Dexamethasone and chronic postsurgical pain: the pendulum meets reductionistic thinking.

Reductionist thinking results in the bulk of anaesthesia trial designs being a single intervention to address what are in fact complex processes. The Perioperative Administration of Dexamethasone and Infection (PADDI) trial assessed the safety of a single preoperative dose of dexamethasone. Surprising to most, in the original report, a single dose of dexamethasone increased the incidence of the secondary outcome chronic postsurgical pain. Was this a chance finding or does dexamethasone increase chronic postsurgical pain? In an attempt to address this question, the PADDI investigators have now analysed this prespecified secondary outcome in two ways: as a substudy published earlier in this Journal, and as a retrospective analysis of the ENIGMA-II chronic pain database in this issue of the Journal. The PADDI investigators have now presented enough data to convince us that indeed a single dose of dexamethasone is safe and effective. However, the increase in chronic postsurgical pain seen in the original PADDI publication highlights the complexities, and the possible immunologic mechanisms, behind the genesis of chronic postsurgical pain. These publications from the PADDI group raise questions about other anti-inflammatory agents we use regularly for long-term postoperative pain management, and highlights the need for well-designed clinical trials to address this critically important patient-centred adverse functional outcome.

Qualitative Exploration Toward the Development of a Parent-Rated Scale for Insomnia in Children with Autism Spectrum Disorder.

Toward the development of a new parent-rating for insomnia, this multi-site qualitative study explored sleep problems and related impacts in children with autism spectrum disorder (ASD) and their families. To ensure content validity of the measure, we conducted six focus groups with caregivers (N = 25) of 24 children (age 3 to 18 years) with ASD. Based on parent report, all children had a history of mild or greater insomnia. The focus group transcripts were systematically coded to identify major themes. Verbatim comments from caretakers were used to generate 134 candidate items. Further review by the research team and an expert panel followed by individual cognitive interviews with 12 parents reduced the item bank to 40. The thematic analysis of focus group transcripts identified 7 categories: (1) Trouble falling asleep; (2) trouble staying asleep; (3) early morning waking; (4) bedtime routines; (5) parental strategies for bedtime management; (6) impact of sleep problems on the child; and (7) impact of sleep problems on the family. The Flesch Kincaid Grade Level of the 40-item version was 7.2 (seventh grade reading level). Insomnia in children with ASD shares features in common with insomnia in the general pediatric population. However, perhaps owing to autistic features such as insistence on sameness, sensory sensitivities, communication impairments, insomnia in children with ASD appears to have unique behavioral manifestations. Content validity and item clarity of the 40-item bank were supported by expert panel review and cognitive interviews with caregivers of children with ASD.

A helium-burning white dwarf binary as a supersoft X-ray source.

Type Ia supernovae are cosmic distance indicators1,2, and the main source of iron in the Universe3,4, but their formation paths are still debated. Several dozen supersoft X-ray sources, in which a white dwarf accretes hydrogen-rich matter from a non-degenerate donor star, have been observed5 and suggested as Type Ia supernovae progenitors6-9. However, observational evidence for hydrogen, which is expected to be stripped off the donor star during the supernova explosion10, is lacking. Helium-accreting white dwarfs, which would circumvent this problem, have been predicted for more than 30 years (refs. 7,11,12), including their appearance as supersoft X-ray sources, but have so far escaped detection. Here we report a supersoft X-ray source with an accretion disk whose optical spectrum is completely dominated by helium, suggesting that the donor star is hydrogen-free. We interpret the luminous and supersoft X-rays as resulting from helium burning near the surface of the accreting white dwarf. The properties of our system provide evidence for extended pathways towards Chandrasekhar-mass explosions based on helium accretion, in particular for stable burning in white dwarfs at lower accretion rates than expected so far. This may allow us to recover the population of the sub-energetic so-called Type Iax supernovae, up to 30% of all Type Ia supernovae13, within this scenario.

Evaluation of the ability of commercial disinfectants to degrade free nucleic acid commonly targeted using molecular diagnostics.

