Abstract
There is a thin transition region (TR) in the solar atmosphere where the temperature rises from 10,000 K in the chromosphere to millions of degrees in the corona. Little is known about the ...mechanisms that dominate this enigmatic region other than the magnetic field plays a key role. The magnetism of the TR can only be detected by polarimetric measurements of a few ultraviolet (UV) spectral lines, the Ly
α
line of neutral hydrogen at 121.6 nm (the strongest line of the solar UV spectrum) being of particular interest given its sensitivity to the Hanle effect (the magnetic-field-induced modification of the scattering line polarization). We report the discovery of linear polarization produced by scattering processes in the Ly
α
line, obtained with the Chromospheric Lyman-Alpha Spectro-Polarimeter (CLASP) rocket experiment. The Stokes profiles observed by CLASP in quiet regions of the solar disk show that the
Q
/
I
and
U
/
I
linear polarization signals are of the order of 0.1% in the line core and up to a few percent in the nearby wings, and that both have conspicuous spatial variations with scales of ∼10 arcsec. These observations help constrain theoretical models of the chromosphere–corona TR and extrapolations of the magnetic field from photospheric magnetograms. In fact, the observed spatial variation from disk to limb of polarization at the line core and wings already challenge the predictions from three-dimensional magnetohydrodynamical models of the upper solar chromosphere.
Abstract
The sizable linear polarization signals produced by the scattering of anisotropic radiation in the core of the Ca
i
4227 Å line constitute an important observable for probing the ...inhomogeneous and dynamic plasma of the lower solar chromosphere. Here we show the results of a three-dimensional (3D) radiative transfer complete frequency redistribution investigation of the line’s scattering polarization in a magnetohydrodynamical 3D model of the solar atmosphere. We take into account not only the Hanle effect produced by the model’s magnetic field but also the symmetry breaking caused by the horizontal inhomogeneities and macroscopic velocity gradients. The spatial gradients of the horizontal components of the macroscopic velocities produce very significant forward scattering polarization signals without the need of magnetic fields, while the Hanle effect tends to depolarize them at the locations where the model’s magnetic field is stronger than about 5 G. The standard 1.5D approximation is found to be unsuitable for understanding the line’s scattering polarization, but we introduce a novel improvement to this approximation that produces results in qualitative agreement with the full 3D results. The instrumental degradation of the calculated polarization signals is also investigated, showing what we can expect to observe with the Visible Spectro-Polarimeter at the upcoming Daniel K. Inouye Solar Telescope.
People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal ...treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options
. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently
. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.
Abstract Background Hip fractures are mainly caused by accidental falls and trips, which magnify forces in well-defined areas of the proximal femur. Unfortunately, the same areas are at risk of rapid ...bone loss with ageing, since they are relatively stress-shielded during walking and sitting. Focal osteoporosis in those areas may contribute to fracture, and targeted 3D measurements might enhance hip fracture prediction. In the FEMCO case-control clinical study, Cortical Bone Mapping (CBM) was applied to clinical computed tomography (CT) scans to define 3D cortical and trabecular bone defects in patients with acute hip fracture compared to controls. Direct measurements of trabecular bone volume were then made in biopsies of target regions removed at operation. Methods The sample consisted of CT scans from 313 female and 40 male volunteers (158 with proximal femoral fracture, 145 age-matched controls and 50 fallers without hip fracture). Detailed Cortical Bone Maps (c.5580 measurement points on the unfractured hip) were created before registering each hip to an average femur shape to facilitate statistical parametric mapping (SPM). Areas where cortical and trabecular bone differed from controls were visualised in 3D for location, magnitude and statistical significance.
Measures from the novel regions created by the SPM process were then tested for their ability to classify fracture versus control by comparison with traditional CT measures of areal Bone Mineral Density (aBMD). In women we used the surgical classification of fracture location (‘femoral neck’ or ‘trochanteric’) to discover whether focal osteoporosis was specific to fracture type. To explore whether the focal areas were osteoporotic by histological criteria, we used micro CT to measure trabecular bone parameters in targeted biopsies taken from the femoral heads of 14 cases. Results Hip fracture patients had distinct patterns of focal osteoporosis that determined fracture type, and CBM measures classified fracture type better than aBMD parameters. CBM measures however improved only minimally on aBMD for predicting any hip fracture and depended on the inclusion of trabecular bone measures alongside cortical regions. Focal osteoporosis was confirmed on biopsy as reduced sub-cortical trabecular bone volume. Conclusion Using 3D imaging methods and targeted bone biopsy, we discovered focal osteoporosis affecting trabecular and cortical bone of the proximal femur, among men and women with hip fracture.
Abstract
Objectives Low adherence to treatment with bisphosphonates significantly impedes its effectiveness. The objectives were: (1) to compare adherence to oral weekly and monthly bisphosphonates ...with emphasis on dosing instructions; and (2) to study associations between adherence and beliefs about the bisphosphonate treatment among women ≥ 55 years.
Methods A multicenter survey was performed in secondary-care patients with osteoporosis. Osteoporosis Specific Morisky Medication Adherence Scale (OS-MMAS), questions on compliance with five dosing instructions and Beliefs about Medicines Questionnaire (BMQ) Specific were used.
Results As many as 363 questionnaires (response rate 95%) were analyzed. Respondents (mean age 69 years) were treated with weekly bisphosphonates (37%) or monthly ibandronate (63%). Based on OS-MMAS, 67% of respondents showed high adherence with no differences between the subgroups. Only 44% of respondents were compliant with all dosing instructions. Compliance with dosing instructions concerning time interval (fasting and staying upright) was 71% in weekly and 52% in monthly subgroups, respectively (p < 0.001). Compliance with dosing instructions correlated positively with education (p = 0.009). The mean BMQ necessity score of 18.4 was greater than the mean BMQ concerns score of 13.3. OS-MMAS score correlated with necessity (p = 0.010). Persistence derived from OS-MMAS correlated with both necessity (p = 0.014) and concerns (p = 0.041).
Conclusion Despite relatively high adherence to the treatment, most patients do not follow dosing instructions. Reduced bioavailability, particularly of monthly ibandronate, can be expected in clinical practice. Adherence-related outcomes are associated with beliefs about the oral treatment with bisphosphonates.
Abstract The aim of this study was to assess the effects of the antiresorptive treatments of alendronate (ALN), risedronate (RIS) and raloxifene (RLX) on the response of bone to endogenous ...parathyroid hormone (PTH) induced by acute hypocalcemia. Forty women (age, 55–80 years) with postmenopausal osteoporosis (treated with ALN, RIS and RLX or untreated-control group) were given infusions of sodium ethylenediaminetetraacetic acid (EDTA; 10 mg/kg of body weight). Serum ionized calcium (iCa), plasma intact PTH and marker of bone resorption, serum β C-terminal telopeptide of type I collagen (β-CTX; β CrossLaps) were followed for 180 min. In all women, decrease in serum iCa following the EDTA load resulted in an acute increase in serum PTH. Between 60 and 180 min, plasma PTH in the ALN and RIS treated women remained significantly higher than in the control group. The integrated β-CTX responses (area under curves, AUCs) to peaks of PTH were significantly lower in the ALN treated women than in those treated with RIS, RLX or control group. There was no significant difference in β-CTX AUC response to PTH between RIS, RLX and control women. Taken together, these findings suggest that in women with postmenopausal osteoporosis treated with ALN, a substantial reduction of bone turnover blunts the acute bone resorbing effect of endogenous PTH.
Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the ...two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no
antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.
PDF
