Resistance to artemisinin-based combination therapy (ACT) in the
parasite is threatening to reverse recent gains in reducing global deaths from malaria. While resistance manifests as delayed parasite ...clearance in patients, the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilize sexual male gametocytes. Whether resistant parasites overcome this sterilizing effect has not, however, been fully tested. Here, we analyzed
clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in the
(PfK13
) gene. As well as demonstrating reduced asexual sensitivity to drug, certain PfK13
isolates demonstrated a marked reduction in sensitivity to artemisinin in an
male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, while sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favor acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favored resistance transmission under ACT coverage could have profound implications for the spread of multidrug-resistant malaria beyond Southeast Asia.
Host genetic factors can confer resistance against malaria
, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between ...candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member
PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.
Abstract We present photometric and spectroscopic data for SN 2022joj, a nearby peculiar Type Ia supernova (SN Ia) with a fast decline rate (Δ m 15,B = 1.4 mag). SN 2022joj shows exceedingly red ...colors, with a value of approximately B − V ≈ 1.1 mag during its initial stages, beginning from 11 days before maximum brightness. As it evolves, the flux shifts toward the blue end of the spectrum, approaching B − V ≈ 0 mag around maximum light. Furthermore, at maximum light and beyond, the photometry is consistent with that of typical SNe Ia. This unusual behavior extends to its spectral characteristics, which initially displayed a red spectrum and later evolved to exhibit greater consistency with typical SNe Ia. Spectroscopically, we find strong agreement between SN 2022joj and double detonation models with white dwarf masses of around 1 M ⊙ and a thin He shell between 0.01 and 0.05 M ⊙ . Moreover, the early red colors are explained by line-blanketing absorption from iron peak elements created by the double detonation scenario in similar mass ranges. The nebular spectra in SN 2022joj deviate from expectations for double detonation, as we observe strong Fe iii emission instead of Ca ii lines as anticipated, though this is not as robust a prediction as early red colors and spectra. The fact that as He shells get thinner these SNe start to look more like normal SNe Ia raises the possibility that this is the triggering mechanism for the majority of SNe Ia, though evidence would be missed if the SNe are not observed early enough.
Context.
QSO B1420+326 is a blazar classified as a flat-spectrum radio quasar (FSRQ). At the beginning of the year 2020, it was found to be in an enhanced flux state and an extensive multiwavelength ...campaign allowed us to trace the evolution of the flare.
Aims.
We search for very high-energy (VHE) gamma-ray emission from QSO B1420+326 during this flaring state. We aim to characterize and model the broadband emission of the source over different phases of the flare.
Methods.
The source was observed with a number of instruments in radio, near-infrared, optical (including polarimetry and spectroscopy), ultraviolet, X-ray, and gamma-ray bands. We use dedicated optical spectroscopy results to estimate the accretion disk and the dust torus luminosity. We performed spectral energy distribution modeling in the framework of combined synchrotron-self-Compton and external Compton scenario in which the electron energy distribution is partially determined from acceleration and cooling processes.
Results.
During the enhanced state, the flux of both SED components of QSO B1420+326 drastically increased and the peaks were shifted to higher energies. Follow-up observations with the MAGIC telescopes led to the detection of VHE gamma-ray emission from this source, making it one of only a handful of FSRQs known in this energy range. Modeling allows us to constrain the evolution of the magnetic field and electron energy distribution in the emission region. The gamma-ray flare was accompanied by a rotation of the optical polarization vector during a low -polarization state. Also, a new superluminal radio knot contemporaneously appeared in the radio image of the jet. The optical spectroscopy shows a prominent FeII bump with flux evolving together with the continuum emission and a MgII line with varying equivalent width.
Background Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter ...at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1 -targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. Methods The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area–adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. Conclusion This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.
Purpose
To quantify potential heterogeneity of treatment effect (HTE), of early sedation with dexmedetomidine (DEX) compared with usual care, and identify patients who have a high probability of ...lower or higher 90-day mortality according to age, and other identified clusters.
Methods
Bayesian analysis of 3904 critically ill adult patients expected to receive invasive ventilation > 24 h and enrolled in a multinational randomized controlled trial comparing early DEX with usual care sedation.