BACKGROUND: Polymerase chain reaction (PCR) is an essential tool for rapid detection of pathogens, but is susceptible to cross-contamination by residual nucleic acid, leading to false-positive results. Adequate surface decontamination would help prevent this, but most protocols target infectious microbes rather than free nucleic acid. The aim of this study was to evaluate the ability of commercial surface disinfectants to degrade different representative classes of nucleic acid. METHODS: Commercial surface disinfectants with various active ingredients, as well as 10% chlorine bleach, were tested. Nucleic acid was dried on to stainless steel coupons and treated with disinfectant for 0-4 min prior to neutralization and quantification by quantitative reverse transcription PCR. The effective disinfectants were also evaluated in the presence of organic load. RESULTS: Only dilute chlorine bleach and the hypochlorite-based commercial disinfectant significantly degraded any type of free nucleic acid. Hydrogen-peroxide- and quaternary-ammonium-based disinfectants gave <1 log reduction after 4 min for all targets. Results were time-dependent for each target, which underscores the importance of adequate contact time. Organic load appeared to have little impact on the efficacy of hypochlorite-based disinfectants for nucleic acid degradation. CONCLUSIONS: This study demonstrates the importance of proper selection and application of disinfectant to remove residual nucleic acid when processing samples for molecular diagnostic testing.

Localized thermonuclear bursts from accreting magnetic white dwarfs.

Nova explosions are caused by global thermonuclear runaways triggered in the surface layers of accreting white dwarfs1-3. It has been predicted4-6 that localized thermonuclear bursts on white dwarfs can also take place, similar to type-I X-ray bursts observed in accreting neutron stars. Unexplained rapid bursts from the binary system TV Columbae, in which mass is accreted onto a moderately strong magnetized white dwarf from a low-mass companion, have been observed on several occasions in the past 40 years7-11. During these bursts, the optical/ultraviolet luminosity increases by a factor of more than three in less than an hour and fades in around ten hours. Fast outflows have been observed in ultraviolet spectral lines7, with velocities of more than 3,500 kilometres per second, comparable to the escape velocity from the white dwarf surface. Here we report on optical bursts observed in TV Columbae and in two additional accreting systems, EI Ursae Majoris and ASASSN-19bh. The bursts have a total energy of approximately 10-6  times than those of classical nova explosions (micronovae) and bear a strong resemblance to type-I X-ray bursts12-14. We exclude accretion or stellar magnetic reconnection events as their origin and suggest thermonuclear runaway events in magnetically confined accretion columns as a viable explanation.

A persistent ultraviolet outflow from an accreting neutron star binary transient.

All disc-accreting astrophysical objects produce powerful disc winds. In compact binaries containing neutron stars or black holes, accretion often takes place during violent outbursts. The main disc wind signatures during these eruptions are blue-shifted X-ray absorption lines, which are preferentially seen in disc-dominated 'soft states'1,2. By contrast, optical wind-formed lines have recently been detected in 'hard states', when a hot corona dominates the luminosity3. The relationship between these signatures is unknown, and no erupting system has as yet revealed wind-formed lines between the X-ray and optical bands, despite the many strong resonance transitions in this ultraviolet (UV) region4. Here we report that the transient neutron star binary Swift J1858.6-0814 exhibits wind-formed, blue-shifted absorption lines associated with C IV, N V and He II in time-resolved UV spectroscopy during a luminous hard state, which we interpret as a warm, moderately ionized outflow component in this state. Simultaneously observed optical lines also display transient blue-shifted absorption. Decomposing the UV data into constant and variable components, the blue-shifted absorption is associated with the former. This implies that the outflow is not associated with the luminous flares in the data. The joint presence of UV and optical wind features reveals a multi-phase and/or spatially stratified evaporative outflow from the outer disc5. This type of persistent mass loss across all accretion states has been predicted by radiation-hydrodynamic simulations6 and helps to explain the shorter-than-expected duration of outbursts7.

Persistent Incisional Pain after Noncardiac Surgery: An International Prospective Cohort Study.

