Opioid addicts are more likely to present with infections suggesting opioids are immune modulators. The potential sites/mechanism(s) for this modulation are controversial and on close inspection not ...well supported by the current literature. It has long been assumed that opioid-induced immune modulation occurs via a combination of direct actions on the immune cell itself, via the hypothalamic-pituitary-adrenal (HPA) axis, or both. Opioid receptors are classified as MOP (μ, mu), DOP (δ, delta), and KOP (κ, kappa)'classical naloxone sensitive receptors'or NOP (the receptor for nociceptin/orphanin FQ), which is naloxone insensitive. Opioids currently used in clinical practice predominantly target the MOP receptor. There do not appear to be classical opioid receptors present on immune cells. The evidence for HPA activation is also poor and shows some species dependence. Most opioids used clinically or as drugs of abuse do not target the NOP receptor. Other possible target sites for immune modulation include the sympathetic nervous system and central sites. We are currently unable to accurately define the cellular target for immune modulation and suggest further investigation is required. Based on the differences observed when comparing studies in laboratory animals and those performed in humans we suggest that further studies in the clinical setting are needed.
Traumatic spinal cord injury occurs when an external physical impact damages the spinal cord and leads to permanent neurological dysfunction and disability, and it is associated with a high ...socioeconomic burden. Conventional MRI plays a crucial role in the diagnostic workup as it reveals extrinsic compression of the spinal cord and disruption of the discoligamentous complex. Additionally, it can reveal macrostructural evidence of primary intramedullary damage such as haemorrhage, oedema, post-traumatic cystic cavities, and tissue bridges. Quantitative MRI, such as magnetisation transfer, magnetic resonance relaxation mapping, and diffusion imaging, enables the tracking of secondary changes across the neuraxis at the microstructural level. Both conventional MRI and quantitative MRI metrics, obtained early after spinal cord injury, are predictive of clinical outcome. Thus, neuroimaging biomarkers could serve as surrogate endpoints for more efficient future trials targeting acute and chronic spinal cord injury. The adoption of neuroimaging biomarkers in centres for spinal cord injury might lead to personalised patient care.
Internal variability in the climate system gives rise to large uncertainty in projections of future climate. The uncertainty in future climate due to internal climate variability can be estimated ...fromlarge ensembles of climate change simulations in which the experiment setup is the same from one ensemble member to the next but for small perturbations in the initial atmospheric state. However, large ensembles are invariably computationally expensive and susceptible to model bias.
Here the authors outline an alternative approach for assessing the role of internal variability in future climate based on a simple analytic model and the statistics of the unforced climate variability. The analytic model is derived from the standard error of the regression and assumes that the statistics of the internal variability are roughly Gaussian and stationary in time. When applied to the statistics of an unforced control simulation, the analytic model provides a remarkably robust estimate of the uncertainty in future climate indicated by a large ensemble of climate change simulations. To the extent that observations can be used to estimate the amplitude of internal climate variability, it is argued that the uncertainty in future climate trends due to internal variability can be robustly estimated from the statistics of the observed climate.
Arctic clouds exhibit a robust annual cycle with maximum
cloudiness in fall and minimum cloudiness in winter. These variations affect energy
flows in the Arctic with a large influence on the surface ...radiative fluxes.
Contemporary climate models struggle to reproduce the observed Arctic cloud
amount annual cycle and significantly disagree with each other. The goal of
this analysis is to quantify the cloud-influencing factors that contribute
to winter–summer cloud amount differences, as these seasons are primarily
responsible for the model discrepancies with observations. We find that
differences in the total cloud amount annual cycle are primarily caused by
differences in low, rather than high, clouds; the largest differences occur between
the surface and 950 hPa. Grouping models based on their seasonal cycles of
cloud amount and stratifying cloud amount by cloud-influencing factors, we
find that model groups disagree most under strong lower tropospheric
stability, weak to moderate mid-tropospheric subsidence, and cold lower
tropospheric air temperatures. Intergroup differences in low cloud amount
are found to be a function of lower tropospheric thermodynamic
characteristics. Further, we find that models with a larger low cloud amount
in winter have a larger ice condensate fraction, whereas models with a
larger low cloud amount in summer have a smaller ice condensate fraction.
Stratifying model output by the specifics of the cloud microphysical scheme
reveals that models treating cloud ice and liquid condensate as separate
prognostic variables simulate a larger ice condensate fraction than those
that treat total cloud condensate as a prognostic variable and use a
temperature-dependent phase partitioning. Thus, the cloud microphysical
parameterization is the primary cause of inter-model differences in the
Arctic cloud annual cycle, providing further evidence of the important role
that cloud ice microphysical processes play in the evolution and modeling of
the Arctic climate system.