Results
HTE was assessed according to age and clusters (based on 12 baseline characteristics) using a Bayesian hierarchical models. DEX was associated with lower 90-day mortality compared to usual care in patients > 65 years (odds ratio OR, 0.83 95% credible interval CrI 0.68–1.00, with 97.7% probability of reduced mortality across broad categories of illness severity. Conversely, the probability of increased mortality in patients ≤ 65 years was 98.5% (OR 1.26 95% CrI 1.02–1.56. Two clusters were identified: cluster 1 (976 patients) mostly operative, and cluster 2 (2346 patients), predominantly non-operative. There was a greater probability of benefit with DEX in cluster 1 (OR 0.86 95% CrI 0.65–1.14) across broad categories of age, with 86.4% probability that DEX is more beneficial in cluster 1 than cluster 2.
Conclusion
In critically ill mechanically ventilated patients, early sedation with dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status. Further studies are needed to confirm these findings.
This paper presents an overview of the polarized sky as seen by Planck HFI at 353 GHz, which is the most sensitive Planck channel for dust polarization. We construct and analyse maps of dust ...polarization fraction and polarization angle at 1° resolution, taking into account noise bias and possible systematic effects. The sensitivity of the Planck HFI polarization measurements allows for the first time a mapping of Galactic dust polarized emission on large scales, including low column density regions. We find that the maximum observed dust polarization fraction is high (pmax = 19.8%), in particular in some regions of moderate hydrogen column density (NH < 2 × 1021 cm-2). The polarization fraction displays a large scatter at NH below a few 1021 cm-2. There is a general decrease in the dust polarization fraction with increasing column density above NH ≃ 1 × 1021 cm-2 and in particular a sharp drop above NH ≃ 1.5 × 1022 cm-2. We characterize the spatial structure of the polarization angle using the angle dispersion function. We find that the polarization angle is ordered over extended areas of several square degrees, separated by filamentary structures of high angle dispersion function. These appear as interfaces where the sky projection of the magnetic field changes abruptly without variations in the column density. The polarization fraction is found to be anti-correlated with the dispersion of polarization angles. These results suggest that, at the resolution of 1°, depolarization is due mainly to fluctuations in the magnetic field orientation along the line of sight, rather than to the loss of grain alignment in shielded regions. We also compare the polarization of thermal dust emission with that of synchrotron measured with Planck, low-frequency radio data, and Faraday rotation measurements toward extragalactic sources. These components bear resemblance along the Galactic plane and in some regions such as the Fan and North Polar Spur regions. The poor match observed in other regions shows, however, that dust, cosmic-ray electrons, and thermal electrons generally sample different parts of the line of sight.
Background and aims
Opioid formulations with properties to deter abuse (abuse‐deterrent formulations; ADFs) have been developed as one response to the prescription opioid ‘epidemic’. As for all ...medicines, ADFs undergo evaluation of safety and efficacy prior to registration for marketing. However, reduced extra‐medical use (the primary intended outcome of ADFs and reason for their introduction) can only be established in post‐marketing observational studies, comparing them to opioid formulations without abuse‐deterrent properties. This has implications for various features of study design and analysis. We discuss proposals for the design, conduct, governance and reporting of post‐marketing studies on the effectiveness of pharmaceutical and opioid ADFs.
Methods
A review of current guidance documents, public work‐shops and forums and our own experience with post‐marketing studies of ADFs.
Results and conclusions
Research questions for post‐marketing studies on ADFs of opioids should reasonably be framed around detecting any probable intended or unintended clinical and/or meaningful changes in specific aspects of extra‐medical use (e.g. injection use) and harms. Outcomes reported by prevalence and frequency of occurrence and disaggregated by specific product and route of administration can illustrate the magnitude of ADF impact. We argue that a multi‐faceted approach is required, using data from both general population and sentinel high‐risk cohorts and from primary and secondary data sources. The comparator (historical non‐ADF formulation of that opioid, equivalent current generic or similar opioid product), duration of monitoring and analytical approach require justification and should be sufficient to add weight to conclusions of causality. To maximize transparency, we recommend explicit declarations of funding and conflict of interest, establishment of an advisory committee, publication of study protocol and access to study results.
Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters using Si-substituted allyl electrophiles. The Si-substituent directs the regioselectivity of ...enantioselective bond formation and provides products containing synthetically versatile pentafluorophenyl ester and vinylsilane moieties. Critical to the efficacy of this process was the recognition that the ancillary ligand on palladium could be altered to prevent formation of a deleterious ether by-product, whilst retaining enantioselectivity through the Lewis base catalyst. Flexibility such as this is unique to cooperative catalysis events and provides efficient access to an array of enantioenriched products that are orthogonally functionalized and easily modified.
Display omitted
PDF