BACKGROUND: The purpose of this study was to determine the incidence, characteristics, impact, and risk factors associated with persistent incisional pain. The hypothesis was that patient demographics and perioperative interventions are associated with persistent pain. METHODS: This was a secondary analysis of an international prospective cohort study from 2012 to 2014. This study included patients who were 45 yr of age or older who underwent major inpatient noncardiac surgery. Data were collected perioperatively and at 1 yr after surgery to assess for the development of persistent incisional pain (pain present around incision at 1 yr after surgery). RESULTS: Among 14,831 patients, 495 (3.3%; 95% CI, 3.1 to 3.6) reported persistent incisional pain at 1 yr, with an average pain intensity of 3.6 ± 2.5 (0 to 10 numeric rating scale), with 35% and 14% reporting moderate and severe pain intensities, respectively. More than half of patients with persistent pain reported needing analgesic medications, and 85% reported interference with daily activities (denominator = 495 in the above proportions). Risk factors for persistent pain included female sex (P = 0.007), Asian ethnicity (P < 0.001), surgery for fracture (P < 0.001), history of chronic pain (P < 0.001), coronary artery disease (P < 0.001), history of tobacco use (P = 0.048), postoperative patient-controlled analgesia (P < 0.001), postoperative continuous nerve block (P = 0.010), insulin initiation within 24 h of surgery (P < 0.001), and withholding nonsteroidal anti-inflammatory medication or cyclooxygenase-2 inhibitors on the day of surgery (P = 0.029 and P < 0.001, respectively). Older age (P < 0.001), endoscopic surgery (P = 0.005), and South Asian (P < 0.001), Native American/Australian (P = 0.004), and Latin/Hispanic ethnicities (P < 0.001) were associated with a lower risk of persistent pain. CONCLUSIONS: Persistent incisional pain is a common complication of inpatient noncardiac surgery, occurring in approximately 1 in 30 adults. It results in significant morbidity, interferes with daily living, and is associated with persistent analgesic consumption. Certain demographics, ethnicities, and perioperative practices are associated with increased risk of persistent pain.

Interventional treatments for chronic, axial or radicular, non-cancer, spinal pain: a protocol for a systematic review and network meta-analysis of randomised trials.

INTRODUCTION: Chronic, non-cancer, axial or radicular spinal pain is a common condition associated with considerable socioeconomic burden. Clinicians frequently offer patients various interventional procedures for the treatment of chronic spine pain; however, the comparative effectiveness and safety of available procedures remains uncertain. METHODS: We will conduct a systematic review of randomised controlled trials that explores the effectiveness and harms of interventional procedures for the management of axial or radicular, chronic, non-cancer, spine pain. We will identify eligible studies through a systematic search of Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and Web of Science from inception without language restrictions. Eligible trials will: (1) enrol primarily adult patients (≥18 years old) with axial or radicular, chronic, non-cancer, spine pain, (2) randomise patients to different, currently available, interventional procedures or to an interventional procedure and a placebo/sham procedure or usual care, and (3) measure outcomes at least 1 month after randomisation.Pairs of reviewers will independently screen articles identified through searches and extract information and assess risk of bias of eligible trials. We will use a modified Cochrane instrument to evaluate risk of bias. We will use frequentist random-effects network meta-analyses to assess the relative effects of interventional procedures, and five a priori hypotheses to explore between studies subgroup effects. We will use the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty in evidence for each outcome, including direct, indirect and network estimates. ETHICS AND DISSEMINATION: No research ethics approval is required for this systematic review, as no confidential patient data will be used. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations, and our review will support development of a BMJ Rapid Recommendations providing contextualised clinical guidance based on this body of evidence. PROSPERO REGISTRATION NUMBER: CRD42020170667.

Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies.