Diagnosis is one of the most important tasks performed by primary care physicians. The World Health Organization (WHO) recently prioritized patient safety areas in primary care, and included ...diagnostic errors as a high-priority problem. In addition, a recent report from the Institute of Medicine in the USA,
', concluded that most people will likely experience a diagnostic error in their lifetime. In this narrative review, we discuss the global significance, burden and contributory factors related to diagnostic errors in primary care. We synthesize available literature to discuss the types of presenting symptoms and conditions most commonly affected. We then summarize interventions based on available data and suggest next steps to reduce the global burden of diagnostic errors. Research suggests that we are unlikely to find a 'magic bullet' and confirms the need for a multifaceted approach to understand and address the many systems and cognitive issues involved in diagnostic error. Because errors involve many common conditions and are prevalent across all countries, the WHO's leadership at a global level will be instrumental to address the problem. Based on our review, we recommend that the WHO consider bringing together primary care leaders, practicing frontline clinicians, safety experts, policymakers, the health IT community, medical education and accreditation organizations, researchers from multiple disciplines, patient advocates, and funding bodies among others, to address the many common challenges and opportunities to reduce diagnostic error. This could lead to prioritization of practice changes needed to improve primary care as well as setting research priorities for intervention development to reduce diagnostic error.
While drawing from general cultural myths, marketplace mythologies are tailored to the competitive characteristics and exigencies of specific market structures, providing meanings and metaphors that ...serve multiple ideological agendas. I illustrate this conceptualization by analyzing mythic narratives that circulate in the natural health marketplace. I propose that a nexus of institutional, competitive, and sociocultural conditions that engender different ideological uses of this marketplace mythology by two types of stakeholders: advertisers of herbal remedies and consumers seeking alternatives to their medical identities. I discuss the implications of this theorization for future analyses of consumer mythologies and for theoretical debates over whether consumers can become emancipated from the ideological influences exerted by the capitalist marketplace.
Bacterial adaptive immunity and genome engineering involving the CRISPR (clustered regularly interspaced short palindromic repeats)–associated (Cas) protein Cas9 begin with RNA-guided DNA unwinding ...to form an RNA-DNA hybrid and a displaced DNA strand inside the protein. The role of this R-loop structure in positioning each DNA strand for cleavage by the two Cas9 nuclease domains is unknown. We determine molecular structures of the catalytically active Streptococcus pyogenes Cas9 R-loop that show the displaced DNA strand located near the RuvC nuclease domain active site. These protein-DNA interactions, in turn, position the HNH nuclease domain adjacent to the target DNA strand cleavage site in a conformation essential for concerted DNA cutting. Cas9 bends the DNA helix by 30°, providing the structural distortion needed for R-loop formation.
The field of plasmonics, which studies the resonant interactions of electromagnetic waves and free electrons in solid-state materials
, has yet to be put to large-scale commercial application
owing ...to the large amount of loss that usually occurs in plasmonic materials
. Organic light-emitting devices (OLEDs)
have been incorporated into billions of commercial products because of their good colour saturation, versatile form factor
and low power consumption
, but could still be improved in terms of efficiency and stability. Although OLEDs incorporating organic phosphors achieve an internal charge-to-light conversion of unity
, their refractive index contrast reduces the observable fraction of photons outside the device to around 25 per cent
. Further, during OLED operation, a localized buildup of slow-decaying
triplet excitons and charges
gradually reduces the brightness of the device in a process called ageing
, which can result in 'burn-in' effects on the display. Simultaneously improving device efficiency and stability is of paramount importance for OLED technology. Here we demonstrate an OLED that uses the decay rate enhancement
of a plasmonic system to increase device stability, while maintaining efficiency by incorporating a nanoparticle-based out-coupling scheme to extract energy from the plasmon mode. Using an archetypal phosphorescent emitter, we achieve a two-fold increase in operational stability at the same brightness as a reference conventional device while simultaneously extracting 16 per cent of the energy from the plasmon mode as light. Our approach to increasing OLED stability avoids material-specific designs
and is applicable to all commercial OLEDs that are currently used for lighting panels, televisions and mobile displays.
Harold Gillies, plastic surgeon, and Donald Morton, surgical oncologist, were iconic pioneers in their respective fields. Both of them made their mark by identifying crucial practical problems and ...finding innovative ways of solving them. Gillies grappled with the challenge of restoring form and function to British military personnel injured in World War I, and he set up a dedicated facility for performing this work. He introduced many new reconstructive techniques that became the foundation of the modern specialty of plastic and reconstructive surgery, which he established and nurtured. Morton, in the United States, applied his problem-solving skills to the long-debated question of the best way to manage regional lymph nodes in patients with melanoma. He developed the innovative technique of sentinel lymph node biopsy and initiated large-scale international clinical trials to establish its validity and clinical value. This and other important contributions to the emerging field of surgical oncology earned Morton his reputation as a pioneer and leader of that specialty. The problems that confronted Gillies and Morton were completely different, but both demonstrated remarkable skills as master problem-solvers in their respective fields and made extraordinary contributions to the body of knowledge and welfare of patients. All surgeons must be problem-solvers because every patient who presents for surgical management represents a new problem (or set of problems) to be addressed. As surgeons, we would do well to consider individuals such as Gillies and Morton as role models for our own problem-solving activities in day-to-day clinical practice.
PDF
