Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, ...thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid ...metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
The first two orbits of the Parker Solar Probe spacecraft have enabled the first in situ measurements of the solar wind down to a heliocentric distance of 0.17 au (or 36 ). Here, we present an ...analysis of this data to study solar wind turbulence at 0.17 au and its evolution out to 1 au. While many features remain similar, key differences at 0.17 au include increased turbulence energy levels by more than an order of magnitude, a magnetic field spectral index of −3/2 matching that of the velocity and both Elsasser fields, a lower magnetic compressibility consistent with a smaller slow-mode kinetic energy fraction, and a much smaller outer scale that has had time for substantial nonlinear processing. There is also an overall increase in the dominance of outward-propagating Alfvénic fluctuations compared to inward-propagating ones, and the radial variation of the inward component is consistent with its generation by reflection from the large-scale gradient in Alfvén speed. The energy flux in this turbulence at 0.17 au was found to be ∼10% of that in the bulk solar wind kinetic energy, becoming ∼40% when extrapolated to the Alfvén point, and both the fraction and rate of increase of this flux toward the Sun are consistent with turbulence-driven models in which the solar wind is powered by this flux.
We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and ...laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.
Changes in diurnal temperature range (DTR) over global land areas are compared from a broad range of independent data sets. All data sets agree that global‐mean DTR has decreased significantly since ...1950, with most of that decrease occurring over 1960–1980. The since‐1979 trends are not significant, with inter‐data set disagreement even over the sign of global changes. Inter‐data set spread becomes greater regionally and in particular at the grid box level. Despite this, there is general agreement that DTR decreased in North America, Europe, and Australia since 1951, with this decrease being partially reversed over Australia and Europe since the early 1980s. There is substantive disagreement between data sets prior to the middle of the twentieth century, particularly over Europe, which precludes making any meaningful conclusions about DTR changes prior to 1950, either globally or regionally. Several variants that undertake a broad range of approaches to postprocessing steps of gridding and interpolation were analyzed for two of the data sets. These choices have a substantial influence in data sparse regions or periods. The potential of further insights is therefore inextricably linked with the efficacy of data rescue and digitization for maximum and minimum temperature series prior to 1950 everywhere and in data sparse regions throughout the period of record. Over North America, station selection and homogeneity assessment is the primary determinant. Over Europe, where the basic station data are similar, the postprocessing choices are dominant. We assess that globally averaged DTR has decreased since the middle twentieth century but that this decrease has not been linear.
Key Points
It is virtually certain globally diurnal temperature range declined since 1950
Large differences/method sensitivities preclude assessment of DTR before 1950
In some regions DTR has very likely increased in the last two to three decades
5-hydroxytryptamine type 3 (5-HT
3
) receptor antagonists are used in the prevention of chemotherapy- induced, radiation-induced and postoperative nausea and vomiting.
CYP2D6
polymorphisms can ...influence the metabolism of some of these drugs (i.e. ondansetron and tropisetron) thereby affecting drug efficacy. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for ondansetron and tropisetron based on
CYP2D6
genotype (updates at
www.pharmgkb.org
).
The properties of quantum materials are commonly tuned using experimental variables such as pressure, magnetic field and doping. Here we explore a different approach using irreversible, plastic ...deformation of single crystals. We show that compressive plastic deformation induces low-dimensional superconductivity well above the superconducting transition temperature (T
) of undeformed SrTiO
, with evidence of possible superconducting correlations at temperatures two orders of magnitude above the bulk T
. The enhanced superconductivity is correlated with the appearance of self-organized dislocation structures, as revealed by diffuse neutron and X-ray scattering. We also observe deformation-induced signatures of quantum-critical ferroelectric fluctuations and inhomogeneous ferroelectric order using Raman scattering. Our results suggest that strain surrounding the self-organized dislocation structures induces local ferroelectricity and quantum-critical dynamics that strongly influence T
, consistent with a theory of superconductivity enhanced by soft polar fluctuations. Our results demonstrate the potential of plastic deformation and dislocation engineering for the manipulation of electronic properties of quantum materials.
The prediction of a supersonic solar wind
was first confirmed by spacecraft near Earth
and later by spacecraft at heliocentric distances as small as 62 solar radii
. These missions showed that plasma ...accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvénic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy
. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams
. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii
, well within the distance at which stream interactions become important. We find that Alfvén waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second-considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age
.
We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S . This evidence includes feedback process ...understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density (PDF) for S given all the evidence, including tests of robustness to difficult‐to‐quantify uncertainties and different priors. The 66% range is 2.6‐3.9 K for our Baseline calculation, and remains within 2.3‐4.5 K under the robustness tests; corresponding 5‐95% ranges are 2.3‐4.7 K, bounded by 2.0‐5.7 K (although such high‐confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent, and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S , in particular using comprehensive models and process understanding to address limitations in the traditional forcing‐feedback paradigm for interpreting past changes.
PDF