OBJECTIVE: To assess the efficacy and harms of adding medical cannabis to prescription opioids among people living with chronic pain. DESIGN: Systematic review. DATA SOURCES: CENTRAL, EMBASE and MEDLINE. MAIN OUTCOMES AND MEASURES: Opioid dose reduction, pain relief, sleep disturbance, physical and emotional functioning and adverse events. STUDY SELECTION CRITERIA AND METHODS: We included studies that enrolled patients with chronic pain receiving prescription opioids and explored the impact of adding medical cannabis. We used Grading of Recommendations Assessment, Development and Evaluation to assess the certainty of evidence for each outcome. RESULTS: Eligible studies included five randomised trials (all enrolling chronic cancer-pain patients) and 12 observational studies. All randomised trials instructed participants to maintain their opioid dose, which resulted in a very low certainty evidence that adding cannabis has little or no impact on opioid use (weighted mean difference (WMD) -3.4 milligram morphine equivalent (MME); 95% CI (CI) -12.7 to 5.8). Randomised trials provided high certainty evidence that cannabis addition had little or no effect on pain relief (WMD -0.18 cm; 95% CI -0.38 to 0.02; on a 10 cm Visual Analogue Scale (VAS) for pain) or sleep disturbance (WMD -0.22 cm; 95% CI -0.4 to -0.06; on a 10 cm VAS for sleep disturbance; minimally important difference is 1 cm) among chronic cancer pain patients. Addition of cannabis likely increases nausea (relative risk (RR) 1.43; 95% CI 1.04 to 1.96; risk difference (RD) 4%, 95% CI 0% to 7%) and vomiting (RR 1.5; 95% CI 1.01 to 2.24; RD 3%; 95% CI 0% to 6%) (both moderate certainty) and may have no effect on constipation (RR 0.85; 95% CI 0.54 to 1.35; RD -1%; 95% CI -4% to 2%) (low certainty). Eight observational studies provided very low certainty evidence that adding cannabis reduced opioid use (WMD -22.5 MME; 95% CI -43.06 to -1.97). CONCLUSION: Opioid-sparing effects of medical cannabis for chronic pain remain uncertain due to very low certainty evidence.PROSPERO registration numberCRD42018091098.

X-ray quasi-periodic eruptions from two previously quiescent galaxies.

Quasi-periodic eruptions (QPEs) are very-high-amplitude bursts of X-ray radiation recurring every few hours and originating near the central supermassive black holes of galactic nuclei1,2. It is currently unknown what triggers these events, how long they last and how they are connected to the physical properties of the inner accretion flows. Previously, only two such sources were known, found either serendipitously or in archival data1,2, with emission lines in their optical spectra classifying their nuclei as hosting an actively accreting supermassive black hole3,4. Here we report observations of QPEs in two further galaxies, obtained with a blind and systematic search of half of the X-ray sky. The optical spectra of these galaxies show no signature of black hole activity, indicating that a pre-existing accretion flow that is typical of active galactic nuclei is not required to trigger these events. Indeed, the periods, amplitudes and profiles of the QPEs reported here are inconsistent with current models that invoke radiation-pressure-driven instabilities in the accretion disk5-9. Instead, QPEs might be driven by an orbiting compact object. Furthermore, their observed properties require the mass of the secondary object to be much smaller than that of the main body10, and future X-ray observations may constrain possible changes in their period owing to orbital evolution. This model could make QPEs a viable candidate for the electromagnetic counterparts of so-called extreme-mass-ratio inspirals11-13, with considerable implications for multi-messenger astrophysics and cosmology14,15.

Physical and ecological isolation contribute to maintain genetic differentiation between fire salamander subspecies.

Landscape features shape patterns of gene flow among populations, ultimately determining where taxa lay along the continuum between panmixia to complete reproductive isolation. Gene flow can be restricted, leading to population differentiation in two non-exclusive ways: "physical isolation", in which geographic distance in combination with the landscape features restricts movement of individuals promoting genetic drift, and "ecological isolation", in which adaptive mechanisms constrain gene flow between different environments via divergent natural selection. In central Iberia, two fire salamander subspecies occur in parapatry across elevation gradients along the Iberian Central System mountains, while in the adjacent Montes de Toledo Region only one of them occurs. By integrating population and landscape genetic analyses, we show a ubiquitous role of physical isolation between and within mountain ranges, with unsuitable landscapes increasing differentiation between populations. However, across the Iberian Central System, we found strong support for a significant contribution of ecological isolation, with low genetic differentiation in environmentally homogeneous areas, but high differentiation across sharp transitions in precipitation seasonality. These patterns are consistent with a significant contribution of ecological isolation in restricting gene flow among subspecies. Overall, our results suggest that ecological divergence contributes to reduce genetic admixture, creating an opportunity for lineages to follow distinct evolutionary trajectories.

