete repair, and repair using a synthetic polytetrafluoroethylene patch. All patients had completed the modified L’Insalata Questionnaire and underwent a clinical examination before surgery. Measurements of tear size, tear thickness, associated shoulder injury, tissue quality, and tendon mobility were recorded intraoperatively.
Results:
The overall retear rate at 6 months after surgery was 17%. Retears occurred in 27% of full-thickness tears and 5% of partial-thickness tears (P < .0001). The best independent predictors of retears were anteroposterior tear length (correlation coefficient r = 0.41, P < .0001), tear size area (r = 0.40, P < .0001), mediolateral tear length (r = 0.34, P < .0001), tear thickness (r = 0.29, P < .0001), age at surgery (r = 0.27, P < .0001), and operative time (r = 0.18, P < .0001). These factors produced a predictive model for retears: logit P = (0.039 × age at surgery in years) + (0.027 × tear thickness in %) + (1 × anteroposterior tear length in cm) + (0.76 × mediolateral tear length in cm) – (0.17 × tear size area in cm2) + (0.018 × operative time in minutes) –9.7. Logit P can be transformed into P, which is the chance of retears at 6 months after surgery.
Conclusion:
A rotator cuff retear is a multifactorial process with no single preoperative or intraoperative factor being overwhelmingly predictive of it. Nevertheless, rotator cuff tear size (tear dimensions, tear size area, and tear thickness) showed stronger associations with retears at 6 months after surgery than did measures of tissue quality and concomitant shoulder injuries.
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