What is in? What is out? Updating the British Society for Cutaneous Allergy facial series.

BACKGROUND: Allergic contact dermatitis (ACD) to cosmetics is widely reported. To ensure we are accurately diagnosing ACD, patch test series should be continually reviewed to identify relevant and emerging allergens and highlight those that are outdated. The current British Society for Cutaneous Allergy (BSCA) facial series recommends 26 allergens and was last modified in 2012. OBJECTIVES: To review and update the BSCA facial series. METHODS: We retrospectively reviewed the results from 12 UK and Ireland patch test centres' facial series from January 2016 to December 2017. We recorded the number of allergens tested in each centre and the detection rate for each allergen. Using a 0·3% positive rate as the inclusion threshold, we established which allergens in the BSCA facial series had positive patch test rates < 0·3% and > 0·3%. Allergens not in the BSCA facial series that had a positive patch test rate > 0·3% were identified. RESULTS: Overall, 4224 patients were patch tested to the facial series. The number of allergens included in individual centres' facial series ranged from 24 to 66, with a total of 103 allergens tested across all centres. Twelve of the 26 allergens in the BSCA facial series had a positive patch test rate < 0·3% and 14 had a rate > 0·3%. Twenty-five allergens not recommended in the BSCA facial series had a positive patch test rate > 0·3%. CONCLUSIONS: This audit has highlighted the significant variation in practice that exists among patch test centres, despite a recommended facial series. The BSCA facial series has been updated and now contains 24 allergens. Fifteen allergens remain, 11 allergens have been dropped and nine new allergens have been added.

Efficacy of novel aqueous photo-chlorine dioxide against a human norovirus surrogate, bacteriophage MS2 and Clostridium difficile endospores, in suspension, on stainless steel and under greenhouse conditions.

AIMS: The efficacy of a novel photochemical method for generating chlorine dioxide (photoClO2 ) was evaluated against human noroviruses (HuNoV) surrogate, bacteriophage MS2, and Clostridium difficile endospores. METHODS AND RESULTS: Chlorine dioxide was generated by mixing 1% sodium chlorite with 10 parts-per-million (ppm) Eosin Y and irradiating with a photo-activator-excitable light. PhotoClO2 efficacy was assessed against bacteriophage MS2 and C. difficile endospores in suspension, on hard surfaces and greenhouse conditions under soiled and unsoiled conditions. The estimated effective photoClO2 produced and consumed was 20·39 ± 0·16 ppm at a rate of 8·16 ppm per min in a 1% sodium chlorite solution. In suspension, MS2 phage was reduced by 3·35 and >5·10 log10 PFU per ml in 120 and 90 min, with and without soil, respectively. At the same time, when dried on stainless steel surface, MS2 phage was reduced by >4·53 log10 PFU per carrier in 30 min under both conditions. On the other hand, C. difficile endospores in suspension were reduced by 2·26 and 3·65 log10 CFU per ml in 120 min with and without soiling, respectively. However, on stainless steel surface, maximal reductions of the C. difficile endospores were 0·8 and 1·5 log10 CFU per carrier with and without soiling, respectively, and a maximal reduction of 2·97 log10 CFU per carrier under greenhouse conditions at 24 h. CONCLUSIONS: Overall, photoClO2 showed promise as a technology to control HuNoV contamination on environmental surfaces but requires further optimization and testing against C. difficile endospores. SIGNIFICANCE AND IMPACT OF THE STUDY: Results from this investigation will serve as a model for how to generate and quantify photoClO2 and how to appropriately evaluate this new class of disinfectants against environmentally resilient pathogens: viruses and bacterial endospores.

Response to "understanding the behavioural determinants of opioid prescribing among family physicians: a qualitative study".

The 2017 Canadian opioid Guideline made both strong recommendations, indicating that all or almost all fully informed patients would choose the recommended course of action, and weak recommendations, in which different choices are appropriate for individual patients based on their values and preferences. The Guideline's recommendation to taper legacy patients prescribed high-dose opioid therapy is weak, and mandatory tapering is expressly discouraged.